Cereblon-binding compounds, compositions thereof and methods of treatment therewith

Abstract

As used herein, the following structure: [Formula 1] TIFF2024526192000103.tif27160 (in the formula, R 1 , R 2 , R 3 , R 4 , R N , L, V, X, Y, A, A', a, n and m are as defined herein. and compositions comprising an effective amount of the piperidinedione compound and methods for treating or preventing androgen receptor mediated diseases.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 215,346, filed June 25, 2021, the disclosure of which is incorporated herein by reference in its entirety.

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

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

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

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

[0006] Androgen deprivation therapy (ADT) is the standard treatment for advanced PCa. Patients with advanced PCa receive ADT with either luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, or bilateral orchiectomy. Although initially responsive to ADT, disease progression is inevitable and the cancer manifests as castration-resistant prostate cancer (CRPC). Up to 30% of prostate cancer patients treated with primary treatment with radiation or surgery will develop metastatic disease within 10 years of primary treatment. Approximately 50,000 patients per year will develop metastatic disease, referred to as metastatic CRPC (mCRPC). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Chen Y et al.,Lancet Oncol,2009,10:981-91 [Non-patent document 2] Mills IG, Nat Rev Cancer,2014,14:187-98 [Non-patent document 3] Taplin ME,Nat Clin Pract Oncol,2007,4:236-44 [Non-patent document 4] Wirth MP et al.,Eur Urol,2007,51(2):306-13 [Non-patent document 5] Brinkmann AO et al., J Steroid Biochem Mol Biol,1999,69:307-13 [Non-patent document 6] Tran C et al.,Science,2009,324:787-90 [Non-Patent Document 7] Murtha P et al.,Biochemistry(Mosc.),1993,32:6459-64 Summary of the Invention [Problem to be solved by the invention]

[0008] There remains a great need for safe and effective methods of treating, preventing, and managing AR-mediated diseases, particularly those that are refractory to standard treatments such as surgery, radiation therapy, chemotherapy, and hormone therapy, while reducing or avoiding the toxicity and / or side effects associated with conventional therapies. [Means for solving the problem]

[0009] Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is prior art to the present application.

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

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

[0012] In one aspect, provided herein are compounds as described in this disclosure, for example, those in Table 1.

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

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

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

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

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

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

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

[0020] An "alkyl" group is a saturated, partially saturated, or unsaturated, straight-chain or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also referred to as an alkenyl or alkynyl group. An "alkenyl" group is an alkyl group having one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group having one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted.When alkyl groups described herein are said to be "substituted," such alkyl groups may be substituted with any one or more substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino. , cycloalkylalkylamino, aralkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocycloalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2.In certain embodiments, when alkyl groups described herein are referred to as "substituted," such alkyl groups can be substituted with any one or more substituents such as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0021] A "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 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, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

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

[0023] A "heteroaryl" group is an aromatic ring system having from 1 to 4 heteroatoms as ring atoms, with the remaining atoms being carbon atoms. In some embodiments, heteroaryl groups have from 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms, in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), isopropyl, ... Examples of heteroaryl groups include midazopyridyl groups (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl groups, triazolopyridyl groups, benzotriazolyl groups (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl groups (e.g., benzo[d]oxazolyl), benzothiazolyl groups, benzothiadiazolyl groups, isoxazolopyridyl groups, thianaphthalenyl groups, purinyl groups, xanthinyl groups, adeninyl groups, guaninyl groups, quinolinyl groups, isoquinolinyl groups (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl groups, quinoxalinyl groups, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

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

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

[0026] As used herein and unless otherwise specified, an "aralkyl" group is a group of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups in which the aryl group is fused to a cycloalkyl group, such as indan-4-ylethyl.

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

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

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

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

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

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

[0033] In one embodiment, an "amino" group is an "alkylamino" group, which is a radical of the formula: -NH-alkyl or -N(alkyl)2, where each alkyl is independently defined above. The terms "cycloalkylamino," "arylamino," "heterocyclylamino," "heteroarylamino," "heterocycloalkylamino," and the like reflect the description of "alkylamino" above, where the term "alkyl" is replaced by "cycloalkyl," "aryl," "heterocyclyl," "heteroaryl," "heterocycloalkyl," and the like, respectively.

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

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

[0036] As used herein and unless otherwise specified, an "amide" group is a group of the formula: -C(O)-NH, -C(O)-NH(R # ), -C(O)-N(R # )2, -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H or -N(R # )-C(O)-(R # )(In the formula, each R # are independently groups as defined above.

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

[0038] In one embodiment, an "amide" group has the formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H or -N(R # )-C(O)-(R # )(In the formula, each R # are independently an "acylamino" group, which is a group of Formula (III) as defined above.

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

[0040] A "urea" group is a group of the formula: -N(alkyl)C(O)N(R # )2, -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH2, -NHC(O)N(R # )2, -NHC(O)NH(R # ) or —NH(CO)NH (wherein each alkyl and R # are independently as defined above).

[0041] Except for alkyl groups, when a group described herein is said to be "substituted," such a group can be substituted with any one or more suitable substituents. Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH), O(alkyl)aminocarbonyl; cycloalkyl ( which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or heterocyclyl (which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl)); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl), aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

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

[0043] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound provided herein that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound will be greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound; greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound; greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound; or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. The compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0044] The use of such compounds in stereoisomerically pure forms, as well as mixtures of these forms, are encompassed by the embodiments disclosed herein. For example, the methods and compositions disclosed herein may employ mixtures containing equal or unequal amounts of the enantiomers of a particular compound. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972);Todd,M.,Separation Of Enantiomers:Synthetic Methods(Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2014);Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

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

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

[0047] As one of ordinary skill in the art will readily appreciate, a wide variety of functional groups and other structures are capable of exhibiting tautomerism, and all tautomers of the compounds of Formula I are within the scope of the invention.

[0048] It should also be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S) or carbon 14 ( 14 It can be radiolabeled with a radioisotope such as deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen 15( 15The radiolabeled and isotopically enriched compounds may be enriched in isotopes such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 132, 133, 144, 145, 150, 151, 162, 170, 171, 182, 192, 193, 194, 195, 1 As used herein, "deuterated" means a compound in which at least one hydrogen (H) has been replaced by deuterium (D or 2 H), i.e., the compound is enriched with deuterium at at least one position.

[0049] It is understood that each compound referred to herein, regardless of its stereoisomeric or isotopic composition, can be provided in the form of any of the pharmaceutically acceptable salts discussed herein.Similarly, it is understood that the isotopic composition can vary regardless of the stereoisomeric composition of each compound referred to herein.Furthermore, although limited to the elements present in each compound or its salt, the isotopic composition can inherently vary regardless of the choice of pharmaceutically acceptable salt of each compound.

[0050] It should be noted that in the event of a discrepancy between a depicted structure and the name of that structure, the depicted structure should be given more weight.

[0051] "Treating," as used herein, means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or arresting the further progression or worsening of such symptoms, or alleviating or eradicating one or more causes of the disorder, disease, or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease or symptom thereof, as described herein.

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

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

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

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

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

[0057] The term "castration-resistant prostate cancer" (CRPC) refers to advanced prostate cancer that worsens or progresses while the patient continues to receive androgen deprivation therapy or other testosterone-reducing therapy, or prostate cancer that is considered hormone-refractory, hormone-naive, androgen-independent, or resistant to chemotherapy 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 defined as a condition characterized by an increase in prostate-specific antigen (PSA) or its serum level, metastasis, bone metastasis, pain, lymph node involvement, an increase in tumor growth size or serum markers, a worsening of prognostic markers, or a patient's condition, as evidenced by a history of surgical castration, treatment with gonadotropin-releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethimide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin), or other agents. Prostate cancer is defined as prostate cancer that continues to progress or worsen, or continues to affect the patient's health, despite ongoing treatment with anti-cancer drugs (e.g., cyclosporine, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib (Cometriq®, also known as XL184)), or other prostate cancer therapies (e.g., vaccines (sipuleucel-T (Provenge®), GVAX, etc.), herbal medicines (PC-SPES), and lyase inhibitors (abiraterone)).

[0058] compound In certain embodiments, Formula I [ka] (In the formula, Y is CR N or N; R N is hydrogen or C 1~3 is alkyl; n is 0 to 3; R 1 is C 1~3 is alkyl; A is CH2 or C=O; A' is NH or O; a is 1 or 2; R 2 and R 3 are each independently H and C 1~3 alkyl, or R 2 and R 3 and the carbon to which they are attached may be substituted or unsubstituted C 3~6 Forming a cycloalkyl; m is 0 to 8; Each R 4 are independently substituted or unsubstituted C 1~3 alkyl or two R 4 The groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, may form a substituted or unsubstituted C 3~6 Form a cycloalkyl or two R 4 groups, taken together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; L is a substituted or unsubstituted -O(C 1~6 alkyl)-, -(C 1~6 alkyl)O-, -O(C 1~6 alkyl)O- or -(C 1~9 alkyl)-; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9alkyl); V is [ka] and B is N, CH or CR B and; Each R B are independently selected from halogen and substituted or unsubstituted C 1~6 alkyl; R C is a halogen, CF3 or SF5; R 5 and R 6 is C 1~3 alkyl or R 5 and R 6 together with the carbon atoms to which they are attached, form a substituted or unsubstituted C 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0059] In certain embodiments, Formula I [ka] (In the formula, Y is CR N or N; R N is hydrogen or C 1~3 is alkyl; n is 0 to 3; R 1 is C 1~3 is alkyl; A is CH2 or C=O; A' is NH or O; a is 1 or 2; R 2 and R 3 are each independently H and C 1~3 alkyl, or R 2 and R3 and the carbon to which they are attached may be substituted or unsubstituted C 3~6 Forming a cycloalkyl; m is 0 to 8; Each R 4 are independently substituted or unsubstituted C 1~3 alkyl or two R 4 The groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, may form a substituted or unsubstituted C 3~6 Form a cycloalkyl or two R 4 groups, taken together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; L is a substituted or unsubstituted -O(C 1~6 alkyl)-, -(C 1~6 alkyl)O- or -(C 1~9 alkyl)-; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); V is [ka] and B is N, CH or CR B and; Each R B are independently selected from halogen and substituted or unsubstituted C 1~6 alkyl; R C is a halogen, CF3 or SF5; R 5 and R 6 is C 1~3 alkyl or R 5 and R 6 together with the carbon atoms to which they are attached, form a substituted or unsubstituted C 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0060] In some embodiments of the compound of Formula I, n is 0. In some embodiments of the compound of Formula I, n is 1 and R 1 is methyl.

[0061] In some embodiments of the compound of Formula I, Y is CR N or N and R N is hydrogen or methyl. In some embodiments of the compound of Formula I, Y is CH. In some embodiments of the compound of Formula I, Y is N.

[0062] In some embodiments of the compound of Formula I, a is 1 and R 2 and R 3 are both H. In some embodiments of the compound of Formula I, a is 2 and R 2 and R 3 are both H. In some embodiments of the compound of Formula I, each R 4 is substituted or unsubstituted methyl. In some embodiments of the compound of Formula I, each R 4 is independently selected from methyl and CF3.

[0063] In some embodiments of the compound of Formula I, A is C=O. In some embodiments of the compound of Formula I, A is CH2.

[0064] In some embodiments of the compound of formula I, A' is NH. In some embodiments of the compound of formula I, A' is O.

[0065] 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.

[0066] In some embodiments of the compound of Formula I, X is N. In some embodiments of the compound of Formula I, X is CR X and;R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 In some embodiments of the compound of Formula I, X is CH.

[0067] In some embodiments of the compound of Formula I, L is substituted or unsubstituted -O(CH) p -, -O(CH2) p O- or -(CH2) p - and p is 1 to 4.

[0068] In some embodiments of the compound of Formula I, L is substituted or unsubstituted -O(CH) p -or-(CH2) p - and p is 1 to 4.

[0069] In some embodiments of the compound of Formula I, L is substituted or unsubstituted -O(CH) p - and p is 2 or 3.

[0070] In some embodiments of the compound of Formula I, L is substituted or unsubstituted -O(CH) p O- and p is 2 or 3.

[0071] In some embodiments of the compound of Formula I, L is a substituted or unsubstituted -(CH) p - and p is 3 or 4.

[0072] In some embodiments of a compound of Formula I, L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -O(CH)(CH)(CH)O-, -O(CH)(CH)(CH)O-, -(CH)(CH)-, -(CH)(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-. In some embodiments of a compound of Formula I, L is -O(CH)(CH)- or -(CH)(CH)(CH)(CH)-.

[0073] In some embodiments of the compound of Formula I, L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -(CH)(CH)-, -(CH)(CH)-, -(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-. In some embodiments of the compound of Formula I, L is -O(CH)(CH)- or -(CH)(CH)(CH)(CH)-.

[0074] In some embodiments of the compound of formula I, B is CH. In some embodiments of the compound of formula I, B is N.

[0075] 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 CF. In some embodiments of the compound of Formula I, R 5 and R 6 is methyl.

[0076] In some embodiments of the compound of Formula I, the compound is [ka] or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in which the variables are as described elsewhere herein.

[0077] In some embodiments of the compound of Formula I, the compound is [ka] or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in which the variables are as described elsewhere herein.

[0078] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, Y is CR N or N; R N is hydrogen or methyl; a is 1 or 2; Each R 4m is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0079] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R N is hydrogen or methyl; a is 1 or 2; Each R 4m is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0080] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, Y is N or CR N and; R N is hydrogen or methyl; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; RC is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0081] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R N is hydrogen or methyl; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0082] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, Y is N or CR N and; R N is hydrogen or methyl; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0083] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R N is hydrogen or methyl; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0084] In some embodiments of the compound of Formula I, the compound is [ka] or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, in which the variables are as described elsewhere herein.

[0085] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, Y is CR N or N; R N is hydrogen or methyl; A' is NH or O; a is 1 or 2; Each R 4m is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0086] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R N is hydrogen or methyl; A' is NH or O; a is 1 or 2; Each R 4m is independently hydrogen or substituted or unsubstituted methyl, the substituents, if present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0087] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, Y is N or CR N and; R N is hydrogen or methyl; A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0088] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, Y is N or CR N and; R N is hydrogen or methyl; A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0089] In certain embodiments of compounds of formula I, A is C=O. In certain embodiments of compounds of formula I, A is CH2.

[0090] In certain embodiments of compounds of Formula X, XI, XII, XIII, and XIV, A' is O. In certain embodiments of compounds of Formula X, XI, XII, XIII, and XIV, A' is NH.

[0091] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and XIV, X is N or CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl)- or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(CH) p -, -O(CH2) p O- or -(CH2) p -, p is 1 to 4; B is CH or N; b is 0; R C is CF3, Cl or SF5; R C is CF3; and R 5 and R 6 is methyl.

[0092] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and XIV, X is N or CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or (C 1~9 alkyl); L is a substituted or unsubstituted -O(CH) p -or-(CH2) p -, p is 1 to 4; B is CH or N; b is 0; R C is CF3, Cl or SF5; R C is CF3; R 5 and R 6 is methyl.

[0093] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and XIV, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)(CH2)O-, -O(CH2)(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)(CH2)-.

[0094] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and XIV, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0095] Further embodiments provided herein include any combination of one or more of the detailed embodiments set forth above.

[0096] In some embodiments of the compound of Formula I, the compound is a compound of Table 1.

[0097] The compounds shown in Table 1 have been tested in the AR mediation assays described herein and found to be active therein. In one embodiment, a compound described herein leads to at least about 50% or more degradation of AR protein at a concentration of 1 μM.

[0098] Method for preparing piperidinedione compounds The compounds described herein can be made using conventional organic synthesis and commercially available starting materials, or using the methods provided herein. By way of example and not limitation, compounds of Formula I (wherein Y, R N , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R B , RC , L, V, X, m, n, a, and b are as defined herein) can be prepared as outlined in the schemes shown below and in the examples provided herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures shown in the illustrative schemes and examples to obtain the desired products.

[0099] [ka] As shown in Scheme 1, a compound of formula (I) (wherein X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4The preparation of (alkyl)- and A is CO and A' is NH) can begin by reacting piperidine derivative a with ester intermediate b (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C) to provide intermediate c. Optionally, an iodide salt can be used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the ester protecting group from intermediate c (e.g., by treatment with a hydroxide base in a solvent, such as LiOH in THF and water when alk is Me, Et, or other alkyl, or by treatment with an acid in a solvent, such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane when alk is tert-butyl) provides intermediate d. Coupling of intermediate d with piperidinedione intermediate e in the presence of a coupling agent (e.g., HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent, such as DCM, DMF, NMP, or a mixture thereof, at a temperature between 0°C and about 70°C, provides compounds of formula (I) (wherein X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 Alternatively, there is provided a compound in which X is N and L is —O(C alkyl)-, A is CO, and A′ is NH. 1~3 alkyl)- or -(C 1~4Intermediate c, which is -O(C alkyl), can be prepared by reacting derivative VL-LG (LG is a suitable leaving group such as Cl, Br, I, triflate or alkyl sulfonate) with a suitably derivatized piperidyl ester derivative f (e.g., where alk is an alkyl group such as Me, Et, Bn or tert-Bu) at elevated temperature (e.g., about 40°C to about 80°C) in a solvent in the presence of a base (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) to provide intermediate c, which upon further reaction gives compounds of formula (I) (where X is N and L is -O(C 1~3 alkyl)- or -(C 1~4 alkyl)-, A is CO, and A' is NH).

[0100] [ka] Compounds of formula (I) wherein X is N and L is -O(C 1~3 alkyl)- or -(C 1~4 The VL-LG derivative (LG is a suitable leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) can also be prepared by reacting the VL-LG derivative with the appropriately derivatized intermediate g in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C) according to the alternative sequence shown in Scheme 2. Optionally, the use of an iodide salt (e.g., sodium iodide or potassium iodide) facilitates this transformation. Alternatively, compounds of formula (I) (where X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4The preparation of compounds of formula (I) (where X is N or CR) can be carried out by reacting compound e with an appropriately functionalized carbonyl intermediate h (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DCM or triethylamine in pyridine) at a temperature between 0° C. and about 60° C. to provide intermediate i. Reaction of i (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) with amine intermediate a in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at an elevated temperature (e.g., about 40° C. to about 80° C.) can provide compounds of formula (I) (where X is N or CR). X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 alkyl)-, A is CO, and A' is NH).

[0101] [ka] Intermediates such as amine g (L) are formed by -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4alkyl)-, A is CO, and A' is NH) can be prepared according to Scheme 3, starting with the reaction of an appropriately functionalized piperazine j with an ester intermediate b (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C) to provide intermediate k. Optionally, the use of an iodide salt (e.g., sodium iodide or potassium iodide) facilitates this transformation. Removal of the ester protecting group from intermediate k (e.g., by treatment with a hydroxide base in a solvent, such as LiOH in THF and water when alk=Me, Et, or other alkyl, or by treatment with an acid in a solvent, such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane when alk=tert-butyl) provides intermediate l. Coupling of intermediate l with piperidinedione intermediate e in the presence of a coupling agent (e.g., HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent, such as DCM, DMF, NMP, or a mixture thereof, at a temperature between 0° C. and about 70° C., provides amine intermediate g, which upon further reaction affords compounds of formula (I) (wherein L is —O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 An intermediate such as amine f can be prepared from intermediate k by removing an N-protecting group P N can be prepared by removing N When P is Boc, by treatment with an acid in a solvent such as HCl in dioxane or EtOAc at room temperature, or TFA in DCM at room temperature, or N is Bn or Cbz by hydrogenation with a metal catalyst in a solvent such as palladium on carbon in methanol).

[0102] [ka] Intermediates such as a (wherein X is N and L is —O(C 1~3 alkyl)- or -(C 1~4 VL-LG (where L is -O(C alkyl)-) can be prepared according to Scheme 4. In the presence of a base (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) in a solvent at elevated temperature (e.g., about 40°C to about 100°C), VL-LG (where L is -O(C alkyl)-) can be prepared according to Scheme 4. 1~3 alkyl)- or -(C 1~4 Treatment of amine n with amine n, where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate, provides intermediate o. Optionally, an iodide salt can be used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the N-protecting group P from intermediate o can be achieved by the addition of an iodide salt. N When removing (for example, P N When P is Boc, by treatment with an acid in a solvent such as HCl in dioxane or EtOAc at room temperature, or TFA in DCM at room temperature, or N is Bn or Cbz, by hydrogenation with a metal catalyst in a solvent such as palladium on carbon in methanol, to intermediate a (wherein X is N and L is —O(C 1~3 alkyl)- or -(C 1~4 alkyl)-) is provided.

[0103] [ka] R Z is an alcohol, a protected alcohol, a leaving group, or a heterocycle (such as a substituted piperidine or piperazine). ZIntermediates such as (e.g., intermediate r) can be prepared according to Scheme 5. Treatment of ester intermediate p (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu) with appropriately derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile q in the presence of a base such as triethylamine in a solvent such as EtOAc at elevated temperatures, for example, from about 70°C to about 90°C, provides intermediate r. Intermediates such as u (where LG is a leaving group (such as Cl, Br, I, triflate, or alkyl sulfonate), and L is -O(C 1~3 alkyl)- or -(C 1~4 alkyl)-) can be reacted with intermediate s, where P O is an alcohol protecting group such as THP, TBS, acetate or benzyl. O When removing (for example, P O When LG is THP, by treatment with catalytic acid in a solvent, e.g., HCl in dioxane, provides the alcohol intermediate t. Activation of the alcohol functionality of t to a leaving group (e.g., by treating t with thionyl bromide in dichloromethane when LG is Br) provides intermediate u, where LG is a leaving group (e.g., Cl, Br, I, triflate, or alkyl sulfonate, etc.), and L is —O(C 1~3 alkyl)- or -(C 1~4 alkyl)-) which can be further reacted to provide compounds of formula (I).

[0104] [ka] Intermediate p (wherein L is -O(C 1~3 alkyl)-, and R Z is a protected alcohol OP O (e.g., THP ether or TBS ether), such as aa, can be prepared according to Scheme 6. Alcohol intermediate v (wherein P Nis an amine protecting group such as Bn or Boc, an electrophile w (where LG is a leaving group such as Cl, Br, I, triflate or alkyl sulfonate, and P O is an oxygen protecting group such as THP or TBS) to provide intermediate x. N When removing (for example, P N When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc, by treatment with HCl in dioxane provides amine intermediate y. Reaction of amine y with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides intermediate aa, which can be further reacted to give compounds of formula (I) (where L=—O(C 1~3 alkyl)-).

[0105] [ka] Intermediate p (wherein L is -(C 1~3 alkyl)-, and R Z is an alcohol or a protected alcohol (e.g., a THP ether or a TBS ether), such as hh, can be prepared according to Scheme 6. The aldehyde intermediate bb (wherein P NStarting from R (where R is an amine protecting group such as Bn or Boc), reaction with an olefinating reagent in the presence of a base (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) in a solvent at temperatures between 0°C and 60°C provides the olefin intermediate cc. Reduction of cc by hydrogenation in the presence of a catalyst (e.g., palladium on carbon in methanol under a hydrogen atmosphere) in a solvent at elevated pressure (e.g., 10-100 psi) provides the intermediate dd. Reduction of the ester functionality can be achieved by treatment with a reducing agent (e.g., diisobutylaluminum hydride in DCM) in a solvent at temperatures between -78°C and 25°C to provide the intermediate ee (where R Y is H). Alternatively, intermediate ee can be prepared by treating intermediate cc with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at temperatures between -78°C and 25°C to provide intermediate ff. Hydrogenation of ff at elevated pressure (e.g., 10-100 psi) in a solvent in the presence of a catalyst (e.g., palladium on carbon in methanol under a hydrogen atmosphere) provides intermediate ee. Removal of the protecting group P of ee N When removing (for example, P N When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc), by treatment with HCl in dioxane provides the amine intermediate gg. Reaction of amine gg with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or an alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides intermediate hh (where R Y is H or an alcohol protecting group (e.g., THP, TBS, or Tr), which upon further reaction provides a compound of formula (I), 1~3 alkyl)-).

[0106] [ka] Intermediate p (wherein L is -(C 1~3 alkyl)O—, and R Z is a heterocycle or cycloalkyl group), such as mm, can be prepared according to Scheme 8. Intermediate ii (wherein P N’ is an amine protecting group, e.g., Bn or Boc, and LG is a leaving group, e.g., Cl, Br, I, triflate, or alkyl sulfonate, to afford alcohol jj, where P N is an amine protecting group, e.g., Bn or Boc), to provide the ether intermediate kk. N’ When removing (for example, P N’ When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N When is Boc, by treatment with HCl in dioxane) provides the amine intermediate ll.

[0107] Reaction of amine 11 with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides intermediate mm, which upon further reaction gives compounds of formula (I) (where L is -(C 1~3 alkyl)O—).

[0108] [ka] Particular intermediate p (wherein L is -O(C 1~3 alkyl)-, and R ZFor groups such as qq, the modified sequence shown in Scheme 9 can be used. N is an amine protecting group such as Bn or Boc, is converted to an electrophilic intermediate nn (where LG is a leaving group such as Cl, Br, I, triflate or alkyl sulfonate, and P N’ is an amine protecting group such as Bn or Boc) to provide the ether intermediate oo. N When removing (for example, P N’ When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc), by treatment with HCl in dioxane provides the amine intermediate pp. Reaction of the amine pp with an ester (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or an alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides the intermediate qq, which can be further reacted to give compounds of formula (I) (where L is —O(C 1~3 alkyl)-).

[0109] [ka] Intermediate nn (wherein X is CR Z Specific examples of intermediates such as vv were prepared according to Scheme 10. The ketone intermediate rr (wherein P Nis olefinated with an amine protecting group (e.g., Bn, Boc, or Cbz) using a base (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) in an olefinating reagent and solvent at temperatures between 0°C and 60°C to provide the olefin intermediate ss. Hydrogenation of ss in a solvent in the presence of a catalyst (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at elevated pressure (e.g., 10-100 psi) provides intermediate tt. Reduction of the ester functionality of tt is achieved by treatment with a reducing agent (e.g., diisobutylaluminum hydride in DCM) in a solvent at temperatures between -78°C and 25°C to provide intermediate uu. Activation of alcohol uu to leaving group LG (e.g., by treatment with thionyl bromide in dichloromethane and DMF when LG is Br, or by treatment with triflic anhydride in dichloromethane when LG is a triflate) provides intermediate vv, which upon further reaction gives compounds of formula (I), where L is —O(C 1~3 alkyl)- and X is CR X ) can be provided.

[0110] [ka] In the presence of a palladium catalyst and a base in a solvent (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and sodium bicarbonate in dioxane and water or XPhos Pd G3 and cesium carbonate in THF and water), a boronic acid derivative xx (wherein R W is an alkyl group (e.g., Me, Et, or Pin) to provide intermediate yy, thereby converting pyridine intermediate e (where Y is CH) to an appropriately derivatized pyridine derivative ww (where P Nis an amine protecting group (e.g., Boc, Cbz, or Bn), and Hal is a halogen or pseudohalogen (e.g., Cl, Br, I, or OTf). Catalytic hydrogenation of yy with hydrogen at high pressure (e.g., 5-100 psi) in a solvent (e.g., palladium on activated carbon in methanol) provides intermediate zz, followed by removal of its protecting group P N When removing (for example, P N When A is Boc, treatment with an acid in a solvent such as HCl in dioxane or trifluoroacetic acid in dichloromethane provides intermediate e, which can be further reacted to provide compounds of formula (I) where Y is CH and A' is NH. Alternatively, intermediates such as e (where Y is CH or CR N Preparation of intermediates (wherein Hal is a halogen (e.g., F, Cl, Br, I)) can begin by coupling intermediate aaa (wherein Hal is a halogen (e.g., F, Cl, Br, I)) with intermediate bbb (wherein Alk is an alkyl group (e.g., Me, Et, tert-Bu)) at elevated temperatures (e.g., 40°C to about 100°C) in a solvent in the presence of a base (e.g., cesium carbonate in acetonitrile), followed by decarboxylation conditions (e.g., a halide salt; lithium chloride in DMSO, etc.) at elevated temperatures (e.g., 80°C to 150°C) to provide intermediate ccc. Coupling intermediate ccc with an acrylate ester (e.g., methyl acrylate or tert-butyl acrylate) at elevated temperatures (e.g., 50°C to 100°C) in a solvent in the presence of a base, optionally with a catalyst (e.g., potassium carbonate and benzyltriethylammonium chloride in toluene) provides ester intermediate ddd (wherein Alk is an alkyl group (e.g., Me or tert-Bu)). Reaction of ddd with a suitably protected ammonia equivalent (e.g., BocNH, BnNH, or PhCNH) at elevated temperatures (e.g., between 40°C and 150°C) in the presence of a catalyst and a base (e.g., Pd(dba) BINAP and cesium carbonate in dioxane) in a solvent affords intermediate eee (wherein P Nis an amine protecting group (e.g., Boc, Bn, or benzophenone imine). Exposure of eee to nitrile hydrolysis conditions (e.g., by treatment with a base and a nucleophile in the presence of a solvent; e.g., potassium carbonate and hydrogen peroxide in DMSO) provides the amide intermediate fff. Cyclization of fff can be achieved by treatment with a coupling agent (e.g., HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent (e.g., DCM, DMF, NMP, or mixtures thereof) at temperatures between 0°C and about 70°C, followed by removal of the protecting group P N When removing (for example, P N is Boc), by treatment with an acid in a solvent such as HCl in dioxane or trifluoroacetic acid in dichloromethane, provides intermediate e, which can be further reacted to give compounds of formula (I) (where Y is CR N and A' is NH).

[0111] [ka] Intermediates such as g, where A is CH, A' is O, and Y is CH, can be prepared according to Scheme 12. An appropriately functionalized piperazine J, where P N is an amine protecting group (e.g., Boc, THP, or Cbz) to intermediate ggg (where LG is a leaving group (e.g., Cl, Br, I, or alkyl sulfonate), and P O is an alcohol protecting group (e.g., Ac, Piv, or TBS) to provide intermediate hhh. O When removing (for example, P O A C by treatment with a base in a solvent such as lithium hydroxide in THF and water, or by P OWhen R is TBS, treatment with a fluoride salt in a solvent such as TBAF in THF provides the alcohol intermediate iii. Coupling of alcohol iii with pyridine aaa, optionally at elevated temperature (e.g., 25°C to 80°C) in a solvent, and optionally in the presence of a base with a palladium catalyst (e.g., sodium hydride and THF), provides intermediate jjj. Coupling of jjj with pyridine aaa in a solvent, and optionally in the presence of a palladium catalyst and a base (e.g., [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) and sodium bicarbonate in dioxane and water or XPhos Pd G3 and cesium carbonate in THF and water), provides intermediate jjj. W Coupling of kkk with an alkyl group (e.g., Me, Et, or Pin) provides intermediate kkk. Catalytic hydrogenation of kkk with high pressure hydrogen (e.g., 5-100 psi) in a solvent (e.g., palladium on activated carbon in methanol) provides intermediate III, which is then protected by the protecting group P. N When removing (for example, P N is Boc), by treatment with an acid in a solvent such as HCl in dioxane or trifluoroacetic acid in dichloromethane, provides intermediate e, which can be further reacted to provide compounds of formula (I) where A is CH, A' is O, and Y is CH.

[0112] [ka] Intermediates such as e (where Y is N) can be prepared according to Scheme 13. In a solvent, in the presence of a base, optionally with a palladium catalyst (e.g., by treatment with potassium carbonate in DMF when Hal is F, or cesium carbonate and XPhos Pd in ​​dioxane when Hal is Cl, Br, or I). The process begins with coupling an appropriately functionalized nitropyridine mmm (where Hal is a halogen (e.g., F, Cl, Br, or I) with 3-aminopropionate nnn (where Alk is an alkyl group (e.g., Me, Et, or tert-Bu)) to provide intermediate ooo. Reaction of ooo with an isocyanate (e.g., potassium isocyanate or sodium isocyanate) in the presence of a solvent (e.g., THF) provides intermediate ppp, which upon treatment with acidic conditions (e.g., concentrated aqueous hydrochloric acid) cyclizes to form intermediate qqq. Reduction of the nitro group in qqq (e.g., by treatment with a reducing agent, e.g., H, in the presence of a catalyst such as Pd / C in a solvent such as EtOH or MeOH; or Fe and NHCl in a solvent such as EtOH and HO) provides intermediate e, which can be further reacted to provide compounds of formula (I) (where Y is N and A' is NH).

[0113] [ka] Intermediates such as g, where A is CH, A' is O, and Y is N, can be prepared according to Scheme 14. An appropriately functionalized nitropyridine rrr, where Hal is a halogen (e.g., F, Cl, or Br), is reacted with an alcohol iii, where P Nis coupled with an amine protecting group (e.g., Cbz, Boc, or Bn) to provide intermediate sss. Reduction of the nitro group of sss (e.g., by treatment with a reducing agent, e.g., H, in the presence of a catalyst such as Pd / C in a solvent such as EtOH or MeOH; or Fe and NHCl in a solvent such as EtOH and HO) provides intermediate ttt, which can be reacted with a chloroformate (e.g., methyl or ethyl chloroformate) in the presence of a base in a solvent (e.g., triethylamine in DCM or pyridine) to provide intermediate uuu (where Alk is an alkyl group (e.g., Me, Et, or Pr)). Coupling of uuu with acrylonitrile in the presence of a base and a Lewis acid in a solvent (e.g., potassium fluoride and aluminum oxide in acetonitrile) provides intermediate vvv. Nitrile hydrolysis of vvv (e.g., by treatment with a base and a nucleophile, e.g., potassium carbonate and hydrogen peroxide in DMSO in the presence of a solvent) provides intermediate www, which is subsequently cyclized by treatment with a base in a solvent (e.g., potassium tert-butoxide in THF) to remove the protecting group P N By removing (e.g., P N is Cbz, by hydrogenation in the presence of a catalyst in a solvent such as palladium on carbon in methanol), to provide intermediate g, which can be further reacted to provide compounds of formula (I) where Y is N, A is CH, A' is O, and X is N.

[0114] How to use In one embodiment, the compounds described herein have utility as pharmaceuticals for treating, preventing, or ameliorating a pathological condition in an animal or human. The compounds described herein have utility as pharmaceuticals for treating, preventing, or ameliorating a pathological condition in an animal or human. Accordingly, numerous uses of the compounds are provided herein, including the treatment or prevention of the diseases described below. In one embodiment, the methods provided herein comprise administering an effective amount of the compound to a subject in need thereof.

[0115] The methods provided herein include administering to a subject in need thereof an effective amount of one or more compounds.

[0116] Provided herein are methods for treating or preventing an androgen receptor (AR)-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0117] Provided herein are methods for treating or preventing an AR-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0118] In another aspect, provided herein is a compound for use in treating or preventing AR-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.In some embodiments, provided herein is a compound for use in treating AR-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.In some embodiments, provided herein is a compound for use in preventing AR-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0119] In some embodiments, the compound used in the methods herein is a compound as described herein. In some embodiments, the compound is a compound of Formula I. In some embodiments, the compound is a compound of Formula II. In some embodiments, the compound is a compound of Formula III. In some embodiments, the compound is a compound of Formula IV. In some embodiments, the compound is a compound of Formula V. In some embodiments, the compound is a compound of Formula VI. In some embodiments, the compound is a compound of Formula VII. In some embodiments, the compound is a compound of Formula VIII. In some embodiments, the compound is a compound of Formula IX. In some embodiments, the compound is a compound of Formula X. In some embodiments, the compound is a compound of Formula XI. In some embodiments, the compound is a compound of Formula XII. In some embodiments, the compound is a compound of Formula XIII. In some embodiments, the compound is a compound of Formula XIV. In some embodiments, the compound is a compound of Table 1.

[0120] 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.

[0121] In certain embodiments, the AR-mediated disease is prostate cancer. In some such embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some such embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In yet another embodiment, the prostate cancer is non-metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is hormone-refractory. In some embodiments, the prostate cancer is resistant to treatment with an AR antagonist. For example, the prostate cancer is resistant to treatment with enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

[0122] Provided herein are methods for reducing AR levels, comprising administering an effective amount of a compound to a subject. Also provided herein are compounds for use in methods for reducing AR levels in cells in vivo, ex vivo, or in vitro, comprising contacting the cells with an effective amount of a compound. In one embodiment, the cells are cells of a patient. In one embodiment, the cells are not cells of a patient. In one embodiment, provided herein are methods for reducing wild-type AR levels in a tumor, comprising administering a therapeutically effective amount of a compound, thereby reducing wild-type AR levels in the tumor. In one embodiment, provided herein are methods for reducing AR full-length (AR-FL) levels in a tumor, comprising administering a therapeutically effective amount of a compound, thereby reducing AR full-length (AR-FL) levels in the tumor. In some embodiments, the AR levels are reduced compared to the AR levels before administration of the compound. In some embodiments, the AR levels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the AR levels before administration of the compound.

[0123] Also provided herein is a method for regulating AR protein activity in a patient in need thereof, comprising administering an amount of a compound to the patient. In some such embodiments, provided herein is a method for reducing AR protein activity in a patient in need thereof, comprising administering an amount of a compound to the patient. In some embodiments, the AR protein activity is reduced compared to the AR protein activity before administration of the compound. In some embodiments, the AR protein activity is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% compared to the AR protein activity before administration of the compound.

[0124] In some embodiments of the methods described herein, the methods additionally include administering one or more second agents selected from AR antagonists (such as cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (such as finasteride and dutasteride), CYP17A1 inhibitors (such as abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (such as leuprorelin and cetrorelix), and antigonadotropins (such as megestrol acetate and medroxyprogesterone acetate).

[0125] In some embodiments, the compounds provided herein can be used in any of the methods described above.

[0126] In some embodiments, the compounds provided herein can be used in any of the methods described above.

[0127] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional dosage forms such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0128] The compounds can be administered to a subject orally, topically, or parenterally in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may contain an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), a disintegrant (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silica, The pharmaceutical compositions can be prepared by conventional methods using conventional organic or inorganic additives such as citric acid, talc, or sodium lauryl sulfate, flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound in the pharmaceutical composition is a level that will produce the desired effect; for example, for both oral and parenteral administration, the unit dosage can be from about 0.005 mg / kg to about 10 mg / kg of subject's body weight.

[0129] The dose of the compound administered to a subject may vary widely and be at the discretion of a medical professional. Generally, the compound may be administered at a dose of about 0.001 mg / kg to about 10 mg / kg of subject's body weight, once to four times daily; however, this dosage may be varied as appropriate depending on the subject's age, body weight, and medical condition, as well as the type of administration. In one embodiment, the dose is about 0.001 mg / kg to about 5 mg / kg of subject's body weight, about 0.01 mg / kg to about 5 mg / kg of subject's body weight, about 0.05 mg / kg to about 1 mg / kg of subject's body weight, about 0.1 mg / kg to about 0.75 mg / kg of subject's body weight, or about 0.25 mg / kg to about 0.5 mg / kg of subject's body weight. In one embodiment, one dose is given daily. 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.

[0130] In another embodiment, provided herein is a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof from about 0.01 mg / day to about 750 mg / day, from about 0.1 mg / day to about 375 mg / day, from about 0.1 mg / day to about 150 mg / day, from about 0.1 mg / day to about 75 mg / day, from about 0.1 mg / day to about 50 mg / day, from about 0.1 mg / day to about 25 mg / day, or from about 0.1 mg / day to about 10 mg / day of a compound.

[0131] In another embodiment, provided herein is a unit dosage formulation comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound.

[0132] In particular embodiments, provided herein are unit dosage formulations containing about 0.1 mg or 100 mg of compound.

[0133] In another embodiment, provided herein is a unit dosage formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound.

[0134] The compound can be administered once, twice, three times, four or more times daily, hi particular embodiments, doses of 100 mg or less are administered as a single daily dose, and doses above 100 mg are administered twice daily in an amount equal to half the total daily dose.

[0135] The compound can be administered orally for convenience. In one embodiment, when administered orally, the compound is administered with food and water. In another embodiment, the compound is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0136] The compounds may also be administered to the ear, nose, eye or skin, intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation or topically. The mode of administration is left to the discretion of the health-care practitioner, and may depend in-part on the site of the medical condition.

[0137] In one embodiment, provided herein is a capsule containing the compound but no additional carriers, excipients, or vehicles.

[0138] In another embodiment, provided herein is a composition comprising an effective amount of a compound and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0139] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or a convenient fraction of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, any composition is prepared according to known methods in pharmaceutical chemistry. Capsules may be prepared by mixing the compound with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0140] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Such preparations usually contain diluents, binders, lubricants, and disintegrants in combination with the compound. Typical diluents include, for example, various starches, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums are also useful, including acacia, alginic acid, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0141] Tablet formulations may require lubricants to prevent the tablet and tablet punches from adhering to the die. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, causing the tablet to break apart and release the compound. These include starch, clay, cellulose, algin, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose can be used, as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavoring and sealant, or with film-forming protective agents to modify the dissolution properties of the tablet. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0142] When it is desired to administer the compound as a suppository, typical bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding waxes to slightly raise its melting point. Water-miscible suppository bases, especially those containing polyethylene glycols of various molecular weights, are widely used.

[0143] The effect of a compound can be delayed or prolonged by appropriate formulation.For example, slowly dissolving pellets of the compound can be prepared and incorporated into tablets or capsules or as sustained-release implantable devices.This technique also includes making pellets with several different dissolution rates and filling capsules with a mixture of these pellets.Tablets or capsules can be coated with a film that resists dissolution for a predictable duration.Even parenteral preparations can be made long-acting by dissolving or suspending the compound in an oily or emulsion-like medium that allows the compound to slowly disperse in serum. [Example]

[0144] The following examples are presented by way of illustration, not limitation. Compound names were assigned using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic chemical structure names adhering to the Cahn-Ingold-Prelog stereochemical rules. Those skilled in the art can modify the procedures shown in the illustrative examples to obtain the desired products.

[0145] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product with a solution of an acid (e.g., aqueous HCl) after chromatographic purification.

[0146] [Table 1]

[0147] Example 1: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] trans-4-(Dibenzylamino)cyclohexan-1-ol. To a mixture of trans-4-aminocyclohexan-1-ol (40 g, 347 mmol, 1.0 equiv.) and cesium carbonate (339 g, 1.04 mol, 3 equiv.) in acetonitrile (900 mL), benzyl bromide (119 g, 698 mmol, 2.01 equiv.) was added dropwise, and the reaction was stirred at room temperature. After 48 h, the reaction mixture was filtered and concentrated. The resulting residue was diluted with DCM (300 mL), washed with water (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated. trans-4-(Dibenzylamino)cyclohexan-1-ol (77 g, 261 mmol, 75% yield) was obtained as a pale pink solid. The crude product was carried on without further purification. MS (ESI) m / z 116.3 [M+1] + ; 1 H NMR400MHz DMSO-d6δ7.27-7.34(m,8H),7.19-7.21(m,2H),4.42(d,J=4.8Hz,1H),3.55(s,4H),2.33 -2.36(m,1H),1.74-1.84(m,4H),1.40(dd,J=12.4Hz,2.0Hz,2H),0.98(d,J=13.2Hz,2H).

[0148] trans-N,N-Dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine. To a mixture of trans-4-(dibenzylamino)cyclohexan-1-ol (60 g, 203 mmol, 1.0 equiv) and tetrabutylammonium hydrogen sulfate (13.8 g, 40.6 mmol, 0.2 equiv) in THF (400 mL) and water (200 mL) at 0 °C, 2-(2-bromoethoxy)tetrahydro-2H-pyran (84.9 g, 406 mmol, 61.5 mL, 2.0 equiv) and sodium hydroxide (200 g, 5.00 mol, 24.6 equiv) were added. The reaction mixture was heated to 65 °C. After 12 h, the reaction mixture was poured into ice water (1.0 L), and the aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography (SiO, 2–50% ethyl acetate in petroleum ether) to afford trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (60 g, 142 mmol, 70% yield) as a colorless oil. 1 H NMR 400MHz CDCl3δ 7.37-7.39(m,4H),.7.28-7.32(m,4H),7.22(m,2H),4.63-4.67(m,1H),3.57-3.89(m,9H),3.23-3.25(m,1H) ,2.55(m,1H),2.08-2.11(m,2H),1.92-1.95(m,5H),1.58-1.64(m,6H),1.54-1.56(m,2H),1.20-1.39(m,2H).

[0149] trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine. To a mixture of trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (65 g, 153 mmol, 1.0 equiv) in methanol (500 mL) under N was added 10% palladium on carbon (6.5 g). The suspension was degassed under vacuum and purged with hydrogen gas three times. The reaction was stirred at room temperature under an atmosphere of hydrogen gas (15 psi). After 1 h, the reaction was filtered and the filtrate was concentrated to give trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (46 g) as an off-white oil. This crude material was carried forward without further purification. 1 H NMR400MHz CDCl3δ 7.34-7.36(m,1H),.4.63-4.65(m,1H),3.82-3.91(m,3H),3.52-3.66(m,5H),3.28(m,1H),2.70-2.71(m,1H),2. 01-2.04(m,2H),1.85-1.89(m,3H),1.58-1.59(m,1H),1.45-1.56(m,8H),1.29-1.32(m,2H),1.11-1.14(m,2H).

[0150] Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate. To a mixture of trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (25 g, 103 mmol, 1.0 equiv) in acetonitrile (175 mL) was added methyl 2-bromo-2-methylpropanoate (37.2 g, 205 mmol, 26.6 mL, 2.0 equiv), potassium carbonate (28.4 g, 205 mmol, 2.0 equiv), and potassium iodide (1.71 g, 10.3 mmol, 0.1 equiv). The reaction was heated to 110° C. After 16 h, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by column chromatography (SiO, 0-50% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54 mmol, 53% yield) as a yellow oil. MS (ESI) m / z 344.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 4.63(t,J=3.2Hz,1H),.3.82-3.87(m,2H),3.70(s,3H),3.61-3.63(m,4H),3.51-3.60(m,2H),3.22-3.24(m,1H) ),2.36(m,1H),1.99(m,2H),1.83-1.86(m,3H),1.62(m,1H),1.53-1.60(m,6H),1.30(m,6H),1.12-1.14(m,2H).

[0151] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54.2 mmol, 1.0 equiv.) in ethyl acetate (130 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (24.7 g, 108 mmol, 2.0 equiv.) and N,N-diisopropylethylamine (14.0 g, 108 mmol, 2.0 equiv.). The reaction was heated to 90° C. with stirring. After 12 hours, the reaction mixture was concentrated, and the resulting crude material was purified by silica gel column chromatography (0–50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (25 g, 46.3 mmol, 86% yield) as a yellow oil.

[0152] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (42.5 g, 78.8 mmol, 1.0 equiv) in dichloromethane (300 mL) was added 4 M hydrochloric acid in 1,4-dioxane (400 mL) dropwise. The reaction was stirred at room temperature. After 1 hour, the reaction mixture was concentrated and purified by silica gel column chromatography (1-20% THF in dichloromethane) to give 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (21 g, 46.1 mmol, 59% yield) as a yellow glassy oil. MS(ESI) m / z 456.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 7.95(d,J=8.0Hz,1H),7.85(m,1H),7.72(dd,J=10.0Hz,1.6Hz,1H),3.73-3.77(m,4H),3.60-3.62(m,2H),3.37-3 .39(m,1H),2.88-2.91(m,2H),2.21-2.24(m,2H),1.97(m,1H),1.83-1.88(m,3H),1.61(s,6H),1.33-1.41(m,2H).

[0153] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a mixture of 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.500 g, 7.72 mmol, 1.0 equiv) in dichloromethane (80 mL) was added N,N-dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol, 2.0 equiv) at 0° C. After 12 h, the reaction was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (9-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.200 g, 8.13 mmol, crude) as a yellow solid. MS (ESI) m / z 518.1 [M+1] + .

[0154] 2,6-Bis(benzyloxy)-3-bromopyridine. To a solution of benzyl alcohol (167 g, 1.55 mol, 3 equiv.) and 3-bromo-2,6-difluoropyridine (100 g, 515 mmol) in acetonitrile (1 L) was added cesium carbonate (369 g, 1.13 mol, 2.2 equiv.). The mixture was stirred at 100°C. After 16 h, the reaction solution was cooled to 20°C, filtered, and concentrated. Petroleum ether (2 L × 3) was added to the residue and stirred at 0°C for 2 h. A precipitate formed, and the mixture was filtered. The filter cake was dried under vacuum to give 2,6-bis(benzyloxy)-3-bromopyridine (300 g, 405 mmol, 78% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 7.89(d,J=8.0Hz,1H),7.42-7.32(m,10H),6.44(d,J=8.4Hz,1H),5.37(d,J=34.0Hz,4H).

[0155] 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (90 g, 243 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (185 g, 729 mmol, 3 equiv.) in DMSO (900 mL, 0.27 M) was added potassium acetate (71.6 g, 729 mmol, 3 equiv.), followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.8 g, 24.3 mmol, 0.1 equiv.) under N2. The reaction solution was stirred at 100 °C under N2. After 16 hours, the reaction mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography (5 to 100% ethyl acetate in petroleum ether) to give 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80 g, 192 mmol, 79% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.85(d,J=7.6Hz,1H),7.54-7.52(m,2H),7.43-7.29(m,8H),6.42(d,J=8.0Hz,1H),5.38(d,J=6.0Hz,4H),1.28(s,12H).

[0156] tert-Butyl (2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)carbamate. To a solution of tert-butyl (4-bromopyridin-2-yl)carbamate (5.00 g, 18.3 mmol, 1 equiv.) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (8.40 g, 20.1 mmol, 1.1 equiv.) in dioxane (100 mL, 0.17 M) and water (10 mL, 0.17 M) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.34 g, 1.83 mmol, 0.1 equiv.) and sodium bicarbonate (2.31 g, 27.5 mmol, 1.5 equiv.). The mixture was stirred under nitrogen at 90°C for 3 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The crude product was purified by silica gel chromatography (20% ethyl acetate in petroleum ether) to give tert-butyl (2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)carbamate (6.60 g, 13.7 mmol, 75% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 9.75(s,1H),8.22(d,J=5.2Hz,1H),8.09(s,1H),7.82(d,J=8.0Hz,1H),7.49-7.43(m,4H),7.41- 7.29(m,6H),7.21(dd,J=5.2,1.6Hz,1H),6.60(d,J=8.0Hz,1H),5.44-5.40(m,4H),1.48(s,9H).

[0157] tert-Butyl (4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate. To a solution of tert-butyl (2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)carbamate (6.00 g, 12.4 mmol, 1 equiv) in methanol (100 mL, 0.06 M) and THF (100 mL, 0.06 M) under nitrogen was added 10% palladium on activated carbon (0.60 g, 0.56 mmol, 0.05 equiv). The suspension was degassed in vacuo and purged with hydrogen three times. The mixture was stirred under a hydrogen atmosphere (15 Psi) at 25°C for 12 hours. The reaction mixture was filtered through a pad of Celite, and the solid was washed with THF (2 x 200 mL). The combined filtrates were concentrated in vacuo to give the crude product. The crude product was purified by silica gel chromatography (3% methanol in dichloromethane) to give tert-butyl (4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate (3.50 g, 11.5 mmol, 92% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.91(s,1H),9.76(s,1H),8.18(d,J=5.2Hz,1H),7.70(s,1H),6.91(dd,J=5.2,1.6Hz,1H),3.92(dd,J=1 2.0,4.8Hz,1H),2.73-2.61(m,1H),2.55-2.51(m,1H),2.25-2.12(m,1H),2.09-1.98(m,1H),1.47(s,9H).

[0158] 3-(2-aminopyridin-4-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl (4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate (3.50 g, 11.5 mmol, 1 equiv.) in water (10 mL, 1.2 M) was added 2 M aqueous hydrogen chloride solution (50 mL, 100 mmol, 8.7 equiv.). The solution was stirred at 25 °C. After 12 h, the reaction solution was frozen and lyophilized to give 3-(2-aminopyridin-4-yl)piperidine-2,6-dione hydrochloride (2.63 g, 12.8 mmol, 95% yield) as a yellow solid. MS (ESI) m / z 206.1 [M+1]+ ; 1 H NMR(400MHz,DMSO-d6)δ 14.03(s,1H),11.01(s,1H),8.23(s,2H),7.93(d,J=6.4Hz,1H),6.90(s,1H),6.79(dd,J=6.4,1.6Hz,1H), 4.05(dd,J=12.0,4.8Hz,1H),2.74-2.62(m,1H),2.59-2.51(m,1H),2.30-2.16(m,1H),2.07-1.96(m,1H).

[0159] (3R,5S)-tert-butyl 4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. A solution of tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5 g, 23.33 mmol, 1 equiv.), methyl bromoacetate (3.57 g, 23.33 mmol, 1 equiv.), and triethylamine (10.2 mL, 70 mmol, 3 equiv.) in THF (100 mL, 0.23 M) was stirred at 50 °C. After 18 h, the reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (6.2 g, 21.6 mmol, 92% yield) as a yellow oil. MS(ESI) m / z 287.2 [M+1] + .

[0160] 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid. To a solution of tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.27 g, 7.93 mmol, 1 equiv.) in THF (20 mL) was added lithium hydroxide (208.8 mg, 8.7 mmol, 1.1 equiv.) in water (5 mL), and the reaction solution was stirred at room temperature. After 18 h, the reaction solution was concentrated in vacuo and azeotroped three times with chloroform to remove residual water, affording crude 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (2.19 g, 7.8 mmol, 99% yield) as an off-white glassy solid. This material was carried forward without further purification. MS(ESI) m / z 273.2 [M+1] + .

[0161] (3R,5S)-tert-butyl 4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. To a flask containing 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetate (276 mg, 0.99 mmol, 1.1 equiv.) and 3-(2-aminopyridin-4-yl)piperidine-2,6-dione hydrochloride (200 mg, 0.83 mmol, 1 equiv.) was added N,N-dimethylformamide (5 mL), 1-methylimidazole (543 mg, 6.62 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (464 mg, 1.66 mmol, 2 equiv.). The reaction was stirred at 25° C. for 15 minutes. Another portion of N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (464 mg, 1.66 mmol, 2 equiv.) was added, and stirring was continued for 15 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The volatile organics were removed under reduced pressure to give a pale yellow oil. This oil was dissolved in ethyl acetate and purified by silica gel column chromatography (0–100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (380 mg, 0.82 mmol, 99% yield) as an off-white foamy semisolid. MS(ESI)m / z 460.0[M+1] + .

[0162] 2-((2R,6S)-2,6-Dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a flask containing tert-butyl (3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (380 mg, 0.83 mmol, 1 equiv.), 4 M hydrochloric acid in 1,4 dioxane (2.0 mL, 8.27 mmol, 10 equiv.) was added. The reaction solution was stirred at 25° C. for 3 hours. Removal of the volatile organics under reduced pressure gave 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride as a white powder, which was carried forward without further purification. MS(ESI) m / z 360.2 [M+1] + .

[0163] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.82 mL, 0.16 mmol, 1 equiv.), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (97 mg, 0.25 mmol, 1.5 equiv.), N,N-diisopropylethylamine (0.11 mL, 0.66 mmol, 4 equiv.), sodium iodide (49 mg, 0.33 mmol), and N,N-dimethylformamide (2.0 mL) were added. The reaction was stirred at 50° C. After 18 h, the reaction solution was diluted with DMSO and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (16.5 mg, 0.019 mmol, 11% yield) as an off-white solid. MS(ESI) m / z 797.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),8.31-8.37(m,2H),8.20(d,J=1.71Hz,1H),7.93-8.07(m,2H),7.12-7.20(m,1H),4.03(br dd,J=4.89,11.86Hz,2H),3.85(br d,J=4.40Hz,4H),3.60(br dd,J=4.22,9.11Hz,2H),3.33-3.42(m,2H),3.05-3.32(m,5H),2.85(br d,J=11.98Hz,2H),2.64-2.75(m,1H),2.52-2.60(m,1H),2.21(dq,J=4.22,12.3 3Hz, 1H), 2.02-2.15 (m, 3H), 1.67-1.78 (m, 2H), 1.55 (s, 6H), 1.16-1.44 (m, 8H).

[0164] Example 2: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] tert-Butyl (2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)carbamate. To a mixture of tert-butyl (5-bromopyridin-2-yl)carbamate (1.96 g, 7.19 mmol, 1 equiv.) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.00 g, 7.19 mmol, 1 equiv.) in dioxane (30 mL, 0.22 M) and water (3 mL, 0.22 M) was added potassium phosphate (2.29 g, 10.78 mmol, 1.5 equiv.) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.53 g, 0.72 mmol, 0.1 equiv.). The reaction mixture was stirred under nitrogen at 100° C. for 12 hours. The resulting mixture was poured into ethyl acetate-water (w / w=1 / 1, 100 mL) and stirred for 15 minutes. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to give tert-butyl (2′,6′-bis(benzyloxy)-[3,3′-bipyridin]-6-yl)carbamate (1.95 g, 4.03 mmol, 56% yield) as a yellow solid. MS (ESI) m / z 483.4 [M+1] + .

[0165] tert-Butyl (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate. To a solution of tert-butyl (2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)carbamate (0.78 g, 1.61 mmol, 1 equiv.) in tetrahydrofuran (10 mL, 0.11 M) and methanol (5 mL, 0.11 M) was added 10% palladium on carbon (0.3 g, 0.28 mmol, 0.2 equiv.) under N2. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 20 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give tert-butyl (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate (0.48 g, 1.57 mmol, 97% yield) as a white solid, which was carried forward without further purification. MS (ESI) m / z 338.2 [M+Na] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.85(s,1H),9.70(s,1H),8.10(d,J=2.1Hz,1H),7.73(d,J=8.6Hz,1H),7.59(dd,J=2.3,8.6Hz,1H),3.85(dd,J=5.0,12.3Hz,1H),1.47(s,9H).

[0166] 3-(6-aminopyridin-3-yl)piperidine-2,6-dione. To a solution of tert-butyl (5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate (0.48 g, 1.57 mmol, 1 equiv.) in dioxane (5 mL, 0.3 M), 4 M hydrochloric acid in dioxane (10 mL, 25.4 equiv.) was added, and the reaction mixture was stirred at 20 °C for 12 hours. The resulting solution was concentrated to give 3-(6-aminopyridin-3-yl)piperidine-2,6-dione hydrochloride (0.37 g, 1.53 mmol, 97% yield) as a yellow solid. MS (ESI) m / z 206.2 [M+1] + .

[0167] (3R,5S)-4-(2-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl. To a flask containing 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetate (276 mg, 0.99 mmol, 1.1 equiv.), 3-(6-aminopyridin-3-yl)piperidine-2,6-dione hydrochloride (200 mg, 0.830 mmol, 1 equiv.), N,N-dimethylformamide (5 mL), 1-methylimidazole (543 mg, 6.62 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (464 mg, 1.66 mmol, 2 equiv.) were added. The reaction was stirred at 25° C. for 15 minutes. Another portion of N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (465 mg) was added, and the reaction was stirred for an additional 15 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The volatile organics were removed under reduced pressure to give a pale yellow oil. This oil was dissolved in ethyl acetate and purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (200 mg, 0.435 mmol, 53% yield) as an off-white foamy semi-solid. MS (ESI) m / z 460.2 [M+1] + .

[0168] 2-((2R,6S)-2,6-Dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a flask containing tert-butyl (3R,5S)-4-(2-((5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (200 mg, 0.440 mmol, 1 equiv.), hydrochloric acid (4 mL, 16 mmol, 36 equiv.) (4.0 M in dioxane) was added. The reaction solution was stirred at 25° C. for 3 hours. Removal of the volatile organics under reduced pressure gave 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride as a white solid. This material was carried forward without further purification. MS(ESI) m / z 360.2 [M+1] + .

[0169] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (200 mg, 0.39 mmol, 1 equiv.), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (200 mg, 0.51 mmol, 1.3 equiv.), N,N-diisopropylethylamine (0.27 mL, 1.54 mmol, 4 equiv.), sodium iodide (69 mg, 0.46 mmol, 11.2 equiv.), and N,N-dimethylformamide (2.0 mL) were added. The reaction was stirred at 60° C. After 18 hours, the reaction solution was diluted with DMSO (1 ml) and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (79 mg, 0.088 mmol, 23% yield) as an off-white solid. MS(ESI) m / z 797.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.91(s,1H),8.34(d,J=8.19Hz,1H),8.27(d,J=2.20Hz,1H),8.20(d,J=1.71Hz,1H),8.05(br d,J=8.07Hz,1H),7.97(dd,J=1.71,8.19Hz,1H),7.79(dd,J=2.26,8.62Hz,1H),3.95(br dd,J=4.83,12.53Hz,4H),3.80-3.90(m,5H),3.56-3.66(m,2H),3.18-3.43(m,5H),2.85(br d,J=11.37Hz,2H),2.66-2.78(m,1H),2.52-2.61(m,1H),2.21-2.33(m,1H),2.08- 2.17(m,2H),1.98-2.07(m,1H),1.68-1.79(m,2H),1.55(s,6H),1.20-1.44(m,8H).

[0170] Example 3: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride [ka] Methyl 3-((6-nitropyridin-3-yl)amino)propanoate. To a solution of 5-fluoro-2-nitropyridine (9.800 g, 68.97 mmol, 1 equiv.) and methyl 3-aminopropanoate hydrochloride (11.55 g, 82.77 mmol, 1.2 equiv.) in N,N-dimethylformamide (150 mL), potassium carbonate (28.60 g, 206.91 mmol, 3 equiv.) was added and the reaction solution was stirred at 80° C. After 12 hours, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (50-100% ethyl acetate in petroleum ether) to give methyl 3-((6-nitropyridin-3-yl)amino)propanoate (15.50 g, 51.69 mmol, 75% yield) as a yellow solid. MS(ESI) m / z 226.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.15(d,J=8.8Hz,1H),7.89(d,J=2.8Hz,1H),7.00(dd,J=2.8,8.8Hz,1H,1H),5.26(br s,1H),3.73(s,3H),3.61-3.54(m,2H),2.69(t,J=6.4Hz,2H).

[0171] Methyl 3-(1-(6-nitropyridin-3-yl)ureido)propanoate. To a solution of methyl 3-((6-nitropyridin-3-yl)amino)propanoate (7.500 g, 25.01 mmol, 1 equiv.) in tetrahydrofuran (160 mL) was added a solution of chlorosulfonyl isocyanate (4.600 g, 32.51 mmol, 2.82 mL, 1.3 equiv.) dropwise under nitrogen at 0 °C. After stirring at 0 °C for 90 min, the reaction solution was diluted with water (200 mL), adjusted to pH 8-9 by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (50-70% ethyl acetate in petroleum ether) to give methyl 3-(1-(6-nitropyridin-3-yl)ureido)propanoate (4.600 g, 15.13 mmol, 61% yield) as a yellow solid. MS(ESI) m / z 269.1 [M+1] + .

[0172] 1-(6-Nitropyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. Concentrated aqueous hydrochloric acid (12 M, 80 mL, 63.47 equiv.) was added to methyl 3-(1-(6-nitropyridin-3-yl)ureido)propanoate (4.600 g, 15.13 mmol, 1 equiv.) at 0 °C. After slowly warming to room temperature over 12 h, the reaction solution was diluted with water (200 mL), adjusted to pH 8-9 by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (4 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 1-(6-nitropyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.580 g, 2.110 mmol, 14% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.74(br s,1H),8.92-8.53(m,1H),8.36(br s,1H),8.16(br s,1H),3.98(br s,2H),2.96-2.67(m,1H).

[0173] 1-(6-aminopyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. A solution of 1-(6-nitropyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.400 g, 10.16 mmol, 1 equiv.) in N,N-dimethylacetamide (40 mL) and THF (40 mL) was added to palladium on carbon (0.3 g, 10% purity) under nitrogen. The suspension was degassed under vacuum, purged with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 hours, the reaction solution was filtered, and the solid was washed with acetonitrile. The combined organics were concentrated and the resulting material was triturated with acetonitrile to give 1-(6-aminopyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.150 g, 5.180 mmol, 51% yield) as a gray solid. MS (ESI) m / z 207.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.29(br s,1H),7.84(d,J=2.4Hz,1H),7.32(dd,J=2.6,8.8Hz,1H),6.44(d,J=8.8Hz,1H),5.97(s,2H),3.65(t,J=6.8Hz,2H),2.67(t,J=6.8Hz,2H).

[0174] tert-Butyl (3R,5S)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. To a 20 mL vial containing 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (323.88 mg, 1.16 mmol, 1.2 equiv.) and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (544.3 mg, 1.94 mmol, 2 equiv.), acetonitrile (2 mL) was added, followed by 1-methylimidazole (0.46 mL, 5.82 mmol, 6 equiv.). The reaction solution was stirred at room temperature for 10 minutes. A solution of 1-(6-aminopyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.9700 mmol) in DMSO (6 mL, 0.12 M) was added. After 30 min, additional N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V) (272.1 mg, 0.97 mmol, 1 equiv.) was added, and the reaction solution was continued to stir at room temperature. After 30 minutes, the crude material was purified by silica gel column chromatography (1-10% methanol in dichloromethane) to give tert-butyl (3R,5S)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (83 mg, 0.18 mmol, 19% yield). MS (ESI) m / z 461.2 [M+1] + .

[0175] 2-((2R,6S)-2,6-Dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride. To a 20 mL vial containing tert-butyl (3R,5S)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (83 mg, 0.18 mmol), 1 mL of dichloromethane was added, followed by 4 M hydrochloric acid in 1,4-dioxane (1.35 mL, 5.41 mmol, 30 equiv). Upon addition of the HCl solution, the starting material / product immediately precipitated as a white solid. Concentration of this material gave 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (68 mg, 0.17 mmol, 95% yield) as a white solid. MS(ESI) m / z 361.2 [M+1] + .

[0176] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (93 mg, 0.18 mmol, 1 equiv.), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (78 mg, 0.18 mmol, 1 equiv.) and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.) in N,N-dimethylformamide (0.45 mL), N,N-diisopropylethylamine (0.31 mL, 1.8 mmol, 10 equiv.) was added and the reaction solution was stirred at 45° C. After 28 hours, the reaction solution was diluted to a total volume of 2 ml with DMSO and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (42 mg, 0.05 mmol, 28% yield). MS(ESI) m / z 789.2 [M+1] + ; 1H NMR(400MHz,CDCl3)δ 9.88(s,1H),8.37-8.28(m,2H),7.94(d,J=8.3Hz,1H),7.87-7.81(m,1H),7.75-7.69(m,1 H),7.65(dd,J=2.7,8.8Hz,1H),7.44(s,1H),3.87(t,J=6.7Hz,2H),3.62(s,2H),3.39-3.2 8(m,1H),2.96-2.69(m,8H),2.56(s,2H),2.27-2.16(m,2H),2.04(t,J=11.0Hz,2H),1.87 -1.74(m,2H),1.62-1.59(m,6H),1.42-1.30(m,2H),1.07-1.05(m,3H),1.05-1.03(m,3H).

[0177] Example 4: 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (2 g, 5.82 mmol, 1 equiv.) in ethyl acetate (1.3234 mL) was added 2-chloro-4-isothiocyanatobenzonitrile (2.27 g, 11.65 mmol, 2 equiv.) and N,N-diisopropylethylamine (2.03 mL, 11.65 mmol, 2 equiv.). The reaction was heated to 90° C. with stirring. After 18 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (2 g, 3.9521 mmol, 68% yield) as a white solid. MS(ESI) m / z 506.2 [M+1] + .

[0178] 2-Chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (4.0 g, 7.9 mmol, 1 equiv) in chloroform (5.7 mL) was added 4 M HCl in dioxane (39.52 mL, 158.08 mmol, 20 equiv) and the reaction was stirred at room temperature. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to give 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.5 g, 2.883 mmol, 36% yield) as an off-white solid. MS(ESI) m / z 422.2 [M+1] + .

[0179] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.51 g, 3.06 mmol) in dichloromethane (38 mL) and N,N-dimethylformamide (3.8 mL) was added thionyl bromide (0.59 mL, 7.64 mmol, 2.5 equiv.) and the reaction was stirred at room temperature. After 1 h, the reaction was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0–80% ethyl acetate in hexanes) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (1.171 g, 2.42 mmol, 79% yield) as a pale yellow solid. MS (ESI) m / z 484.0 [M+1]+.

[0180] 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (173.8 mg, 0.40 mmol, 1.3 equiv) in N,N-dimethylformamide (3.09 mL) was added 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (150.0 mg, 0.31 mmol, 1.0 equiv), sodium iodide (93.4 mg, 0.62 mmol, 2.0 equiv) and N,N-diisopropylethylamine (0.38 mL, 2.17 mmol, 7.0 equiv). The vial was sealed, and the mixture was heated to 60° C. and stirred for 36 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (148.2 mg, 0.18 mmol, 58% yield) as a light reddish-brown solid. MS (ESI) m / z 763.0 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.96(s,1H),10.70(br s,1H),8.33(d,1H,J=5.4Hz),8.1-8.2(m,1H),8.01(br s,1H),7.92(d,1H,J=1.8Hz),7.61(dd,1H,J=1.8,8.3Hz),7.14(dd,1H,J=1.3,5.3Hz),4.02(br dd,1H,J=4.9,11.7Hz),3.84(t,2H,J=4.2Hz),3.81(br s,1H),3.5-3.6(m,5H),3.36(tt,2H,J=4.1,11.0Hz),3.27(br s,2H),3.11(br s,2H),2.85(q,2H,J=12.1Hz),2.70(tt,1H,J=5.4,12.2Hz),2.53(td,1H,J=4.2,16.8Hz),2.21(dq,1H,J=4.5,12.4Hz),2.0-2.1(m,3H),1.72(br d,2H,J=11.6Hz),1.53(s,6H),1.3-1.4(m,2H),1.21(br s,6H).

[0181] Examples 5 and 6: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((S)-3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide Hydrochloride and 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-((R)-3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] 4-(3-(trans-4-(2-((3R,5S)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (2.300 g, 4.440 mmol, 1 equiv.), (2R,6S)-2,6-dimethylpiperazine (0.608 g, 5.320 mmol, 1.2 equiv.) in N,N-dimethylformamide (30 mL), N,N-diisopropylethylamine (2.32 mL, 13.31 mmol, 3 equiv.) and sodium iodide (0.200 g, 1.330 mmol, 0.3 equiv.) were added, and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (3% methanol in dichloromethane) to give 4-(3-(trans-4-(2-((3R,5S)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (2.540 g, 4.549 mmol, 98% yield) as a yellow solid. MS (ESI) m / z 552.2 [M+1] + ; 1H NMR(400MHz,CDCl3)δ 7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),3.83-3.54(m ,3H),3.33(m,1H),3.07-2.94(m,2H),2.93-2.70(m,4H),2.59(t,J=6.0Hz,2H),2.20(br d,J=12.0Hz,2H),1.82(br d,J=12.0Hz,2H),1.74(br t,J=10.8Hz,2H),1.60(s,6H),1.42-1.28(m,2H),1.08(d,J=6.4Hz,6H).

[0182] 2-(6-Chloropyridin-3-yl)propanenitrile. To a mixture of 2-(6-chloropyridin-3-yl)acetonitrile (12.60 g, 82.58 mmol, 1 equiv.) and potassium tert-butoxide (11.12 g, 99.10 mmol, 1.2 equiv.) in THF (200 mL, 0.41 M) was added iodomethane (12.89 g, 90.84 mmol, 1.1 equiv.) at -20 °C. After stirring at -20 °C for 2 h, the reaction solution was diluted with 10% aqueous citric acid (100 mL), adjusted to pH 8-9 by adding saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (8% ethyl acetate in petroleum ether) to give 2-(6-chloropyridin-3-yl)propanenitrile (8.200 g, 49.22 mmol, 60% yield) as a yellow oil. MS (ESI) m / z 167.1 [M+1] + ; 1 H NMR(400MHz,CDCl3-d)δ 8.39(d,J=2.4Hz,1H),7.71(dd,J=2.4,8.0Hz,1H),7.39(d,J=8.0Hz,1H),3.96(q,J=7.2Hz,1H),1.68(d,J=7.2Hz,3H).

[0183] Methyl 4-(6-chloropyridin-3-yl)-4-cyanopentanoate. To a solution of 2-(6-chloropyridin-3-yl)propanenitrile (8.200 g, 49.22 mmol, 1 eq.) and potassium carbonate (13.58 g, 98.43 mmol, 2 eq.) in toluene (80 mL), benzyltrimethylammonium hydroxide (1.55 mL, 9.840 mmol, 0.2 eq.) and methyl acrylate (8.92 mL, 98.43 mmol, 2 eq.) were added, and the reaction solution was stirred at 65 °C. After 4 h, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (9% ethyl acetate in petroleum ether) to give methyl 4-(6-chloropyridin-3-yl)-4-cyanopentanoate (9.900 g, 39.18 mmol, 80% yield) as a yellow oil. MS (ESI) m / z 253.1 [M+1] + ; 1 H NMR(400MHz,CDCl3-d)δ 8.51(d,J=2.8Hz,1H),7.74(dd,J=2.8,8.4Hz,1H),7.44-7.34(d,J=8.4Hz,1H),3.65(s,3H),2.59-2.46(m,1H),2.41-2.21(m,3H),1.78(s,3H).

[0184] Methyl 4-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-4-cyanopentanoate. To a solution of methyl 4-(6-chloropyridin-3-yl)-4-cyanopentanoate (9.900 g, 39.18 mmol, 1 equiv.), tert-butyl carbamate (6.880 g, 58.77 mmol, 1.5 equiv.), and cesium carbonate (38.29 g, 117.5 mmol, 3 equiv.) in 1,4-dioxane (200 mL), di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (1.870 g, 3.920 mmol, 10 mol%) and palladium(II) acetate (0.440 g, 1.960 mmol, 5 mol%) were added under nitrogen, and the reaction solution was stirred at 110° C. After 12 h, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give methyl 4-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-4-cyanopentanoate (8.700 g, 26.10 mmol, 67% yield) as a yellow solid. MS (ESI) m / z 334.2 [M+1] + ; 1 H NMR(400MHz,CDCl3-d)δ 8.36(d,J=2.0Hz,1H),8.00(d,J=9.2Hz,1H),7.83(s,1H),7.69(dd,J=2.4,9.2Hz, 1H),3.65(s,3H),2.56-2.43(m,1H),2.38-2.19(m,3H),1.75(s,3H),1.55(s,9H).

[0185] 3-(6-Aminopyridin-3-yl)-3-methylpiperidine-2,6-dione. To a solution of methyl 4-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-4-cyanopentanoate (4.700 g, 14.10 mmol, 1 equiv.) in acetic acid (30 mL), concentrated sulfuric acid (10.0 mL, 980 mmol, 70 equiv.) was added, and the reaction solution was stirred at 120 °C. After 12 h, the reaction solution was diluted with water (100 mL) and adjusted to pH 7-8 by the addition of saturated aqueous sodium bicarbonate. The solution was filtered, and the filtrate was extracted with ethyl acetate (5 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The filter cake and the resulting concentrated organic layer were purified by semi-preparative reverse-phase HPLC (1%-17% acetonitrile + 10 mM aqueous ammonium bicarbonate) to give 3-(6-aminopyridin-3-yl)-3-methylpiperidine-2,6-dione (0.260 g, 1.186 mmol, 8% yield) as a white solid. MS (ESI) m / z 220.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.85(s,1H),7.74(d,J=2.4Hz,1H),7.32(dd,J=2.4,8.4Hz,1H),6.43(d,J=8.4Hz,1H ),6.12-5.68(m,2H),2.46-2.38(m,1H),2.28(m,1H),2.18-1.96(m,2H),1.38(s,3H).

[0186] Enantiomers 1 and 2 of 3-(6-aminopyridin-3-yl)-3-methylpiperidine-2,6-dione. Racemic 3-(6-aminopyridin-3-yl)-3-methylpiperidine-2,6-dione (0.260 g, 1.190 mmol) was separated by chiral SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm) with 50% methanol as mobile phase) to give Enantiomer 1 (0.090 g, 0.410 mmol) and Enantiomer 2 (0.100 g, 0.456 mmol) of 3-(6-aminopyridin-3-yl)-3-methylpiperidine-2,6-dione as white solids. The absolute configurations of Enantiomers 1 and 2 were not determined, so each enantiomer was carried forward separately to the following step.

[0187] Enantiomer 1 of 2-chloro-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. To a solution of enantiomer 1 of 3-(6-aminopyridin-3-yl)-3-methylpiperidine-2,6-dione (0.090 g, 0.410 mmol, 1 equiv.), N,N-diisopropylethylamine (0.21 mL, 1.230 mmol, 3 equiv.), and 4-dimethylaminopyridine (0.005 g, 0.040 mmol, 10 mol%) in N,N-dimethylformamide (4 mL) was added 2-chloroacetyl chloride (0.07 mL, 0.820 mmol, 2 equiv.) at 0 °C, and the reaction solution was allowed to warm slowly to room temperature with stirring. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (1% methanol in dichloromethane) to give enantiomer 1 of 2-chloro-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.090 g, 0.304 mmol, 74% yield) as a yellow solid. MS (ESI) m / z 296.1 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),10.88(s,1H),8.24(d,J=2.0Hz,1H),8.04(br d,J=8.4Hz,1H),7.78(dd,J=2.4,8.4Hz,1H),4.34(s,2H),2.58-2.52(m,1H),2.41(m,1H),2.23-2.04(m,2H),1.49(s,3H).

[0188] Enantiomer 1 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. A solution of 4-(3-(trans-4-(2-((3R,5S)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.165 g, 0.300 mmol, 1 equiv.) and 2-chloro-N-(5 To a solution of enantiomer 1 of N-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.088 g, 0.300 mmol, 1 equiv.), sodium iodide (0.045 g, 0.300 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.16 mL, 0.900 mmol, 3 equiv.) were added, and the reaction solution was stirred at 70° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give enantiomer 1 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.002 g, 0.0029 mmol, 1% yield) as a yellow solid. MS(ESI) m / z 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.15-10.73(m,2H),8.34(d,J=8.0Hz,1H),8.28(d,J=2.4Hz,1H),8.19(d,J=1.6Hz,1H),8.07(br d,J=7.6Hz,1H),7.97(dd,J=1.6,8.0Hz,1H),7.85(dd,J=2.0,8.4Hz,1H) ,4.19-4.01(m,3H),3.72-3.49(m,4H),3.40-3.08(m,5H),2.97-2.74(m,2 H),2.59-2.53(m,1H),2.42(m,3H),2.24-2.15(m,1H),2.14-2.00(m,3H) ,1.79-1.66(m,2H),1.54(s,6H),1.50(s,3H),1.43-1.33(m,2H),1.30(br s,6H).

[0189] Enantiomer 2 of 2-chloro-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. To a solution of enantiomer 2 of 3-(6-aminopyridin-3-yl)-3-methylpiperidine-2,6-dione (0.180 g, 0.820 mmol, 1 equiv.), N,N-diisopropylethylamine (0.43 mL, 2.460 mmol, 3 equiv.), and 4-dimethylaminopyridine (0.010 g, 0.0800 mmol, 10 mol%) in N,N-dimethylformamide (5 mL) was added 2-chloroacetyl chloride (0.13 mL, 1.64 mmol, 2 equiv.) at 0 °C, and the reaction was allowed to warm slowly to room temperature with stirring. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (1% methanol in dichloromethane) to give enantiomer 2 of 2-chloro-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.200 g, 0.586 mmol, 71% yield) as a yellow solid. MS (ESI) m / z 296.0 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),10.88(s,1H),8.24(d,J=2.0Hz,1H),8.04(d,J=8.8Hz,1H),7.78(dd,J=2.4,8.8Hz,1H),4.34(s,2H),2.58-2.52(m,1H),2.41(m,1H),2.24-2.02(m,2H),1.49(s,3H).

[0190] Enantiomer 2 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. A solution of 4-(3-(trans-4-(2-((3R,5S)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.095 g, 0.170 mmol, 1 equiv.) and 2-chloro-N-(5 To a solution of enantiomer 2 of N-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.059 g, 0.1700 mmol, 1 equiv.), sodium iodide (0.052 g, 0.340 mmol, 2 equiv.) and N,N-diisopropylethylamide (0.09 mL, 0.520 mmol, 3 equiv.) were added, and the reaction solution was stirred at 70° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give enantiomer 2 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.041 g, 0.0510 mmol, 29% yield) as a yellow solid. MS(ESI) m / z 811.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),9.89(br s,1H),8.33(d,J=8.0Hz,1H),8.26-8.14(m,2H),8.07(d,J=8.8Hz,1H),7.97(br d,J=8.0Hz,1H),7.77(dd,J=2.4,8.8Hz,1H),3.91-3.76(m,1H),3.53(m,2H),3.28-3.22(m ,4H),2.90-2.75(m,4H),2.74-2.60(m,3H),2.43-2.35(m,3H),2.24-2.15(m,1H),2.10(br s,1H),2.05-2.01(m,1H),1.84(m,2H),1.71(m,2H),1.61-1.50(m,6H),1.49-1.41(m,3H),1.39-1.27(m,2H),0.95(br d,J=6.0Hz,6H)

[0191] Example 7: 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride [ka] trans-N,N-Dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine. To a solution of trans-4-(dibenzylamino)cyclohexanol (60.00 g, 203.1 mmol, 1 equiv) in xylene (450 mL, 0.45 M) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (113.28 g, 507.75 mmol, 2.5 equiv), tetra-N-butylammonium bromide (13.09 g, 40.62 mmol, 0.2 equiv), and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 equiv), and the reaction solution was stirred at room temperature. After 24 hours, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (100% petroleum ether) to give trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (40.0 g, 91.4 mmol, 45% yield) as a pale yellow oil. MS (ESI) m / z 438.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.38-7.32(m,4H),7.31-7.28(m,4H),7.24-7.22(m,2H),4.61-4.57( m,1H),3.88-3.84(m,2H),3.63(s,4H),3.55-3.52(m,4H),3.51-3.16( m,1H),2.54-2.09(m,1H),2.08-2.07(m,2H),1.92-1.90(m,2H),1.61 -1.60(m,2H),1.59-1.57(m,6H),1.55-1.53(m,2H),1.38-1.16(m,2H)

[0192] trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine. To a solution of trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (20.0 g, 45.7 mmol, 1 equiv.) in methanol (100 mL) was added 10% palladium on carbon (10.0 g, 9.39 mmol). The reaction flask was evacuated and purged with hydrogen gas three times, then stirred under a hydrogen atmosphere (15 psi) at room temperature. After 12 h, the reaction solution was filtered, and the filtrate was concentrated to give trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (11.00 g, 42.74 mmol, 94% yield) as a pale yellow oil. This material was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.52(m,1H),3.79-3.61(m,2H),3.50-3.30(m,4H),3.18-3.05(m,1H),1.94-1.83( m,2H),1.77-1.65(m,6H),1.64-1.55(m,1H),1.53-1.38(m,4H),1.20-0.91(m,4H).

[0193] Methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate. To a solution of trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (7.00 g, 27.2 mmol, 1 equiv) and methyl 2-bromo-2-methyl-propanoate (12.5 mL, 108.79 mmol, 4 equiv) in acetonitrile (10 mL) was added potassium iodide (0.451 g, 2.72 mmol, 0.1 equiv) and potassium carbonate (7.518 g, 54.4 mmol, 2 equiv). The reaction vessel was sealed and heated to 110° C. with stirring. After 12 h, the reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (10-80% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (8.00 g, 22.4 mmol, 82% yield) as a pale yellow oil. MS(ESI) m / z 358.4 [M+1] + .

[0194] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.0 g, 14.0 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (6.4 g, 28.0 mmol, 2 equiv.) in ethyl acetate (50 mL) was added N,N-diisopropylethylamine (4.6 mL, 28.0 mmol, 2 equiv.) and the reaction was stirred at 90° C. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (10-50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol, 84% yield) as a brown oil. MS(ESI) m / z 554.4 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),4.60-4.58(m ,1H),3.84-3.82(m,2H),3.71-3.61(m,1H),3.60-3.52(m,2H),3.50-3.49(m, 2H),3.47-3.32(m,1H),2.22-2.20(m,2H),2.19(d,J=12.0Hz,2H),1.88-1.87 (m,6H),1.85-1.84(m,2H),1.60(s,6H),1.56-1.55(m,2H),1.54-1.35(m,2H).

[0195] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol) in methanol (50 mL) was added 1 M aqueous hydrochloric acid (5.0 mL, 5 mmol), and the reaction was stirred at room temperature. After 2 h, the reaction was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 91% yield) as a brown oil. MS(ESI) m / z 470.2 [M+1] + .

[0196] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 1 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 4 equiv.) at 0° C., and the reaction was allowed to warm gradually to room temperature. After 12 h, the reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 9.4 mmol, 88% yield) as a pale yellow oil. MS (ESI) m / z 534.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),3.71-3.61(m,1H),3.60-3.53(m,2H),3.52(t,J=6.4 Hz,2H),3.35-3.32(m,1H),2.21(d,J=12.0Hz,2H),2.19-2.05(m,2H),1.83(d,J=12.0Hz,2H),1.65(s,2H),1.60(s,6H),1.35-1.32(m,2H).

[0197] Methyl 3-((2-nitropyridin-4-yl)amino)propanoate. To a solution of 4-chloro-2-nitropyridine (7.500 g, 47.310 mmol, 1 equiv.) and methyl 3-aminopropanoate hydrochloride (8.580 g, 61.500 mmol, 1.3 equiv.) in dioxane (150 mL) was added cesium carbonate (46.24 g, 141.92 mmol, 3 equiv.) and palladium(II) acetate (1.060 g, 4.730 mmol, 0.1 equiv.), followed by dicyclohexyl[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (4.510 g, 9.460 mmol, 0.2 equiv.), and the reaction solution was stirred at 110 °C. After 12 h, the reaction solution was diluted with ethyl acetate (300 mL), filtered, and concentrated. The crude material was purified by silica gel column chromatography (30-50% ethyl acetate in hexane) to give methyl 3-((2-nitropyridin-4-yl)amino)propanoate (1.900 g, 8.440 mmol, 18% yield) as a brown solid. MS(ESI) m / z 226.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.16(t,J=5.6Hz,1H),7.37(t,J=2.4Hz,1H),6.71(dd,J=5.6,2.4Hz,1H),5.37(s,1H),3.72(s,3H),3.60-3.56(m,2H),2.69-2.66(m,2H).

[0198] Methyl 3-(1-(2-nitropyridin-4-yl)ureido)propanoate. To a solution of methyl 3-((2-nitropyridin-4-yl)amino)propanoate (1.900 g, 8.440 mmol, 1 equiv.) in THF (150 mL), chlorosulfonyl isocyanate (1.430 g, 10.120 mmol, 1.2 equiv.) was added and the reaction solution was stirred at 0 °C. After 1 h, the reaction solution was diluted with water (200 mL), adjusted to pH 6-7 by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (50% ethyl acetate in petroleum ether) to give methyl 3-(1-(2-nitropyridin-4-yl)ureido)propanoate (1.600 g, 5.850 mmol, 69% yield) as a gray solid. MS (ESI) m / z 269.1 [M+Na] + .

[0199] Methyl 3-(1-(2-aminopyridin-4-yl)ureido)propanoate. To a solution of methyl 3-(1-(2-nitropyridin-4-yl)ureido)propanoate (2.400 g, 8.950 mmol, 1 equiv.) in THF (40 mL) was added palladium on activated carbon (0.300 g, 10% purity), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 h, the reaction solution was filtered and concentrated to give methyl 3-(1-(2-aminopyridin-4-yl)ureido)propanoate (2.070 g, 8.690 mmol, 97% yield) as a brown solid, which was carried forward without further purification. MS (ESI) m / z 239.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=5.6Hz,1H),6.38(dd,J=5.6,1.6Hz,1H),6.29(d,J=1.6Hz,1H),6.04 (s,2H),5.93(s,2H),3.79(t,J=6.4Hz,2H),3.53(s,3H),2.48(t,J=6.4Hz,2H).

[0200] 1-(2-aminopyridin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride. A mixture of methyl 3-(1-(2-aminopyridin-4-yl)ureido)propanoate (2.070 g, 8.690 mmol, 1 equiv.) in concentrated aqueous hydrochloric acid (12 M, 20 mL) was stirred at 25 °C under a nitrogen atmosphere for 12 h. The reaction solution was concentrated under reduced pressure to give a residue, which was purified by semi-preparative reverse-phase HPLC (0% to 15% acetonitrile in water with 0.05% hydrogen chloride, 10 min) to give 1-(2-aminopyridin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (1.000 g, 3.830 mmol, 44% yield) as a white solid. MS (ESI) m / z 207.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 13.67(s,1H),10.80(s,1H),8.03(s,2H),7.90(s,1H),6.98(d,J=6.0Hz, 1H),6.93(d,J=6.0Hz,1H),3.91(t,J=6.4Hz,2H),2.73(t,J=6.4Hz,2H).

[0201] (3R,5S)-tert-butyl 4-(2-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. To a flask containing 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetate (581 mg, 2.13 mmol, 1.1 equiv.) and 1-(2-aminopyridin)-4-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (400 mg, 1.94 mmol, 1 equiv.), N,N-dimethylformamide (5 mL), 1-methylimidazole (1.54 g, 19.4 mmol, 10 equiv.), and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (1.08 mg, 3.88 mmol, 2 equiv.) were added. The reaction was stirred at 25° C. for 15 minutes. Additional N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (1.08 mg, 3.88 mmol, 2 equiv.) was added and stirring was continued for 15 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (0 to 100% ethyl acetate in hexanes) to afford tert-butyl (3R,5S)-4-(2-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (286 mg, 0.62 mmol, 32% yield) as an off-white foamy semisolid, which was carried forward without further purification. MS(ESI)m / z 461.2[M+1] + .

[0202] 2-((2R,6S)-2,6-Dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide. To a solution of tert-butyl (3R,5S)-4-(2-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (286 mg, 0.62 mmol, 1 equiv.) in dichloromethane (0.5 mL), 4 M hydrochloric acid in 1,4-dioxane (1.55 mL, 6.2 mmol, 10 equiv.) was added, and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated to give 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (241 mg, 0.61 mmol, 98% yield) as a yellow solid, which was carried forward without further purification. MS(ESI) m / z 361.3 [M+1] + .

[0203] 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride. To a mixture of 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (147 mg, 0.28 mmol, 1.2 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (100 mg, 0.23 mmol, 1 equiv.) in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (60 mg, 0.46 mmol, 2 equiv.) was added, and the reaction solution was stirred at 50° C. After 16 h, the reaction solution was diluted with DMSO and purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (59.08 mg, 0.07 mmol, 31% yield) as a yellow solid. MS(ESI) m / z 812.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.43-11.00(m,1H),10.71(br s,1H),8.42-8.31(m,2H),8.27-8.17(m,2H),7.98(dd,J=1.6,8.4Hz,1H),7.48-7.48(m,1H),7.33(br d,J=4.0Hz,1H),4.05-3.74(m,5H),3.67-3.44(m,4H),3.38-3.01(m,5H),2.97-2.71(m,4H ),2.56-2.52(m,2H),2.14-1.91(m,4H),1.80-1.67(m,2H),1.56(s,6H),1.42-1.14(m,8H).

[0204] Examples 8 and 9: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-((S)-3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide Hydrochloride and 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] Ethyl 2-(2-bromopyridin-4-yl)-2-cyanopropanoate. To a mixture of 2-bromo-4-fluoropyridine (7.000 g, 39.77 mmol, 1 equiv.) and ethyl 2-cyanopropanoate (6.068 g, 47.73 mmol, 1.2 equiv.) in acetonitrile (20 mL), cesium carbonate (14.256 g, 43.75 mmol, 1.1 equiv.) was added and stirred at 50 °C. After 12 h, the reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (9-20% ethyl acetate in petroleum ether) to give ethyl 2-(2-bromopyridin-4-yl)-2-cyanopropanoate (5.000 g, 23.69 mmol, 60% yield) as a colorless oil. MS (ESI) m / z 283.0 [M+1] + .

[0205] 2-(2-Bromopyridin-4-yl)propanenitrile. To a mixture of ethyl 2-(2-bromopyridin-4-yl)-2-cyanopropanoate (5.000 g, 17.66 mmol, 1 equiv.) in DMSO (20 mL), lithium chloride (0.823 g, 19.43 mmol, 1.1 equiv.) and water (0.100 mL) were added, and the reaction solution was stirred at 140 °C. After 12 h, the reaction solution was diluted with water (40 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic layers were concentrated. The resulting crude material was purified by silica gel column chromatography (0–30% ethyl acetate in petroleum ether) to give 2-(2-bromopyridin-4-yl)propanenitrile (3.600 g, 17.06 mmol, 96% yield) as a colorless oil. MS (ESI) m / z 211.0 [M+1] + .

[0206] Methyl 4-(2-bromopyridin-4-yl)-4-cyanopentanoate. To a solution of 2-(2-bromopyridin-4-yl)propanenitrile (3.600 g, 17.06 mmol, 1 equiv.) and methyl acrylate (4.405 g, 51.17 mmol, 3 equiv.) in toluene (20 mL), benzyl(triethyl)ammonium hydroxide (7.14 g, 3.41 mmol, 0.2 equiv.) and potassium carbonate (4.714 g, 34.11 mmol, 2 equiv.) were added, and the reaction solution was stirred at 65 °C. After 4 h, the reaction solution was filtered and purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to give methyl 4-(2-bromopyridin-4-yl)-4-cyanopentanoate (3.000 g, 10.10 mmol, 59% yield). MS(ESI)m / z 297.1[M+1] + .

[0207] Methyl 4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyanopentanoate. To a mixture of methyl 4-(2-bromo-4-pyridyl)-4-cyanopentanoate (3.000 g, 10.10 mmol, 1 equiv.) and tert-butyl carbamate (3.548 g, 30.29 mmol, 3 equiv.) in 1,4-dioxane (20 mL) was added potassium carbonate (2.093 g, 15.14 mmol, 1.5 equiv.) and BrettPhos Pd G3 (0.915 g, 1.01 mmol, 10 mol%). The reaction was stirred under nitrogen at 90° C. for 12 h. The reaction solution was filtered and purified by silica gel column chromatography (15-30% ethyl acetate in petroleum ether) to obtain crude methyl 4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyanopentanoate (4.000 g, 12.00 mmol) as a pale yellow semi-solid. MS(ESI) m / z 278.1 [M-55] + .

[0208] 5-Amino-4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-methyl-5-oxopentanoic acid. To a mixture of methyl 4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyanopentanoate (4.000 g, 12.00 mmol, 1 equiv.) in DMSO (20 mL), potassium carbonate (4.975 g, 35.99 mmol, 3 equiv.) and 30% hydrogen peroxide (6.801 g, 59.99 mmol, 5 equiv.) were added and the reaction solution was stirred at 40° C. After 12 hours, the reaction solution was filtered and concentrated to give crude 5-amino-4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-methyl-5-oxopentanoic acid (2.000 g, 5.93 mmol, 49.4% yield, crude) as a yellow solid. MS (ESI) m / z 282.2 [M-55] + .

[0209] tert-Butyl (4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate. To a mixture of 5-amino-4-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-methyl-5-oxopentanoic acid (0.400 g, 1.19 mmol, 1 equiv.) and 4-dimethylaminopyridine (0.029 g, 0.24 mmol, 2 equiv.) in DMF (4 mL), carbonyldiimidazole (0.384 g, 2.37 mmol, 2 equiv.) was added and the reaction solution was stirred at 40° C. After 12 h, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were concentrated and purified by silica gel column chromatography (5% methanol in dichloromethane) to give tert-butyl (4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate (0.150 g, 0.47 mmol, 40% yield) as a yellow solid. MS (ESI) m / z 264.2 [M-55] + .

[0210] 3-(2-aminopyridin-4-yl)-3-methylpiperidine-2,6-dione. To a mixture of tert-butyl (4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)carbamate (0.150 g, 0.47 mmol, 1 eq.) in dichloromethane (5 mL), 4 M hydrochloric acid in 1,4-dioxane (1.17 mL, 4.7 mmol, 10 eq.) was added, and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to give 3-(2-aminopyridin-4-yl)-3-methylpiperidine-2,6-dione (0.150 g, crude), which was carried forward without further purification. MS (ESI) m / z 219.9 [M+1] + .

[0211] tert-Butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate. To 3-(2-aminopyridin-4-yl)-3-methylpiperidine-2,6-dione (0.150 g, 0.68 mmol, 1 equiv.) and 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.223 g, 0.82 mmol, 1.2 mL) in pyridine (4 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine (0.393 g, 2.05 mmol, 3 equiv.), and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were concentrated and purified by preparative TLC (5% methanol in dichloromethane) to give tert-butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (0.080 g, 0.17 mmol, 25% yield). MS (ESI) m / z 474.3 [M+1] + .

[0212] Enantiomers 1 and 2 of tert-butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate. Racemic tert-butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (480 mg, 0.98 mmol) was purified by chiral SFC (column: Diacel Chiralpak IG; mobile phase: 40% Separation with 0.1% ethanol gave tert-butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate Enantiomer 1 (0.075 g, 0.16 mmol, 99.7% ee) and Enantiomer 2 (0.082 g, 0.17 mmol, 97.3% ee). The absolute configurations of Enantiomers 1 and 2 were not determined, so each enantiomer was carried forward separately to the following step.

[0213] Enantiomer 1 of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. To a mixture of enantiomer 1 of tert-butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (0.075 g, 0.16 mmol, 1 equiv.) in dichloromethane (4 mL), 33% hydrogen bromide in acetic acid (0.388 g, 1.58 mmol, 10 equiv.) was added, and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated to give crude enantiomer 1 of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.086 g, crude) as a pale yellow solid, which was carried forward without further purification. MS(ESI) m / z 474.3 [M+1] + .

[0214] Enantiomer 1 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a mixture of enantiomer 1 of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.086 g, 0.23 mmol, 1 equiv.) and 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.131 g, 0.25 mmol, 1.1 equiv.) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.149 g, 1.15 mmol, 5 equiv.) was added, and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was filtered and purified by standard methods to give enantiomer 1 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.054 g, 0.066 mmol, 29% yield) as a yellow solid. MS(ESI) m / z 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.17-11.08(m,1H),11.06(s,1H),8.39(d,J=5.6Hz,1H),8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),8.05(br s,1H),7.97(dd,J=1.6,8.4Hz,1H),7.25(dd,J=1.6,5.4Hz,1H),5.07-4.88(m,2H),4.28-3.95(m,3H),3.86(br d,J=4.4Hz,3H),3.73-3.57(m,2H),3.41-3.21(m,5H),2.91-2.76(m,2H),2.56-2.51(m,1H),2.40-2.29(m,1H) ,2.20-2.08(m,4H),1.77-1.66(m,2H),1.55(s,6H),1.47(s,3H),1.37(d,J=13.6Hz,2H),1.31(d,J=3.2Hz,6H).

[0215] Enantiomer 2 of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. To a mixture of enantiomer 2 of tert-butyl (3R,5S)-3,5-dimethyl-4-(2-((4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)piperazine-1-carboxylate (0.080 g, 0.17 mmol, 1 equiv.) in dichloromethane (4 mL), 33% hydrogen bromide in acetic acid (0.414 g, 1.69 mmol, 10 equiv.) was added, and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated to give crude enantiomer 2 of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.088 g, crude) as a pale yellow solid, which was carried forward without further purification. MS(ESI) m / z 374.3 [M+1] + .

[0216] Enantiomer 2 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a mixture of enantiomer 2 of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.080 g, 0.21 mmol, 1 equiv.) and 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.122 g, 0.24 mmol, 1.1 equiv.) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.138 g, 1.07 mmol, 5 equiv.) was added, and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was filtered and purified by standard methods to give enantiomer 2 of 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(3-methyl-2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.052 g, 0.063 mmol, 30% yield) as a yellow solid. MS(ESI) m / z 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),11.01-10.86(m,1H),8.38(d,J=5.6Hz,1H),8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),8.05(br s,1H),7.97(dd,J=1.6,8.4Hz,1H),7.24(dd,J=1.6,5.6Hz,1H),5.28-4.99(m,2H),4.24-3.93(m,2H),3.85(br s,3H),3.71-3.54(m,2H),3.43-3.13(m,5H),2.91-2.78(m,2H),2.55-2.51(m,1H),2.39-2.31(m,1H), 2.20-2.08(m,4H),1.77-1.67(m,2H),1.55(s,6H),1.47(s,3H),1.43-1.33(m,2H),1.33-1.20(m,6H).

[0217] Example 10: 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.148 g, 0.280 mmol, 1 equiv.) in N,N-dimethylformamide (2 mL), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (100 mg, 0.280 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.240 mL, 1.390 mmol, 5 equiv.) were added, and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.102 g, 0.126 mmol, 45% yield) as a yellow solid. MS (ESI) m / z 811.3 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ 10.92(s,1H),8.34(d,J=8.0Hz,1H),8.27(d,J=1.2Hz,1H),8.20(d,J=1.6Hz,1H),8.05(d,J=7.2Hz,1H ),7.98-7.96(dd,J=8.4Hz,1H),7.80(d,J=8.4Hz,1H),3.98-3.94(m,1H),3.88-3.82(m,2H),3.67-3.6 2(m,2H),3.53-3.50(t,J=5.6Hz,2H),3.29-3.89(m,6H),2.88-2.74(m,2H),2.73-2.67(m,2H),2.58-2 .51(m,1H),2.33-2.22(m,2H),2.09-1.96(m,6H),1.73(d,J=10Hz,2H),1.56(s,6H),1.34-1.27(m,8H).

[0218] Example 11: 4-(3-(trans-4-(2-((3R,5S)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] Benzyl (3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 3,5-dimethylpiperazine-1-carboxylate (20.00 g, 80.54 mmol, 1 equiv.) in acetonitrile (200 mL), 2-bromoethanol (30.19 g, 241.62 mmol, 31 equiv.), sodium iodide (12.07 g, 80.54 mmol, 1 equiv.), and potassium carbonate (20.82 g, 161.08 mmol, 2 equiv.) were added, and the reaction solution was stirred at 100 °C. After 12 h, the reaction solution was filtered and concentrated. The crude material was purified by semi-preparative reverse-phase HPLC (22–52% acetonitrile + 0.05% aqueous ammonium hydroxide, 20 min). The collected fractions were concentrated to remove most of the acetonitrile, and the residue was extracted with ethyl acetate (50 mL x 8). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give benzyl (3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (12.70 g, 43.44 mmol, 54% yield) as a yellow oil. MS (ESI) m / z 293.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.43-7.31(m,5H),5.16(s,2H),4.00-3.82(m,2H),3.60(t,J=6.0Hz,2H),2.79(t,J=6.4Hz,2H),2.76-2.57(m,4H),1.12(d,J=5.6Hz,6H).

[0219] Benzyl (3S,5R)-3,5-dimethyl-4-(2-((5-nitropyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (5.000 g, 17.10 mmol, 1 equiv.) in tetrahydrofuran (20 mL), sodium hydride (1.230 g, 51.30 mmol, 3 equiv.) was added and the reaction solution was stirred at 0 °C. After 1 h, 2-chloro-5-nitropyridine (4.070 g, 25.65 mmol, 1.5 equiv.) in tetrahydrofuran (30 mL) was added and the reaction solution was stirred and allowed to warm slowly to room temperature. After 12 h, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10-30% ethyl acetate in hexanes) to give benzyl (3S,5R)-3,5-dimethyl-4-(2-((5-nitropyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate (5.600 g, 13.51 mmol, 79% yield) as a yellow solid. MS (ESI) m / z 415.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.08(d,J=2.8Hz,1H),8.48(dd,J=2.8,9.2Hz,1H),7.41-7.29(m,5H),7.01(d,J=9.2Hz,1H),5.08(s,2H),4.4 3(t,J=6.4Hz,2H),3.80(d,J=9.6Hz,2H),3.00(t,J=6.4Hz,2H),2.55(d,J=10.8Hz,4H),1.07(d,J=4.4Hz,6H).

[0220] Benzyl (3S,5R)-4-(2-((5-aminopyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 3,5-dimethyl-4-(2-((5-nitropyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate (5.600 g, 13.51 mmol, 1 equiv) in ethanol (60 mL) and water (6 mL) was added iron powder (2.260 g, 40.54 mmol, 3 equiv) and ammonium chloride (2.890 g, 54.05 mmol, 4 equiv), and the mixture was stirred at 80 °C. After 2 h, the reaction solution was filtered, the filter cake was washed with ethanol (100 mL), and the combined organics were concentrated. This material was diluted with water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10-70% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(2-((5-aminopyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.500 g, 6.502 mmol, 48% yield) as a yellow oil. MS (ESI) m / z 385.0 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.48(d,J=2.8Hz,1H),7.41-7.28(m,5H),7.00(dd,J=2.8,8.4Hz,1H),6.50(d,J=8.8Hz,1H),5.08(s,2H),4.73( s,2H),4.13(t,J=6.8Hz,2H),3.80(d,J=10.0Hz,2H),2.91(t,J=6.8Hz,2H),2.55(s,4H),1.05(d,J=3.6Hz,6H).

[0221] Benzyl (3S,5R)-4-(2-((5-((methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 4-(2-((5-aminopyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.500 g, 6.500 mmol, 1 equiv.) in tetrahydrofuran (25 mL), pyridine (5.25 mL, 65.02 mmol, 10 equiv.) and methyl chloroformate (1.01 mL, 13.00 mmol, 2 equiv.) were added at 0° C., and the reaction solution was allowed to warm slowly to room temperature. After 8 h, the reaction solution was diluted with water (60 mL) and washed with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (50-70% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(2-((5-((methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.600 g, 5.876 mmol, 90% yield) as a yellow oil. MS(ESI) m / z 443.4 [M+1] + .

[0222] Benzyl (3S,5R)-4-(2-((5-((2-cyanoethyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 4-(2-((5-((methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.600 g, 5.880 mmol, 1 equiv.) in acetonitrile (26 mL), acrylonitrile (1.160 mL, 17.63 mmol, 3 equiv.), potassium fluoride (0.680 g, 11.75 mmol, 2 equiv.), and aluminum oxide (2.400 g, 23.50 mmol, 4 equiv.) were added, 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 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10–60% ethyl acetate in petroleum ether) to afford benzyl (3S,5R)-4-(2-((5-((2-cyanoethyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.770 g, 5.589 mmol, 95% yield) as a yellow oil. MS (ESI) m / z 496.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=2.8Hz,1H),7.66(dd,J=2.8,8.4Hz,1H),7.43-7.28(m,5H),6.83(d,J=8.8Hz,1H),5.08(s,2H),4.28(t,J=6.8 Hz,2H),3.87-3.78(m,4H),3.60(s,3H),2.97(t,J=6.8Hz,2H),2.75(t,J=6.4Hz,2H),2.56(s,4H),1.08(d,J=4.0Hz,6H).

[0223] Benzyl (3S,5R)-4-(2-((5-((3-amino-3-oxopropyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 4-(2-((5-((2-cyanoethyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.770 g, 5.590 mmol, 1 equiv) in DMSO (30 mL) was added 30% hydrogen peroxide (9.580 g, 25.3 mmol) and potassium carbonate (2.340 g, 18.07 mmol) at 0° C. The reaction solution was allowed to warm slowly to room temperature over 2 hours. The reaction solution was diluted with saturated aqueous sodium sulfite (40 mL) to quench excess peroxide. The aqueous solution was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give benzyl (3S,5R)-4-(2-((5-((3-amino-3-oxopropyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.545 g, 4.955 mmol, 88.6% yield) as a yellow oil, which was carried forward without further purification. MS (ESI) m / z 514.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.18(s,1H),7.75(d,J=8.0Hz,1H),7.49-7.27(m,5H),6.76(d,J=8.8Hz,1H),5.08(s,2H),4.17(t,J=6.4Hz,2H),3.78(d,J=11 .6Hz,2H),3.66(s,3H),2.83-2.77(m,2H),2.57(d,J=1.6Hz,2H),2.50-2.40(m,4H),1.77-1.69(m,2H),1.00(d,J=5.6Hz,6H).

[0224] Benzyl (3S,5R)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of (3S,5R)-benzyl 4-(2-((5-((3-amino-3-oxopropyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.550 g, 4.960 mmol, 1 equiv.) in tetrahydrofuran (25 mL) was added potassium tert-butoxide (0.550 g, 4.960 mmol, 1 equiv.) at 0° C. After stirring at 0° C. for 1 hour, the reaction was diluted with 1 M aqueous hydrogen chloride solution (10 mL), and then the solution was adjusted to pH 7 by adding saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0–2% methanol in dichloromethane) to afford benzyl (3S,5R)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.750 g, 3.532 mmol, 71% yield) as a yellow oil. MS (ESI) m / z 482.0 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.42(s,1H),8.12(d,J=2.4Hz,1H),7.70(dd,J=2.8,8.8Hz,1H),7.40-7.29(m,5H),6.82(d,J=8.8Hz,1H),5.08(s,2H),4.28(t,J=6.4Hz ,2H),3.81(d,J=9.6Hz,2H),3.76(t,J=6.4Hz,2H),2.97(t,J=6.8Hz,2H),2.72(t,J=6.4Hz,2H),2.62-2.53(m,4H),1.08(d,J=4.0Hz,6H).

[0225] 1-(6-(2-((2S,6R)-2,6-dimethylpiperazin-1-yl)ethoxy)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. To a mixture of (3S,5R)-benzyl 4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.750 g, 3.630 mmol, 1 equiv.) in methanol (40 mL) was added 10% palladium on carbon (0.300 g, 2.820 mmol), and the reaction solution was stirred under an atmosphere of hydrogen gas (15 psi). After 8 hours at room temperature, the reaction solution was filtered, the solid washed with methanol, and the combined organics concentrated to give 1-(6-(2-((2S,6R)-2,6-dimethylpiperazin-1-yl)ethoxy)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.506 g, 1.404 mmol, 37% yield) as a yellow solid. MS (ESI) m / z 348.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.68-10.13(m,1H),8.12(d,J=2.8Hz,1H),7.69(dd,J=2.8,8.8Hz,1H),6.81(d,J=8.8Hz,1H),4.27(t,J=7.2Hz,2H),3.76(t,J =6.8Hz,2H),3.18(s,2H),2.91(t,J=6.87Hz,2H),2.81-2.72(m,2H),2.70(s,2H),1.04(d,J=6.0Hz,2H),1.00(d,J=6.0Hz,4H).

[0226] 4-(3-(trans-4-(2-((3R,5S)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol, 1 equiv.), 1-(6-(2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethoxy)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione dihydrochloride (164 mg, 0.35 mmol, 1.2 equiv.), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 equiv.), sodium iodide (52 mg, 0.35 mmol, 1.2 equiv.), and N,N-dimethylformamide (2.0 mL, 0.15 M) were added. The reaction was stirred at 50° C. After 15 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (96 mg, 0.109 mmol, 38% yield) as an off-white solid. MS (ESI) m / z 785.5 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.55(s,1H),8.34(d,J=8.19Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.65,8.25Hz,1H),7.22(br d,J=7.70Hz,1H),7.02(q,J=7.30Hz,2H),4.20(s,3H),3.92-4.03(m,4H),3.74 -3.91(m,9H),3.21-3.44(m,4H),2.80-2.91(m,2H),2.73-2.79(m,2H),2.10(br d,J=11.13Hz,2H),1.72(br d,J=10.64Hz,2H),1.55(s,7H),1.23-1.51(m,8H).

[0227] Example 12: 4-(3-(trans-4-(2-((3R,5S)-4-(3-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] Benzyl (3S,5R)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (4.000 g, 16.110 mmol, 1 equiv.) and 3-bromopropan-1-ol (3.360 g, 24.160 mmol, 2.18 mL, 1.5 equiv.) in N,N-dimethylformamide (50 mL) was added sodium iodide (2.410 g, 16.110 mmol, 1 equiv.) and N,N-diisopropylethylamine (6.250 g, 48.320 mmol, 8.42 mL, 3 equiv.) in one portion at 25 °C. The mixture was heated to 70 °C and stirred for 12 h. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (25% to 45% acetonitrile in water with 0.05% ammonia hydroxide, 15 min) to give benzyl (3S,5R)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate (3.400 g, 11.100 mmol, 69% yield) as a pale yellow oil. MS (ESI) m / z 307.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.29-7.41(m,5H),5.13(s,2H),3.81-4.03(m,2H),3.76(t,J=5.4Hz,2H),3.60-3.74(m,1H),2.85(t, J=6.8Hz,2H),2.60-2.78(m,2H),2.40-2.55(m,2H),1.70(quin,J=6.0Hz,2H),1.17(d,J=6.0Hz,6H).

[0228] Benzyl (3S,5R)-3,5-dimethyl-4-(3-((5-nitropyridin-2-yl)oxy)propyl)piperazine-1-carboxylate. To a mixture of benzyl (3S,5R)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate (3.000 g, 9.790 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added sodium hydride (0.700 g, 29.37 mmol, 3 equiv.), and the mixture was stirred at 0° C. for 1 hour. Then, 2-chloro-5-nitropyridine (2.330 g, 14.69 mmol, 1.5 equiv.) in tetrahydrofuran (30 mL) was added, and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10-40% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-3,5-dimethyl-4-(3-((5-nitropyridin-2-yl)oxy)propyl)piperazine-1-carboxylate (1.500 g, 3.501 mmol, 36% yield) as a yellow oil. MS(ESI) m / z 429.0 [M+1] + .

[0229] Benzyl (3S,5R)-4-(3-((5-aminopyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3S,5R)-3,5-dimethyl-4-(3-((5-nitropyridin-2-yl)oxy)propyl)piperazine-1-carboxylate (3.100 g, 7.230 mmol, 1 equiv.) in ethanol (30 mL) and water (3 mL), iron powder (1.210 g, 21.70 mmol, 3 equiv.) and ammonium chloride (1.550 g, 28.94 mmol, 4 equiv.) were added and the reaction solution was stirred at 80° C. After 12 h, the reaction solution was filtered, and the filter cake was washed with ethanol (1000 mL) and concentrated. The resulting material was diluted with water (80 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (20-60% ethyl acetate in petroleum ether) to afford benzyl (3S,5R)-4-(3-((5-aminopyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (3.500 g, 8.353 mmol, 98% yield) as a yellow solid. MS (ESI) m / z 399.4 [M+1] + .

[0230] Benzyl (3S,5R)-4-(3-((5-((methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3S,5R)-4-(3-((5-aminopyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (3.500 g, 8.780 mmol, 1 equiv.) in tetrahydrofuran (25 mL) was added pyridine (7.09 mL, 87.83 mmol, 10 equiv.) and methyl chloroformate (1.36 mL, 17.57 mmol, 2 equiv.) at 0° C. After stirring for 8 hours, the reaction solution was diluted with water (60 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (50-70% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(3-((5-((methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (2.030 g, 4.447 mmol, 51% yield) as a red oil. MS(ESI) m / z 457.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.04(d,J=2.8Hz,1H),7.61(dd,J=2.8,8.8Hz,1H),7.38-7.32(m,5H),6.86-6.69(m,2H),5.08(s,2H),4.27(t,J=6.8Hz,2 H),3.83-3.73(m,4H),3.57(s,3H),2.97(t,J=6.8Hz,2H),2.58-2.55(m,2H),2.29(t,J=7.2Hz,2H),1.08(d,J=4.4Hz,6H).

[0231] Benzyl (3S,5R)-4-(3-((5-((2-cyanoethyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3S,5R)-4-(3-((5-((methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (2.030 g, 4.450 mmol, 1 equiv.) in acetonitrile (20 mL), acrylonitrile (0.88 mL, 13.34 mmol, 3 equiv.), potassium fluoride (0.517 g, 8.890 mmol, 2 equiv.), and aluminum oxide (1.810 g, 17.79 mmol, 4 equiv.) were added, 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 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10–60% ethyl acetate in petroleum ether) to afford benzyl (3S,5R)-4-(3-((5-((2-cyanoethyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.600 g, 3.140 mmol, 71% yield) as a yellow oil. MS (ESI) m / z 510.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.10(d,J=2.4Hz,1H),7.65(dd,J=2.8,8.8Hz,1H),7.47-7.27(m,5H),6.8 3(d,J=8.8Hz,1H),5.08(s,2H),4.24(t,J=6.0Hz,2H),3.84(t,J=6.4Hz,2H ),3.79(d,J=11.2Hz,2H),3.60(s,3H),2.84-2.78(m,2H),2.74(t,J=6.4H z,2H),2.53(s,2H),2.47(m,2H),1.81-1.72(m,2H),1.01(d,J=5.6Hz,6H).

[0232] Benzyl (3S,5R)-4-(3-((5-((3-amino-3-oxopropyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3S,5R)-4-(3-((5-((2-cyanoethyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.600 g, 3.140 mmol, 1 equiv) in DMSO (15 mL) was added 30% hydrogen peroxide (5.380 g, 47.45 mmol) and potassium carbonate (1.310 g, 10.15 mmol) at 0° C., and the reaction solution was stirred at room temperature. After 2 hours, saturated sodium sulfite was added to quench excess peroxide, and the reaction solution was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0–2% methanol in dichloromethane) to give benzyl (3S,5R)-4-(3-((5-((3-amino-3-oxopropyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (0.700 g, 1.327 mmol, 42% yield) as a yellow oil. MS (ESI) m / z 528.4 [M+1] + .

[0233] Benzyl (3S,5R)-4-(3-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3S,5R)-4-(3-((5-((3-amino-3-oxopropyl)(methoxycarbonyl)amino)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (0.700 g, 1.330 mmol, 1 equiv.) in tetrahydrofuran (7 mL) was added potassium tert-butoxide (0.148 g, 1.330 mmol, 1 equiv.) and the reaction solution was stirred at 0° C. After 1 h, 1 M aqueous hydrochloric acid (18 mL) was added, followed by saturated sodium carbonate to adjust the solution to pH 7. The aqueous solution was extracted with ethyl acetate (3×30 mL), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give benzyl (3S,5R)-4-(3-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (0.600 g, 1.185 mmol, 89% yield) as a yellow oil. MS (ESI) m / z 496.5 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.50-10.34(m,1H),8.12(d,J=2.4Hz,1H),7.69(dd,J=2.8,8.8Hz,1H),7.44- 7.27(m,5H),6.83(d,J=8.8Hz,1H),5.08(s,2H),4.24(t,J=6.0Hz,2H),4.10(d, J=4.8Hz,2H),3.83-3.77(m,2H),3.77-3.72(m,2H),2.84-2.78(m,2H),2.72(t ,J=6.4Hz,2H),2.47(m,2H),1.81-1.72(t,J=6.4Hz,2H),1.01(d,J=5.6Hz,6H).

[0234] 1-(6-(3-((2S,6R)-2,6-dimethylpiperazin-1-yl)propoxy)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. To a mixture of benzyl (3S,5R)-4-(3-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (0.600 g, 1.210 mmol) in methanol (15 mL) was added 10% palladium on carbon (0.129 g, 1.210 mmol), and the reaction solution was stirred at room temperature under a hydrogen atmosphere. After 12 hours, the reaction solution was filtered, the filter cake washed with methanol (2 x 10 mL), and the combined organic solutions concentrated to give crude 1-(6-(3-((2S,6R)-2,6-dimethylpiperazin-1-yl)propoxy)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.611 g) as a yellow solid, which was carried forward without further purification. MS (ESI) m / z 362.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 10.57-10.25(m,1H),8.12(d,J=2.4Hz,1H),7.69(dd,J=2.8,8.8Hz,1H),6.8 3(d,J=8.4Hz,1H),4.23(t,J=6.0Hz,2H),3.75(t,J=6.8Hz,2H),3.28-3.08( m,2H),2.79-2.75(m,2H),2.74-2.66(m,4H),2.46-2.28(m,1H),1.82-1.74( m,2H),1.64(t,J=10.4Hz,1H),0.97(d,J=6.4Hz,4H),0.93(d,J=6.0Hz,2H).

[0235] 4-(3-(trans-4-(2-((3R,5S)-4-(3-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol, 1 equiv.), 1-(6-(3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propoxy)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (125 mg, 0.35 mmol, 1.2 equiv.), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 equiv.), sodium iodide (52 mg, 0.35 mmol, 1.2 equiv.), and N,N-dimethylformamide (2.0 mL, 1.5 M) were added. The reaction was stirred at 50° C. After 15 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(3-((5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (65 mg, 0.077 mmol, 27% yield) as an off-white solid. MS(ESI) m / z 799.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.43(s,1H),8.34(d,J=8.31Hz,1H),8.20(d,J=1.59Hz,1H),8.15(d,J=2.69Hz,1H),7.9 7(dd,J=1.77,8.25Hz,1H),7.73(dd,J=2.81,8.80Hz,1H),6.90(d,J=8.80Hz,1H),4.38(br t,J=5.75Hz,2H),3.91-4.16(m,3H),3.84(br s,3H),3.76(br t,J=6.72Hz,3H),3.22-3.51(m,7H),2.77-2.93(m,2H),2.68-2.76(m,2H) ),2.00-2.23(m,4H),1.65-1.79(m,2H),1.55(s,6H),1.28-1.47(m,8H).

[0236] Example 13: 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.100 g, 0.278 mmol, 1 equiv.) and 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.178 g, 0.330 mmol, 1.2 equiv.) in N,N-dimethylformamide (2 mL, 0.14 M) was added N,N-diisopropylethylamine (0.24 mL, 1.390 mmol, 5 equiv.). The reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with DMSO and purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (93.91 mg, 0.116 mmol, 42% yield) as a yellow solid. MS(ESI) m / z 811.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.96(s,1H),11.21(s,1H),10.97(s,1H),8.42-8.28(m,2H),8.19(d,J=1.6Hz,1H),8.09- 7.91(m,2H),7.19(d,J=4.8Hz,1H),4.50-3.53(m,8H),3.51(t,J=5.6Hz,2H),3.33-3.19(m, 3H),3.13-3.02(m,2H),2.87-2.65(m,3H),2.58-2.51(m,1H),2.28-2.15(m,1H),2.07(dd, J=8.4,3.2Hz,3H),2.00(d,J=6.0Hz,2H),1.72(d,J=10.4Hz,2H),1.55(s,6H),1.31(s,8H).

[0237] Example 14: 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride [ka] tert-Butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate. To a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (2.000 g, 7.770 mmol, 1 equiv.) and N,O-dimethylhydroxylamine hydrochloride (0.830 g, 8.550 mmol, 1.1 equiv.) in N,N-dimethylformamide (20 mL, 0.38 M), N,N-diisopropylethylamine (6.94 mL, 38.86 mmol) and HATU (4.430 g, 11.66 mmol, 5 equiv.) were added, and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0–30% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.200 g, 7.323 mmol, 94% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.41(s,1H),3.66(s,3H),3.37(s,1H),3.17(s,3H),2.31-2.29(d,J=6.4Hz ,2H),2.04-1.97(m,2H),1.85-1.79(m,3H),1.43(s,9H),1.18-1.02(m,4H).

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

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

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

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

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

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

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

[0245] 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.090 g, 0.170 mmol, 1 equiv.) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.073 g, 0.200 mmol, 1.2 equiv.) in N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (0.15 mL, 0.8500 mmol, 5 equiv.) was added and the reaction solution was stirred at 50° C. After 13 hours, the reaction solution was concentrated and purified by standard methods to give 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (42.1 mg, 0.051 mmol, 30% yield) as a yellow solid. MS(ESI) m / z 809.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 12.02(s,1H),11.22(s,1H),10.96(s,1H),8.41-8.30(m,2H),8.19(d,J=1.6Hz,1H),8.07-7. 94(m,2H),7.19(d,J=4.8Hz,1H),4.31-3.79(m,6H),3.67(d,J=8.8Hz,2H),3.28(s,2H),3.04( s,2H),2.76-2.65(m,3H),2.55(d,J=4.0Hz,1H),2.28-2.15(m,1H),2.11-2.00(m,1H),1.81(d ,J=11.6Hz,2H),1.77-1.69(m,4H),1.54(s,6H),1.32(s,8H),1.22(s,3H),1.14-1.00(m,2H).

[0246] Example 15: 4-(3-(trans-4-(2-((3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] (3R,5S)-tert-butyl 4-(2-acetoxyethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (3.0 g, 14.0 mmol) in N,N-dimethylformamide (25 mL) was added sodium iodide (2.11 g, 14.0 mmol), N,N-diisopropylethylamine (7.31 mL, 42.0 mmol), and N,N-dimethylformamide (25 mL). The reaction mixture was heated at 60 °C for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Volatile organics were removed under reduced pressure to give a dark brown oil. The oil was dissolved in ethyl acetate and purified by silica gel column chromatography using 0-100% ethyl acetate in hexanes over 20 CV. Fractions containing the desired product (detectable at 200 nm) were combined and the volatile organics were removed under reduced pressure to give tert-butyl (3R,5S)-4-(2-acetoxyethyl)-3,5-dimethylpiperazine-1-carboxylate (1.45 g, 4.83 mmol, 34.5% yield) as a pale yellow solid. MS(ESI) m / z 301.2 [M+1] + .

[0247] tert-Butyl (3R,5S)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(2-acetoxyethyl)-3,5-dimethylpiperazine-1-carboxylate (1.45 g, 4.83 mmol) in methanol (20 mL) was added potassium carbonate (0.68 g, 4.83 mmol). The reaction mixture was stirred at 25° C. for 1 hour. The reaction was filtered. The filtrate was collected and the volatile organics were removed under reduced pressure to give a pale yellow oil. The oil was partitioned between ethyl acetate and water. The organic layer was removed and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Removal of the volatile organics under reduced pressure gave tert-butyl (3R,5S)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (1.18 g, 4.57 mmol, 94.6% yield) as a colorless oil. MS(ESI) m / z 259.2 [M+1] + .

[0248] tert-Butyl (3R,5S)-4-(2-((4-bromopyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (1.18 g, 4.57 mmol) in tetrahydrofuran (20 mL) at 0° C. was added sodium hydride (548 mg, 13.7 mmol). The reaction was stirred for 1 hour, and then a solution of 4-bromo-2-fluoropyridine (1.60 g, 9.13 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The volatile organics were removed under reduced pressure to give a light brown oil. The oil was dissolved in ethyl acetate and purified by silica gel column chromatography using over 2000 mL of 0-100% ethyl acetate in hexanes. Fractions containing the desired product were combined and the volatile organics were removed under reduced pressure to give tert-butyl (3R,5S)-4-(2-((4-bromopyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (873 mg, 2.11 mmol, 46.1% yield) as a light brown foamy semi-solid. MS (ESI) m / z 416.2 [M+1] + .

[0249] (3R,5S)-tert-butyl 4-(2-((2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(2-((4-bromopyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (873 mg, 2.11 mmol) in 1,4-dioxane (8.0 mL) and water (0.80 mL) was added potassium carbonate (886 mg, 6.32 mmol), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (776 mg, 2.32 mmol), and dichloro1,1'-bis(diphenylphosphino)ferrocenepalladium(II) (172 mg, 0.21 mmol). The reaction vial was purged with nitrogen, sealed, and heated at 90°C for 1 hour. The reaction mixture was filtered through Celite. The filter cake was washed with ethyl acetate. The filtrate was collected, and the volatile organics were removed under reduced pressure to give a dark black residue. This residue was partitioned between ethyl acetate and brine. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The volatile organics were removed under reduced pressure to give a dark black solid. This solid was dissolved in ethyl acetate and purified by silica gel column chromatography using 0-100% ethyl acetate in hexanes over 2000 mL. Fractions containing the desired product were combined and the volatile organics removed under reduced pressure to give tert-butyl (3R,5S)-4-(2-((2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.15 g, 1.84 mmol, 87.4% yield) as a brown foamy semi-solid. MS(ESI) m / z 625.4 [M+1] + .

[0250] (3R,5S)-tert-butyl 4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(2-((2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.15 g, 1.84 mmol) in ethanol (20 mL) was added palladium on carbon (150 mg, 1.41 mmol). The reaction flask was evacuated and stirred under hydrogen gas (balloon) for 18 hours. LCMS shows only partial reduction. Additional palladium (150 mg, 1.41 mmol) was added and the reaction was stirred under hydrogen for an additional 24 hours. The reaction mixture was filtered through Celite, and the filter cake was washed with additional ethanol. The filtrate was collected, and the volatile organics were removed under reduced pressure to give a dark brown solid. This solid was dissolved in ethyl acetate and purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (320 mg, 0.717 mmol, 38.9% yield) as a white foamy semi-solid. MS (ESI) m / z 447.2 [M+1] + .

[0251] 3-(2-(2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethoxy)pyridin-4-yl)piperidine-2,6-dione dihydrochloride. To a vial containing tert-butyl (3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (320 mg, 0.72 mmol), hydrochloric acid (2.0 mL, 8 mmol) (4.0 M in dioxane) was added. The reaction mixture was stirred at room temperature for 1 hour. Removal of the volatile organics under reduced pressure gave 3-(2-(2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethoxy)pyridin-4-yl)piperidine-2,6-dione dihydrochloride (428 mg, 1.02 mmol, 142.4% yield) as a pale yellow solid, which was carried forward without further purification. MS(ESI) m / z 347.2 [M+1] + .

[0252] 4-(3-(trans-4-(2-((3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol) was added 3-(2-(2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethoxy)pyridin-4-yl)piperidine-2,6-dione dihydrochloride (145 mg, 0.35 mmol), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol), sodium iodide (52 mg, 0.35 mmol), and N,N-dimethylformamide (2.0 mL). The reaction was stirred at 50° C. for 18 hours. The reaction mixture was dissolved in dimethyl sulfoxide (1.0 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (79 mg, 0.092 mmol, 31.9% yield) as an off-white solid. MS(ESI) m / z 784.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.92(s,1H),8.34(d,J=8.31Hz,1H),8.19(d,J=1.83Hz,1H),8.15(d,J=5.38Hz,1H) ,7.97(dd,J=1.65,8.25Hz,1H),6.97(dd,J=1.28,5.32Hz,1H),6.78(s,1H),4.58(br s,2H),4.09(br s,2H),3.93(dd,J=4.83,12.04Hz,1H),3.84(br s,3H),3.72(br s,4H),3.24-3.46(m,5H),2.84(br d,J=11.49Hz,2H),2.61-2.74(m,1H),2.54(q,J=3.75Hz,1H),2.20-2.32(m,1H) ,2.07-2.17(m,2H),1.96-2.06(m,1H),1.67-1.77(m,2H),1.55(s,6H),1.45(br d,J=5.62Hz,6H),1.29-1.41(m,2H).

[0253] Example 16: 4-(3-(trans-4-(2-((3R,5S)-4-(3-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] tert-Butyl (3R,5S)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (2.0 g, 9.33 mmol) in acetonitrile (20 mL) was added potassium carbonate (2.62 g, 18.67 mmol), sodium iodide (1.41 g, 9.33 mmol), and 3-bromopropan-1-ol (3.89 g, 28 mmol). The reaction mixture was heated at 80° C. for 18 hours. The mixture was filtered through Celite, and the filter cake was washed with additional acetonitrile. The filtrate was collected, and the volatile organics were removed under reduced pressure to give a yellow oil. The oil was partitioned between ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Removal of the volatile organics under reduced pressure gave tert-butyl (3R,5S)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate (2.5 g, 9.18 mmol, 98.3% yield) as a yellow oil, which was carried forward without further purification. MS(ESI) m / z 273.2 [M+1] + .

[0254] tert-Butyl (3R,5S)-4-(3-((4-bromopyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate (2.5 g, 9.18 mmol) in tetrahydrofuran (30 mL) at 0° C. was added sodium hydride (1.10 g, 27.5 mmol). The reaction was stirred for 1 hour, and then a solution of 4-bromo-2-fluoropyridine (3.23 g, 18.4 mmol) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The volatile organics were removed under reduced pressure to give a light brown oil. The oil was dissolved in ethyl acetate and purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give tert-butyl (3R,5S)-4-(3-((4-bromopyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.42 g, 3.32 mmol, 36.1% yield) as a light brown foamy semi-solid. MS(ESI) m / z 430.2 [M+1] + .

[0255] (3R,5S)-tert-butyl 4-(3-((2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(3-((4-bromopyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.42 g, 3.31 mmol) in 1,4-dioxane (12 mL) and water (1.20 mL) was added potassium carbonate (1.39 g, 9.94 mmol), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (1.22 g, 3.65 mmol), and dichloro1,1'-bis(diphenylphosphino)ferrocenepalladium(II) (272 mg, 0.33 mmol). The reaction vial was purged with nitrogen, sealed, and heated at 90 °C for 1 hour. The reaction mixture was filtered through Celite. The filter cake was washed with ethyl acetate. The filtrate was collected, and the volatile organics were removed under reduced pressure to give a dark residue. This residue was partitioned between ethyl acetate and brine. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The volatile organics were removed under reduced pressure to give a dark solid. This solid was dissolved in ethyl acetate and purified by silica gel column chromatography (0 to 100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(3-((2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.81 g, 2.83 mmol, 85.5% yield) as a brown foamy semi-solid. MS(ESI)m / z 639.4[M+1].

[0256] tert-Butyl (3R,5S)-4-(3-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of tert-butyl (3R,5S)-4-(3-((2,6-bis(benzyloxy)-[3,4'-bipyridin]-2'-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.81 g, 2.83 mmol) in ethanol (30 mL) was added palladium on carbon (250 mg, 2.35 mmol). The flask was evacuated and purged with hydrogen gas three times. The reaction mixture was stirred under hydrogen for 18 hours. Additional palladium (200 mg) was added and the reaction was stirred under hydrogen for an additional 24 hours. LCMS showed some desired product, but still mostly incomplete reduction. The reaction mixture was filtered through Celite. The Celite was further washed with ethanol. The filtrate was collected, and the volatile organics were removed under reduced pressure to give a dark brown solid. This solid was dissolved in ethyl acetate and purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(3-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (144 mg, 0.31 mmol, 11.1% yield) as a white foamy semi-solid. MS(ESI) m / z 461.2 [M+1] + .

[0257] 3-(2-(3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propoxy)pyridin-4-yl)piperidine-2,6-dione dihydrochloride. To a vial containing tert-butyl (3R,5S)-4-(3-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (144 mg, 0.31 mmol) was added hydrochloric acid (2.0 mL, 8 mmol) (4.0 M in dioxane). The reaction mixture was stirred at room temperature for 1 hour. The volatile organics were removed under reduced pressure to give 3-(2-(3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propoxy)pyridin-4-yl)piperidine-2,6-dione dihydrochloride (177 mg, crude) as a pale yellow solid, which was carried forward without further purification. MS (ESI) m / z 361.2 [M+1] + .

[0258] 4-(3-(trans-4-(2-((3R,5S)-4-(3-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol) was added 3-(2-(3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propoxy)pyridin-4-yl)piperidine-2,6-dione dihydrochloride (150 mg, 0.35 mmol), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol), and N,N-dimethylformamide (2 mL). The reaction was stirred at 50° C. for 18 hours. The reaction mixture was dissolved in dimethyl sulfoxide (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(3-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (70 mg, 0.081 mmol, 28.1% yield) as an off-white solid. MS(ESI) m / z 798.4 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 10.91(s,1H),8.34(d,J=8.31Hz,1H),8.20(d,J=1.59Hz,1H),8.12(d,J=5.38Hz,1H) ,7.97(dd,J=1.71,8.19Hz,1H),6.91(dd,J=1.16,5.32Hz,1H),6.77(s,1H),4.38(br t,J=5.50Hz,2H),4.02(br s,2H),3.91(dd,J=4.89,12.10Hz,1H),3.80-3.88(m,3H),3.77(br d,J=12.10Hz,2H),3.27-3.53(m,6H),2.84(br d,J=11.98Hz,2H),2.60-2.73(m,1H),2.52-2.56(m,1H),2.19-2.31(m,1 H),1.96-2.17(m,6H),1.67-1.79(m,2H),1.55(s,6H),1.29-1.47(m,8H).

[0259] Example 17: 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide [ka] tert-Butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate. To a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (2.000 g, 7.770 mmol, 1 equiv.) and N,O-dimethylhydroxylamine hydrochloride (0.830 g, 8.550 mmol, 1.1 equiv.) in N,N-dimethylformamide (20 mL, 0.38 M), N,N-diisopropylethylamine (6.94 mL, 38.86 mmol) and HATU (4.430 g, 11.66 mmol, 5 equiv.) were added, and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0–30% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.200 g, 7.323 mmol, 94% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.41(s,1H),3.66(s,3H),3.37(s,1H),3.17(s,3H),2.31-2.29(d,J=6.4Hz ,2H),2.04-1.97(m,2H),1.85-1.79(m,3H),1.43(s,9H),1.18-1.02(m,4H)

[0260] tert-Butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate. To a solution of tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.2 g, 7.320 mmol, 1 equiv.) in dichloromethane (10 mL) was added a solution of 70% bis(2-methoxyethoxy)aluminum hydride (4.08 mL, 14.65 mmol, 2 equiv.) in sodium and toluene at 0 °C. After stirring for 2 h, the reaction solution was diluted with water (20 mL) and saturated aqueous ammonium chloride solution (10 mL). The solution was extracted with dichloromethane (3 × 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was purified by silica gel column chromatography (0–25% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.008 mmol, 82% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 9.65-9.64(t,J=2.0Hz,1H),6.69-6.64(m,1H),3.19-3.13(m,1H),2.55-2.52(m,1H),2 .29-2.27(m,2H),1.75-1.64(m,5H),1.36(s,9H),1.17-1.08(m,2H),1.06-0.83(m,2H).

[0261] Ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate. To a solution of tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.010 mmol, 1 equiv.) in toluene (10 mL, 0.6 M), ethyl 2-(triphenylphosphoranylidene)acetate (2.300 g, 6.610 mmol, 1.1 equiv.) was added, and the reaction mixture was stirred at 80 °C. After 12 h, the reaction solution was concentrated, and the resulting crude material was purified by silica gel column chromatography (0–20% ethyl acetate in hexanes) to give ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.858 mmol, 48% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 6.95-6.88(m,1H),5.82-5.78(m,1H),4.36(s,1H),4.24-4.14(m,2H),3.37(s,1H),2.12-2.08(m,2H),2 .05-1.99(m,2H),1.79-1.76(m,2H),1.46-1.36(m,10H),1.31-1.27(t,J=7.2Hz,3H),1.13-0.99(m,4H).

[0262] tert-Butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate. To a solution of sodium borohydride (0.811 g, 21.43 mmol, 7.5 equiv.) in ethanol (16 mL) and THF (16 mL) was added anhydrous lithium chloride (0.900 g, 21.43 mmol, 7.5 equiv.) at 0° C., and the solution was stirred for 10 minutes. To this reaction solution was added a solution of ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.860 mmol, 1 equiv.) in THF (8 mL), and the reaction solution was stirred at 15° C. After 12 hours, the reaction was quenched by slow addition of 1 M aqueous hydrochloric acid (10 mL), and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0–25% ethyl acetate in hexanes) to give tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.763 mmol, 96% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.37(s,1H),3.66-3.62(t,J=6.8Hz,2H),3.36(s,1H),2.00-1.98(m,2H),1.78-1.75(m,2H ),1.58-1.51(m,2H),1.44(s,9H),1.40-1.32(m,2H),1.28-1.14(m,4H),1.08-0.94(m,4H).

[0263] 4-(trans-4-aminocyclohexyl)butan-1-ol. To a solution of tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.760 mmol, 1 equiv.) in dichloromethane (2 mL) was added 4 M hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol, 5.8 equiv.), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated to remove the organic solvent, then diluted with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.394 mmol, 87% yield) as a white solid, which was carried forward without further purification. 1 H NMR(400MHz,CDCl3)δ 3.62-3.59(t,J=6.4Hz,2H),2.61-2.54(m,1H),1.85-1.81(m,2H),1.75-1.72(m,2H),1.56 -1.49(m,4H),1.39-1.31(m,2H),1.25-1.12(m,3H),1.10-1.00(m,2H),0.97-0.87(m,2H).

[0264] Methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate. To a solution of methyl 2-bromo-2-methylpropanoate (1.733 g, 9.570 mmol, 4 equiv.) and 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.390 mmol, 1 equiv.) in acetonitrile (3 mL), potassium carbonate (0.993 g, 7.180 mmol, 3 equiv.) and sodium iodide (0.072 g, 0.480 mmol, 0.2 equiv.) were added, and the reaction solution was stirred at 80 °C. After 12 h, the reaction solution was diluted with ethyl acetate, filtered, and concentrated to give crude methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, crude) as a brown oil. MS(ESI)m / z272.3[M+1] + .

[0265] 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, 2.320 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.556 g, 2.440 mmol, 1.1 equiv.) in ethyl acetate (12 mL), N,N-diisopropylethylamine (1.15 mL, 6.960 mmol, 3 equiv.) was added and the reaction mixture was stirred at 80° C. After 3 h, the reaction solution was diluted with ethyl acetate (20 mL) and concentrated. The crude oil was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.736 mmol, 32% yield) as a brown solid. MS(ESI) m / z 468.1 [M+1] + .

[0266] 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.770 mmol, 1 equiv.) in dichloromethane (3 mL), N,N-dimethylformamide (0.30 mL) and thionyl bromide (0.400 g, 1.920 mmol, 2.5 equiv.) were added, and the reaction solution was stirred at 15 °C. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.280 g, 0.517 mmol, 67% yield) as a brown solid. MS(ESI) m / z 530.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.96-7.94(d,J=8.4Hz,1H),7.86-7.85(d,J=1.6Hz,1H),7.75-7.72(d,J=8.4,1.6Hz,1H),3.85(s,1H),3.45-3.41(t,J=6.8Hz,2H),2.6 9(s,2H),1.95-1.92(m,2H),1.88-1.83(m,4H),1.61(s,6H),1.50-1.44(m,2H),1.36-1.34(m,1H),1.27-1.25(m,2H),1.11-1.01(m,2H).

[0267] 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride. To a mixture of 4-(3-((trans)-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.156 g, 0.290 mmol) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide (0.100 g, 0.230 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.450 mmol), and the reaction solution was stirred at 50° C. After 8 h, the reaction solution was concentrated and the resulting crude material was purified by standard methods to give 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (0.121 g, 0.148 mmol, 66% yield) as a yellow solid. MS(ESI) m / z: 810.6 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.22-11.08(m,1H),10.70(s,1H),8.38-8.32(m,2H),8.20(d,J=1.6Hz,2H),7.97(dd,J =1.2,8.0Hz,1H),7.33(dd,J=1.6,2.8Hz,1H),3.92(t,J=6.4Hz,3H),3.88-3.76(m,2H), 3.65-3.53(m,2H),3.24-3.07(m,2H),3.06-2.99(m,2H),2.80-2.69(m,4H),1.82(d,J=1 2.0Hz,2H),1.73(m,4H),1.55(s,6H),1.37-1.25(m,6H),1.24(s,6H),1.18-1.00(m,3H).

[0268] Example 18: 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide [ka] 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride. To a mixture of 4-(3-((trans)-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.156 g, 0.290 mmol) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide (0.100 g, 0.230 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.450 mmol), and the reaction solution was stirred at 50° C. After 8 hours, the reaction solution was filtered and concentrated, and the crude material was purified by standard methods to give 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)acetamide hydrochloride (0.121 g, 0.148 mmol, 66% yield) as a yellow solid. MS(ESI) m / z 810.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 12.09-11.43(m,1H),11.22-10.71(m,1H),10.50(s,1H),8.37(d,J=2.4Hz,1H),8.34(d,J=8.0Hz,1H),8. 19(d,J=1.6Hz,1H),8.12-8.01(m,1H),7.97(dd,J=1.6,8.4Hz,1H),7.84(dd,J=2.8,8.8Hz,1H),3.81(br t,J=6.4Hz,4H),3.75-3.60(m,2H),3.33-3.10(m,2H),3.06(br d,J=6.8Hz,2H),2.84-2.67(m,4H),2.55-2.51(m,2H),1.88-1.77(m,2H),1.77-1.64(m,4H),1.55(s,6H),1.31(br s,8H),1.26-1.12(m,4H),1.12-1.00(m,2H).

[0269] Example 19: 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.271 g, 0.750 mmol) in DMF (2 mL) was added 4-(3-((1s,4r)-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.200 g, 0.380 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.330 mL, 1.890 mmol), and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.344 g, 0.039 mmol, 30% yield) as a white solid. MS (ESI) m / z 809.2 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ 10.91(s,1H),10.82-10.04(m,1H),8.34(d,J=8.38Hz,1H),8.27-8.18(m,2H),8.10-8.02 (m,1H),8.00-7.95(m,1H),7.80-7.73(m,1H),3.96(d,J=3.50Hz,1H),3.90-3.77(m,3H), 3.43-3.34(m,2H),3.04(dd,J=8.57,6.94Hz,3H),2.82-2.70(m,4H),2.61-2.59(m,1H),2 .30-2.22(m,1H),2.06-2.00(m,1H),1.87-1.65(m,7H),1.55(s,6H),1.36-1.07(m,14H).

[0270] Example 20: 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] tert-Butyl (trans-4-formylcyclohexyl)carbamate. To a mixture of tert-butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate (240 g, 1.05 mol, 1 equiv.) in acetonitrile (1.60 L) was added IBX (352 g, 1.26 mol, 1.2 equiv.) at 15 °C. The reaction was stirred at 65 °C for 1 h. The two batches were combined for workup and purification. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl (trans-4-formylcyclohexyl)carbamate (470 g, crude) as a white solid. The crude material was used directly in the next step without further purification. 1H NMR(400MHz CDCl3)δ 9.62(s,1H),4.43(s,1H),4.41(s,1H),2.10-2.14(m,3H),2.01-2.05(m,2H),1.45(s,9H),1.38-1.41(m,2H),1.14-1.18(m,2H).

[0271] Ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate. To a mixture of sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2 equiv.) in THF (900 mL) at 0° C. was added ethyl 2-(diethoxyphosphoryl)acetate (255 g, 1.14 mol, 1.1 equiv.) dropwise. The reaction was stirred at 0° C. for 1 hour. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (235 g, 1.03 mol, 1 equiv.) in THF (500 mL) was added dropwise at 0° C. The reaction was stirred at 25° C. for 2 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 phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (560 g, crude) as a pale yellow solid. This material was carried forward without further purification. 1 H NMR(400MHz CDCl3)δ 6.88(dd,J=15.6Hz,6.8Hz 1H),5.75-5.79(m,1H),4.40(s,1H),4.12-4.23(m,3H),3.39(s,1H),2.04-2.08(m,3H), 1.81-1.85(m,2H),1.44(s,9H),1.33-1.35(m,1H),1.26-1.30(m,6H),1.10-1.16(m,3H).

[0272] tert-Butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate. The reaction is set up as two parallel reactions. To a solution of the compound (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl acrylate (280 g, 942 mmol, 1 equiv.) in dichloromethane (1.12 L) at −78° C. under an argon atmosphere was added diisobutylaluminum hydride (1 M, 1.88 L, 2 equiv.). The reaction was stirred at −78° C. for 1 hour. The reaction was quenched with MeOH (280 mL) at −60° C. The two reaction mixtures The combined material was poured into saturated citric acid (1.0 kg citric acid in 4.0 L HO) at <10 °C. The mixture was extracted with ethyl acetate (2.0 L, 1.5 L). The combined organic layer was washed with aqueous sodium bicarbonate (2.0 L), brine (2.0 L), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (420 g, 1.645 mol, 87% yield) as a pale yellow solid. 1 H NMR(400MHz CDCl3)δ 5.58-5.60(m,2H),4.39(s,1H),4.06-4.07(m,2H),3.35(s,1H),1.80-2.00(m,3H),1.74-1.78(m,2H),1.42(s,9H),1.08-1.20(m,4H).

[0273] tert-Butyl ((trans-4-(3-hydroxypropyl)cyclohexyl)carbamate. Four batches of this reaction were carried out in parallel. A mixture of tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (105 g, 411 mmol, 1 equiv.) and palladium on carbon (10.5 g, 10% purity) in MeOH (600 mL) was degassed and purged with H2 three times, then the mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The four batches were combined for workup and purification. The reaction solution was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to give 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) as white solids. 1 H NMR(400MHz CDCl3)δ 4.38(s,1H),3.63(t,J=6.4Hz,2H),3.37(s,1H),1.98-2.01(m,2H),1.60-1.79 (m,2H),1.55-1.59(m,2H),1.44(s,9H),1.22-1.28(m,3H),0.95-1.05(m,4H).

[0274] 3-(trans-4-Aminocyclohexyl)propan-1-ol hydrochloride. Two reactions were carried out in parallel. To a solution of tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (115 g, 447 mmol, 1 equiv.) in methanol (200 mL) was added 4 M hydrochloric acid in methanol (500 mL). The reaction was stirred at 15° C. for 6 hours. The two batches were combined for workup and purification. The reaction solution was filtered and concentrated to give 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (160 g, 92% yield) as a pale yellow solid. This material was carried forward without further purification. 1H NMR(400MHz DMSO-d6)δ 8.09(s,4H),4.62(s,2H),3.35(t,J=6.8Hz,2H),2.87(d,J=4.4Hz,1H),1.93(d,J=10.8Hz,2H),1. 73(d,J=12.8Hz,2H),1.38-1.42(m,2H),1.29-1.31(m,3H),1.13-1.17(m,3H),0.89-0.92(m,2H).

[0275] Methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate. To a mixture of 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (120 g, 619 mmol, 1 equiv.) in acetonitrile (750 mL), potassium carbonate (428 g, 3.10 mol, 5 equiv.) and methyl 2-bromo-2-methylpropanoate (449 g, 2.48 mol, 4 equiv.) were added. The mixture was stirred at 110 °C for 12 h. The reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (5 to 100% ethyl acetate in petroleum ether) to give methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 34% yield) as a yellow oil. MS(ESI)m / z 258.2[M+1] + .

[0276] 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (62.2 g, 273 mmol, 1.3 equiv.) in ethyl acetate (350 mL) was added N,N-diisopropylethylamine (54.2 g, 420 mmol, 2 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (10–100% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (63 g, 139 mmol, 66% yield) as a yellow solid. 1 H NMR(400MHz CDCl3)δ7.94-7.96(m,1H),7.85(m,1H),7.72-7.75(m,1H),3.64-3.67(m,2H),2.69(s,2H),1.9 5(d,J=12.8Hz,2H),1.84(d,J=11.2Hz,2H),1.61(s,7H),1.29-1.37(m,5H),1.05-1.08(m,2H).

[0277] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.820 g, 1.81 mmol, 1 equiv.) in N,N-dimethylformamide (0.800 mL) and dichloromethane (8 mL) was added thionyl bromide (0.752 g, 3.620 mmol, 2 equiv.) slowly at 0° C. After stirring at 0°C for 2 hours, the reaction solution was concentrated and purified by silica gel column chromatography (15-25% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.650 g, 1.259 mmol, 70% yield) as a brown solid. MS(ESI) m / z 516.1 [M+1] + .

[0278] (R)-tert-Butyl 4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a 40 mL vial was added (R)-tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol), N,N-diisopropylethylamine (0.69 mL, 3.93 mmol, 2 equiv.), methyl bromoacetate (1.09 mL, 11.8 mmol, 6 equiv.), and THF (20 mL, 0.1 M). The reaction solution was stirred at room temperature. After 18 hours, 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 ethyl acetate (2 × 50 mL). The combined organic layers were then dried over magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1-50% ethyl acetate in hexanes) to give (R)-tert-butyl 4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.557 g, 1.71 mmol, 88% yield) as a yellow oil. MS(ESI) m / z 227 [M-99] + .

[0279] (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid. To a solution of (R)-tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (250 mg, 0.7 mmol) in THF (5 mL) was added 1 M lithium hydroxide in water (0.71 mL, 0.71 mmol) and methanol (2 mL), and the reaction solution was stirred at room temperature. After 8 h, the reaction solution was concentrated and azeotroped with chloroform to remove traces of water, yielding crude (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid, which was carried forward without further purification. MS (ESI) m / z 213.2 [M-99] + .

[0280] (3R)-tert-butyl 4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a solution of (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.700 g, 2.241 mmol) and 3-(2-aminopyridin-4-yl)piperidine-2,6-dione (0.690 g, 3.362 mmol) in pyridine (10 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.859 g, 4.480 mmol) was added, and the reaction solution was stirred at 50 °C. After 12 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give (3R)-tert-butyl 4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.550 g, 1.101 mmol, 49% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.94(s,1H),10.11(s,1H),8.27(d,J=5.2Hz,1H),8.01(s,1H),7.03(dd,J=5.2,1.2Hz,1H),4.07-3.91(m,2H),3.78-3.44(m,5H), 3.26-3.03(m,1H),2.86(s,2H),2.74-2.64(m,1H),2.56-2.51(m,1H),2.20(qd,J=12.4,4.4Hz,1H),2.08-2.00(m,1H),1.39(s,9H).

[0281] N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide. To a solution of (3R)-tert-butyl 4-(2-((4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.550 g, 1.101 mmol) in dichloromethane (10 mL), 33% hydrobromic acid in acetic acid (10 mL, 2.85 mmol) was added, and the reaction solution was stirred at room temperature. After 1 h, the reaction solution was concentrated to give crude N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide, which was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),10.68(s,1H),9.21(s,1H),8.70(s,1H),8.32(d,J=5.4Hz,1H),7.92(s,1H),7.18(d,J=5.4Hz,1H),4.14(d,J=5.4Hz,2H),3 .74-3.65(m,2H),3.59-3.45(m,1H),3.34-3.04(m,5H),2.76-2.65(m,1H),2.58-2.53(m,1H),2.21(qd,J=12.4,3.6Hz,1H),2.04(s,1H).

[0282] 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.100 g, 0.250 mmol) and 4-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.155 g, 0.300 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.22 mL, 1.25 mmol), and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was concentrated and the crude material was purified by standard methods to give 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.124 g, 0.142 mmol, 57% yield) as a yellow solid. MS(ESI) m / z 835.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.43(s,1H),10.96(s,1H),10.87-10.69(m,1H),8.39-8.27(m,2H),8.19(d,J=1.6Hz,1H),8.13-7. 92(m,2H),7.26-7.10(m,1H),4.46-4.20(m,1H),4.06(dd,J=12.0,4.8Hz,1H),3.74(s,2H),3.62(d,J =9.6Hz,2H),3.51(d,J=8.0Hz,2H),3.39-2.96(m,5H),2.83-2.63(m,3H),2.57-2.52(m,1H),2.27-2 .14(m,1H),2.10-2.00(m,1H),1.88-1.67(m,6H),1.55(s,6H),1.31-1.15(m,3H),1.14-1.03(m,2H).

[0283] Example 21: 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 4-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.100 g, 0.190 mmol) and N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide; hydrobromide (0.139 g, 0.290 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.770 mmol), and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was concentrated and the resulting crude material was purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (40.38 mg, 0.0461 mmol, 24% yield) as a white solid. MS(ESI) m / z 837.1 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),10.97(s,1H),10.86(s,1H),8.35-8.33(d,J=8.4Hz,2H),8.20-8.19(t,J=2.0Hz, 1H),8.00-7.96(m,2H),7.23-7.16(m,1H),4.42(m,1H),4.09-4.06(m,2H),3.91-3.85(m,3H),3 .74(s,2H),3.53-3.35(m,5H),3.23-3.15(m,3H),2.89-2.84(m,2H),2.75-2.66(m,1H),2.56(m ,1H),2.24-2.18(m,1H),2.08-2.04(m,3H),1.77-1.71(m,2H),1.55(s,6H),1.39-1.31(m,2H).

[0284] Example 22: 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] 5-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (6.70 g, 19.51 mmol, 1 equiv.), 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.94 g, 39.0 mmol, 2 equiv.), and N,N-diisopropylethylamine (6.8 mL, 39.0 mmol, 2 equiv.) were mixed in ethyl acetate (56 mL, 0.35 M) and heated to 90° C. in a sealed tube for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10% to 100% ethyl acetate in hexanes) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.5 g, 6.4743 mmol, 33% yield) as a brown solid. MS (ESI) m / z 541.3 [M+1] + .

[0285] 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.50 g, 6.47 mmol, 1 equiv.) in dichloromethane (30 mL) was added 4 M hydrochloric acid (16.2 mL, 64.7 mmol, 10 equiv.), and the reaction solution was stirred at room temperature. After 3 hours, the reaction solution was concentrated to give 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.4 mmol, 99% yield) as a reddish oil. The crude material was carried forward without further purification. MS(ESI) m / z 457.0 [M+1] + .

[0286] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.49 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.26 mL, 16.2 mmol, 2.5 equiv.), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated, and the crude material was purified by silica gel column chromatography (5% to 80% ethyl acetate in hexane) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (2.00 g, 3.85 mmol, 59% yield) as a reddish-brown oil. MS(ESI) m / z 519.8 [M+1] + .

[0287] 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of 5-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.100 g, 0.190 mmol) and N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.139 g, 0.290 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.770 mmol), and the reaction solution was stirred at 50° C. After 12 hours, the reaction solution was concentrated and the resulting crude material was purified by standard methods to give 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.044 g, 0.051 mmol, 27% yield) as an off-white solid. MS(ESI) m / z 838.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.39(s,1H),10.95(s,1H),10.65-10.57(m,2H),9.15-9.14(d,J=1.6Hz,1H),8.75-8.74(t,J=1.6H z,1H),8.31-8.29(m,1H),7.12-7.11(m,1H),4.42-4.29(m,1H),4.05-4.00(m,3H),3.73(s,4H),3.5 3-3.51(m,2H),3.38-3.35(m,3H),3.16-3.14(m,3H),2.89-2.84(m,2H),2.74-2.65(m,1H),2.55-2. 54(m,1H),2.25-2.17(m,1H),2.08-2.04(m,3H),1.76-1.71(m,2H),1.57(s,6H),1.40-1.32(m,2H).

[0288] Example 23: 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.47 g, 5.71 mmol, 1 equiv.) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.44 g, 6.28 mmol, 1.1 equiv.) in ethyl acetate (15 mL, 0.38 M) was added N,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equiv.), and the reaction solution was stirred at 80 °C. After 16 h, the reaction solution was concentrated under reduced pressure and the crude material was purified by standard methods to give 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 69% yield) as a brown solid. MS(ESI) m / z 455.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.72(m,1H),3.65(t,J=6.4Hz,2H),2.72-2.70(m,2H),1 .97-1.94(m,2H),1.85-1.82(m,2H),1.63(s,6H),1.58-1.54(m,1H),1.42-1.29(m,4H),1.12-1.02(m,2H).

[0289] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 1 equiv.) in dichloromethane (18 mL, 0.22 M) and N,N-dimethylformamide (1.8 mL) was added thionyl bromide (1.650 g, 7.92 mmol, 2 equiv.) slowly at 0° C. The reaction solution was stirred at 0° C. After 12 hours, the reaction solution was diluted with water (30 mL) and extracted with dichloromethane (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (5 to 80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.75 g, 3.38 mmol, 85% yield) as a brown solid. MS (ESI) m / z 516.9 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.71(m,1H),3.42(t,J=6.8Hz,2H),2 .74-2.72(m,2H),1.96-1.79(m,6H),1.63(s,6H),1.40-1.33(m,3H),1.13-1.04(m,2H).

[0290] 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.070 g, 0.150 mmol) and 5-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.075 g, 0.150 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.730 mmol), and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.059 g, 0.067 mmol, 46% yield) as a yellow solid. MS (ESI) m / z: 836.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.26-11.03(m,1H),11.01-10.87(m,1H),10.61-10.34(m,1H),9.70-9.51(m,1H),9.15(d,J=1.6Hz,1H), 8.75(d,J=2.0Hz,1H),8.35-8.24(m,1H),8.07-7.90(m,1H),7.15-6.98(m,1H),4.47-4.37(m,1H),4.00(br dd,J=4.8,11.6Hz,1H),3.93-3.80(m,1H),3.77-3.66(m,2H),3.66-3.58(m,1H),3.57-3.31(m,2H),3.27-2.93(m,5H),2.8 7-2.65(m,3H),2.59-2.53(m,1H),2.28-2.12(m,1H),2.11-1.99(m,1H),1.94-1.65(m,6H),1.57(s,6H),1.37-0.94(m,5H).

[0291] Example 24: 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.070 g, 0.150 mmol) and 4-(3-((1r,4r)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.077 g, 0.150 mmol) in DMF (0.5000 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.730 mmol), and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.056 g, 0.063 mmol, 43% yield) as a white solid. MS (ESI) m / z 851.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.18-11.00(m,1H),10.98-10.87(m,1H),10.59-10.34(m,1H),9.55-9.30(m,1H),8.34(d,J=8.4Hz,1H), 8.31-8.25(m,1H),8.19(d,J=1.6Hz,1H),8.07-7.92(m,2H),7.15-7.04(m,1H),4.42-4.37(m,1H),4.01(br dd,J=4.8,12.0Hz,1H),3.87-3.78(m,1H),3.73(br s,2H),3.65(br d,J=10.0Hz,1H),3.58-3.35(m,4H),3.32-2.96(m,6H),2.90-2.76(m,2H),2.72-2.62(m,1H),2.58-2.52(m,1H) ),2.28-2.13(m,1H),2.12-2.02(m,3H),2.02-1.89(m,2H),1.79-1.65(m,2H),1.55(s,6H),1.41-1.21(m,2H).

[0292] Example 25: 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] 5-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.00 g, 14.0 mmol, 1 equiv.) and 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (6.41 g, 28.0 mmol, 2 equiv.) in ethyl acetate (50 mL, 0.28 M) was added N,N-diisopropylethylamine (4.62 mL, 28.0 mmol, 2 equiv.), and the reaction solution was stirred at 90 °C. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography (10–50% 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-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 90% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 8.95(s,1H),8.23(s,1H),4.55-4.51(m,1H),3.81-3.78(m,2H),3.70-3.68(m,1H),3.57-3.54(m,2H),3.48-3.45(m, 2H),3.29-2.87(m,1H),2.85(d,J=10.8Hz,2H),1.85-1.80(m,8H),1.60(s,6H),1.56-1.52(m,4H),1.32-1.29(m,2H).

[0293] 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 1 equiv.) in methanol (50 mL) was added 1 M hydrogen chloride (5.0 mL, 5 mmol), and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 84% yield) as a brown oil. MS (ESI) m / z 471.2 [M+1] + .

[0294] 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 1 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 2 equiv.) at 0° C. After stirring for 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. (ESI) m / z 535.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.98(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),3.76-3.65(m,1H),3.62(t,J=5.6Hz,2H),3.53(t,J=6.4Hz,2H),3.40-3. 29(m,1H),2.89(s,2H),2.30-2.18(m,2H),2.16-2.05(m,2H),1.83(d,J=12.4Hz,2H),1.63(s,6H),1.45-1.24(m,2H).

[0295] 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride. To a solution of N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.070 g, 0.150 mmol) and 5-(3-((trans)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.078 g, 0.150 mmol) in DMF (0.50 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.13 mL, 0.730 mmol), and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide hydrochloride (0.061 g, 0.070 mmol, 48% yield) as a yellow solid. MS (ESI) m / z 852.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.00-10.72(m,2H),10.49(br s,1H),9.45-9.25(m,1H),9.14(d,J=1.6Hz,1H),8.74(d,J=2.0Hz,1H),8.35-8.23(m,1H),8.05-7.91(m,1 H),7.15-7.00(m,1H),4.44-4.30(m,1H),3.99-3.97(m,1H),3.89-3.83(m,1H),3.81-3.70(m,2H),3.69-3. 61(m,1H),3.57-3.34(m,4H),3.33-2.97(m,6H),2.90-2.75(m,2H),2.71-2.61(m,1H),2.58-2.52(m,1H),2 .27-2.14(m,1H),2.13-2.02(m,3H),2.01-1.89(m,2H),1.79-1.66(m,2H),1.57(s,6H),1.42-1.25(m,2H).

[0296] Example 26: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (1.400 g, 6.110 mmol) and (trans)-N,N-dibenzyl-4-(2-bromoethoxy)cyclohexanamine (3.680 g, 9.157 mmol) in xylene (30 mL) was added tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.600 g, 4.721 mmol, 77% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.41-7.24(m,8H),7.23-7.13(m,2H),4.18-4.01(m,2H),3.63-3.52(m,5H),3.47(dd,J=2.8,9.2Hz,4H),3.19(t,J=10.8Hz,1 H),2.39(t,J=11.6Hz,1H),1.98(d,J=10.2Hz,2H),1.85-1.66(m,6H),1.39(s,11H),1.24(d,J=7.2Hz,6H),1.01-0.88(m,2H).

[0297] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.600 g, 1.089 mmol) in methanol (5 mL) and THF (5 mL) was added 10% palladium on activated carbon (0.115 g, 1.089 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 Psi) at 25° C. for 12 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give crude (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) as a colorless oil, which was carried forward without further purification. MS(ESI) m / z 371.3 [M+1] + .

[0298] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) and methyl 2-bromo-2-methylpropanoate (0.977 g, 5.400 mmol) in acetonitrile (1 mL), potassium carbonate (0.448 g, 3.239 mmol) and sodium iodide (0.016 g, 0.108 mmol) were added, and the reaction solution was stirred at 110° C. After 12 hours, the reaction solution was filtered and concentrated to give crude (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol), which was carried forward without further purification. MS(ESI) m / z 471.4 [M+1] + .

[0299] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.300 g, 0.637 mmol) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.146 g, 0.637 mmol) in ethyl acetate (5 mL) was added N,N-diisopropylethylamine (0.33 mL, 1.910 mmol). The mixture was stirred at 90° C. for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product. The residue was purified by flash silica gel chromatography (0–27% ethyl acetate in petroleum ether) to give (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.340 g, 0.509 mmol, 80% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 9.14(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),3.83(s,1H),3.63(t,J=4.0Hz,1H),3.57-3.53(m,3H),3.32-3.25(m,1 H),2.82(d,J=11.2Hz,2H),2.04(d,J=10.8Hz,2H),1.76-1.66(m,7H),1.55(s,6H),1.39(s,9H),1.34-1.23(m,10H).

[0300] 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.340 g, 0.509 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL, 25.78 mmol). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give crude 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.290 g, 0.511 mmol), which was carried forward without further purification. MS(ESI) m / z 568.3 [M+1] + .

[0301] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate tert-butyl. To a solution of 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.290 g, 0.511 mmol) and tert-butyl 2-bromoacetate (0.149 g, 0.766 mmol) in acetonitrile (5 mL), N,N-dimethylformamide (0.44 mL, 2.55 mmol) was added and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography to give tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.270 g, 0.396 mmol, yield 78%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 9.14(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),3.84(s,1H),3.49(s,4H),3.34(s,2H),3.29-3.23(m,2H),2.88-2.70(m,4H),2.04(d, J=10.4Hz,2H),1.88(d,J=12.0Hz,2H),1.70(d,J=11.2Hz,2H),1.56(s,6H),1.40(s,9H),1.32(d,J=12.8Hz,2H),1.08-0.91(m,8H).

[0302] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.270 g, 0.396 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.0 mL, 12.89 mmol) and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to give crude 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.250 g, 0.400 mmol), which was carried forward without further purification. MS(ESI) m / z 626.3 [M+1] + .

[0303] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.200 g, 0.320 mmol) and 3-(2-( To a solution of (4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.177 g, 0.639 mmol) was added N,N-diisopropylethylamine (0.17 mL, 0.9600 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.177 g, 0.639 mmol), 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 (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (13.32 mg, 0.016 mmol, 5% yield). MS(ESI) m / z 813.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.95(s,1H),9.96(s,1H),9.14(d,J=1.6Hz,1H),8.74(d,J=1.6Hz,1H),8.26(d,J=5.2Hz,1H),7.99(s,1H),7.0 4(dd,J=1.6,5.2Hz,1H),3.97(dd,J=4.8,12.0Hz,1H),3.85(s,1H),3.52(s,4H),3.25(s,2H),2.82(d,J=11.2Hz, 2H),2.74-2.64(m,3H),2.55-2.52(m,1H),2.20(dq,J=4.4,12.4Hz,1H),2.09-2.00(m,3H),1.90(d,J=10.4Hz,2H) ),1.71(d,J=12.0Hz,2H),1.56(s,6H),1.37-1.29(m,2H),1.23(s,2H),1.14-1.07(m,2H),1.04(d,J=6.4Hz,6H).

[0304] Example 27: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (trans)-N,N-dibenzyl-4-(2-bromoethyl)cyclohexanamine (5.660 g, 14.65 mmol) and (2S,4r,6R)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 12.21 mmol) in o-xylene (60 mL) was added potassium hydroxide (3.080 g, 54.95 mmol) and tetra-n-butylammonium bromide (0.790 g, 2.440 mmol), and the reaction mixture was stirred at 15 °C. After 12 h, the reaction solution was concentrated and purified by standard methods to give (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.545 mmol, 53.6% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.43-7.36(m,5H),7.30-7.26(m,4H),7.22-7.18(m,1H),4.28-4.20(m,2 H),3.63(s,3H),3.56-3.52(m,1H),3.42-3.39(m,2H),2.50-2.44(m,1H), 1.97-1.87(m,4H),1.80-1.77(m,2H),1.72-1.66(m,2H),1.62-1.55(m,2 H),1.47(s,9H),1.44-1.38(m,4H),1.32-1.30(m,6H),0.90-0.82(m,2H).

[0305] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.540 mmol) in methanol (40 mL) was added ammonium hydroxide (0.23 g, 6.54 mmol) and palladium on activated carbon (0.350 g, 0.330 mmol), and the reaction mixture was stirred under a molecular hydrogen atmosphere (15 Psi) at 20° C. for 12 h. The reaction mixture was poured into methanol (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.000 g, 5.640 mmol, 86% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 4.12-4.08(m,2H),3.57-3.55(m,1H),3.41-3.38(m,5H),2.45-2.39(m,1H),1. 73-1.65(m,8H),1.39-1.35(m,11H),1.25(d,J=6.8Hz,6H),0.98-0.84(m,4H).

[0306] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 5.360 mmol) and methyl 2-bromo-2-methylpropanoate (3.880 g, 21.44 mmol) in acetonitrile (6 mL), potassium carbonate (2.220 g, 16.08 mmol) and sodium iodide (0.080 g, 0.540 mmol) were added and the reaction solution was stirred at 110° C. After 15 hours, the reaction solution was diluted with ethyl acetate (15 mL), filtered, and concentrated to give crude (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (4.8 g), which was carried forward without further purification.

[0307] (2R,4r,6S)-tert-Butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 2.640 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.200 g, 5.280 mmol) in ethyl acetate (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.38 mL, 7.920 mmol) and the reaction mixture was stirred at 80° C. After 12 h, the reaction was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.150 g, 1.767 mmol, 67% yield) as a brown oil. MS (ESI) m / z 551.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.97-7.95(d,J=8.0Hz,1H),7.87(d,J=1.6Hz,1H),7.76-7.73(dd,J=8.0,1.6Hz,1 H),4.29-4.25(m,2H),3.87(s,1H),3.61-3.56(m,1H),3.49-3.46(t,J=6.0Hz,2H) ,2.69(s,2H),1.98-1.91(m,4H),1.88-1.85(m,2H),1.75-1.69(m,2H),1.63(s,6H ),1.54-1.51(m,3H),1.49(s.9H),1.35-1.34(d,J=6.8Hz,6H),1.18-1.07(m,2H).

[0308] 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.150 g, 1.770 mmol) in dichloromethane (15 mL) was added 2,2,2-trifluoroacetic acid (5 mL, 65.34 mmol), and the reaction mixture was stirred at room temperature. After 2 hours, the reaction was concentrated, and the resulting material was taken up in saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to provide 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.870 g, 1.580 mmol, 90% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.96-7.95(d,J=8.0Hz,1H),7.86(d,J=1.6Hz,1H),7.75-7.72(dd,J=8.0,1.6Hz,1H),3.86(s,1H),3.52-3.49(m,2H),3.35-3.27(m,1H), 2.75-2.59(m,4H),2.02-1.92(m,4H),1.86-1.83(m,2H),1.61(s,6H),1.52-1.49(m,3H),1.16-1.14(d,J=6.4Hz,6H),1.10-0.96(m,4H).

[0309] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate. To a solution of 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.870 g, 1.580 mmol) in acetonitrile (9 mL) was added benzyl 2-bromoacetate (0.723 g, 3.160 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.83 mL, 4.740 mmol) and the reaction was stirred at room temperature. After 12 h, the reaction was concentrated and purified by standard methods to provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (1.100 g, 1.574 mmol) as a brown solid. MS(ESI) m / z 699.3 [M+1] + .

[0310] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (1.100 g, 1.570 mmol) in THF (12 mL) and water (1.5 mL) was added lithium hydroxide (0.189 g, 7.870 mmol) and the reaction was stirred at 50° C. After 12 h, the reaction was concentrated and extracted with 10:1 DCM / methanol (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.900 g, 1.478 mmol, 93% yield) as a brown solid, which was carried on without further purification. MS (ESI) m / z 609.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.34-8.32(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.98-7.96(dd,J=8.0,1.6Hz,1H),3.79(s,2H),3.16(s,2H),2.72-2.67(m,2H) ),2.03-2.00(m,2H),1.81-1.70(m,4H),1.54(s,6H),1.45-1.38(m,5H),1.27-1.19(m,7H),1.15-1.01(m,3H),0.87-0.80(m,2H).

[0311] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.105 g, 0.170 mmol) and 3-(2-aminopyridine-4 To a solution of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.095 g, 0.340 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.690 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.095 g, 0.340 mmol), 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 (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (0.029 g, 0.035 mmol, 20% yield) as a yellow solid. MS(ESI) m / z 796.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.93(s,1H),9.95(s,1H),8.34-8.32(d,J=8.0Hz,1H),8.26-8.25(d,J=5.2Hz,1H),8.20(s,1H),7.9 9-7.97(m,2H),7.05-7.03(d,J=5.2Hz,1H),3.99-3.95(m,1H),3.85(br,s,1H),3.47-3.44(t,J=5.8Hz ,2H),3.24(s,2H),2.72-2.64(m,5H),2.40-2.37(m,1H),2.24-2.16(m,1H),2.08-2.02(m,1H),1.91-1 .88(m,2H),1.83-1.80(m,2H),1.74-1.71(m,2H),1.55(s,6H),1.41-1.23(m,4H),1.14-1.04(m,10H).

[0312] Example 28: 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2S,4r,6R)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (3.000 g, 13.08 mmol) and (trans)-N,N-dibenzyl-4-(3-bromopropyl)cyclohexanamine (6.290 g, 15.70 mmol) in xylene (45 mL) was added tetrabutylammonium bromide (0.840 g, 2.620 mmol) and potassium hydroxide (3.5 mL, 65.41 mmol), and the reaction solution was stirred at 30 °C. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The crude material was purified by standard methods to give (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (5.300 g, 9.657 mmol, 74% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.34-7.26(m,8H),7.21-7.16(m,2H),4.15-4.02(m,2H),3.57-3.52(m,5H),2.39-2.31(m,1H),1.81(d,J=11. 6Hz,2H),1.76-1.68(m,6H),1.53-1.26(m,15H),1.23(d,J=7.2Hz,6H),1.16-1.11(m,3H),0.77-0.66(m,2H).

[0313] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (5.300 g, 9.657 mmol) in methanol (100 mL) and ammonium hydroxide (2 mL) was added 10% palladium on activated carbon (3.000 g, 28.19 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 Psi) at 25° C. for 12 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give crude (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (3.000 g, 8.140 mmol, 84% yield), which was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.17-4.03(m,2H),3.56(q,J=4.0Hz,1H),3.35(s,2H),2.47-2.39(m,1H),1.77-1 .60(m,8H),1.52-1.44(m,2H),1.39(s,9H),1.27-1.12(m,9H),1.01-0.79(m,4H).

[0314] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.500 g, 4.070 mmol) and methyl 2-bromo-2-methylpropanoate (3.680 g, 20.35 mmol) in acetonitrile (5 mL) was added sodium iodide (0.060 g, 0.410 mmol) and potassium carbonate (1.690 g, 12.21 mmol). The mixture was stirred at 110 °C. After 12 hours, the reaction solution was filtered and concentrated to give crude 2R,4r,6S)-tert-butyl 4-(3-((1r,4R)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.054 mmol, 99.6% yield), which was carried forward without further purification. MS(ESI) m / z 469.4 [M+1] + .

[0315] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.050 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.930 g, 4.050 mmol) in ethyl acetate (10 mL), N,N-diisopropylethylamine (2.11 mL, 12.16 mmol) was added and the reaction solution was stirred at 90° C. After 12 h, the reaction solution was filtered, concentrated, and purified by standard methods to give (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 3.610 mmol, 89% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),4.14-4.06(m,2H),3.90-3.74(m,1H),3.59-3.54(m,1H),3.40-3.3 7(m,2H),2.80-2.63(m,2H),1.80(d,J=12.0Hz,2H),1.75-1.70(m,6H) ,1.56-1.47(m,8H),1.39(s,9H),1.27-1.23(m,9H),1.18-1.16(m,2H).

[0316] 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrobromide. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((transn)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 3.610 mmol) in dichloromethane (20 mL) was added 33% hydrogen bromide in acetic acid (20 mL, 3.610 mmol), and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to give crude 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrobromide (2.000 g, 3.542 mmol, 98% yield), which was carried forward without further purification. MS(ESI) m / z 565.3 [M+1] + .

[0317] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate. To a solution of 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile and benzyl 2-bromoacetate (1.220 g, 5.310 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (3.080 mL, 17.71 mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by standard methods to give 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.800 g, 1.122 mmol, 32% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 8.33(d,J=8.4Hz,1H),8.20(d,J=2.0Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),7.38-7.32(m,5H),5.09(s,2H),3.83(s,1H),3.53(s,2H),3.23-3.1 5(m,1H),2.79-2.66(m,4H),1.88-1.77(m,4H),1.71(d,J=10.4Hz,2H), 1.54(s,6H),1.50-1.42(m,3H),1.23-1.15(m,4H),1.06-0.95(m,10H).

[0318] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.800 g, 1.120 mmol) in THF (3 mL), methanol (3 mL), water (3 mL) was added lithium hydroxide (0.135 g, 5.610 mmol) and the mixture was stirred at room temperature. After 12 hours, the reaction solution was adjusted to pH=7 by addition of aqueous HCl and concentrated to give crude 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (1.000 g, 1.606 mmol) as a yellow oil, which was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),3.83(s,1H),3.36(s,3H),3.18(s,4H),2.67(d,J=2.0Hz,2H),1 .88(d,J=12.4Hz,2H),1.81-1.78(m,2H),1.70(d,J=11.6Hz,2H),1.54(s,6H),1.48(d,J=7.2Hz,2H),1.18(s,3H),1.09(d,J=6.4Hz,10H).

[0319] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.200 g, 0.321 mmol) and 3-(2-aminopyridin-4-yl)piperidine-2 in DMF (5 mL) To a solution of 4,6-dione (0.132 g, 0.642 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.178 g, 0.642 mmol), dimethylaminopyridine (0.008 g, 0.064 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.9600 mmol) were added, and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (5.01 mg, 0.006 mmol, 2% yield) as a white solid. MS(ESI) m / z 810.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.93(s,1H),9.95(s,1H),8.33(d,J=8.0Hz,1H),8.26(d,J=5.2Hz,1H),8.20(s,1H),8.00-7.95(m,2H),7.04( d,J=4.8Hz,1H),3.97(dd,J=4.8,11.6Hz,1H),3.84(s,1H),3.41-3.39(m,2H),3.24(s,3H),2.69(dd,J=5.6,11. 2Hz,6H),2.24-2.13(m,1H),2.08-1.98(m,1H),1.89(d,J=14.4Hz,2H),1.81(d,J=11.6Hz,2H),1.72(d,J=10.4H) z,2H),1.55(s,6H),1.49(s,2H),1.43-1.43(m,1H),1.23(s,4H),1.08(d,J=11.6Hz,3H),1.04(d,J=6.0Hz,6H).

[0320] Example 29: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (1.400 g, 6.110 mmol) and (trans)-N,N-dibenzyl-4-(2-bromoethoxy)cyclohexanamine (3.680 g, 9.157 mmol) in xylene (30 mL) was added tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol), and the reaction was stirred at room temperature. After 12 h, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by a standard method to provide (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.600 g, 4.721 mmol, 77% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.41-7.24(m,8H),7.23-7.13(m,2H),4.18-4.01(m,2H),3.63-3.52(m,5H),3.47(dd,J=2.8,9.2Hz,4H),3.19(t, J=10.8Hz,1H),2.39(t,J=11.6Hz,1H),1.98(d,J=10.2Hz,2H),1.85-1.66(m,6H),1.39(s,11H),1.24(d,J=7.2Hz,6H),1.01-0.88(m,2H).

[0321] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.600 g, 1.089 mmol) in methanol (5 mL) and THF (5 mL) was added 10% palladium on activated carbon (0.115 g, 1.089 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (15 Psi) at 25° C. for 12 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give crude (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) as a colorless oil, which was carried forward without further purification. MS (ESI) m / z 371.3 [M+1] + .

[0322] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) and methyl 2-bromo-2-methylpropanoate (0.977 g, 5.400 mmol) in acetonitrile (1 mL), potassium carbonate (0.448 g, 3.239 mmol) and sodium iodide (0.016 g, 0.108 mmol) were added and the reaction solution was stirred at 110° C. After 12 hours, the reaction solution was filtered and concentrated to give crude (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol), which was carried forward without further purification. MS(ESI) m / z 471.4 [M+1] + .

[0323] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.242 g, 1.062 mmol) in ethyl acetate (5 mL) was added N,N-diisopropylethylamine (0.55 mL, 3.19 mmol), and the reaction solution was stirred at 90° C. After 12 hours, the reaction solution was concentrated and purified by silica gel column chromatography to give (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.470 g, 0.705 mmol, 66% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ 8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.0Hz,1H) ,3.82(s,1H),3.62-3.60(m,2H),3.57-3.54(m,2H),3.31-3.25(m,1H),2. 81(d,J=12.8Hz,2H),2.04(d,J=10.8Hz,2H),1.89(d,J=11.2Hz,2H),1.7 5-1.72(m,5H),1.54(s,6H),1.39(s,9H),1.26(s,6H),1.20-1.15(m,4H).

[0324] 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.470 g, 0.705 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL, 25.78 mmol). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give crude 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.400 g, 0.706 mmol), which was carried forward without further purification.

[0325] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate tert-butyl. To a solution of 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.400 g, 0.706 mmol) and tert-butyl 2-bromoacetate (0.206 g, 1.059 mmol) in acetonitrile (5 mL) was added N,N-dimethylformamide (0.61 mL, 3.530 mmol) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by standard methods to give tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.150 g, 0.220 mmol, 31% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.33(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(d d,J=1.6,8.4Hz,1H),3.83(s,1H),3.49(s,4H),3.29-3.22(m,2H),2.83-2.7 1(m,4H),2.04(d,J=10.8Hz,2H),1.88(dd,J=4.0,11.6Hz,2H),1.70(d,J=10 .4Hz,2H),1.54(s,6H),1.40(s,9H),1.36-1.25(m,2H),1.06-0.92(m,10H).

[0326] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.150 g, 0.220 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.0 mL, 12.89 mmol) and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to give crude 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.240 mmol), which was carried forward without further purification.

[0327] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide. 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.110 g, 0.176 mmol) and 3-(2-amino To a solution of (pyridin-4-yl)piperidine-2,6-dione (0.072 g, 0.352 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (0.097 g, 0.352 mmol) and N,N-diisopropylethylamine (0.092 mL, 0.528 mmol) were added, and the reaction solution was stirred at 50 °C. After 12 hours, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide (17.62 mg, 0.022 mmol, 12% yield) as a white solid. MS(ESI) m / z 812.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.94(s,1H),9.95(s,1H),8.34(d,J=8.4Hz,1H),8.26(d,J=5.2Hz,1H),8.20(s,1H),8.02-7.94(m,2H),7.0 4(dd,J=1.2,5.2Hz,1H),3.97(dd,J=4.8,12.0Hz,1H),3.84(s,1H),3.52(s,4H),3.25(s,2H),2.88-2.63(m, 5H),2.55-2.52(m,1H),2.20(dq,J=4.4,12.4Hz,1H),2.06(dd,J=4.4,9.2Hz,3H),1.90(d,J=11.6Hz,2H),1. 71(d,J=10.8Hz,2H),1.54(s,6H),1.37-1.27(m,2H),1.23(s,2H),1.15-1.07(m,2H),1.04(d,J=6.4Hz,6H).

[0328] Example 30: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-)dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(4-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (trans)-N,N-dibenzyl-4-(2-bromoethyl)cyclohexanamine (5.660 g, 14.65 mmol) and (2S,4r,6R)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 12.21 mmol) in o-xylene (60 mL) was added potassium hydroxide (3.080 g, 54.95 mmol) and tetra-n-butylammonium bromide (0.790 g, 2.440 mmol), and the reaction mixture was stirred at 15 °C. After 12 h, the reaction solution was concentrated and purified by standard methods to give (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.545 mmol, 53.6% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.43-7.36(m,5H),7.30-7.26(m,4H),7.22-7.18(m,1H),4.28-4.20(m,2 H),3.63(s,3H),3.56-3.52(m,1H),3.42-3.39(m,2H),2.50-2.44(m,1H), 1.97-1.87(m,4H),1.80-1.77(m,2H),1.72-1.66(m,2H),1.62-1.55(m,2 H),1.47(s,9H),1.44-1.38(m,4H),1.32-1.30(m,6H),0.90-0.82(m,2H).

[0329] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.540 mmol) in methanol (40 mL) was added ammonium hydroxide (0.23 g, 6.54 mmol) and palladium on activated carbon (0.350 g, 0.330 mmol), and the reaction mixture was stirred under a molecular hydrogen atmosphere (15 Psi) at 20° C. for 12 h. The reaction mixture was poured into methanol (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.000 g, 5.640 mmol, 86% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 4.12-4.08(m,2H),3.57-3.55(m,1H),3.41-3.38(m,5H),2.45-2.39(m,1H),1. 73-1.65(m,8H),1.39-1.35(m,11H),1.25(d,J=6.8Hz,6H),0.98-0.84(m,4H).

[0330] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 5.360 mmol) and methyl 2-bromo-2-methylpropanoate (3.880 g, 21.44 mmol) in acetonitrile (6 mL) was added potassium carbonate (2.220 g, 16.08 mmol) and sodium iodide (0.080 g, 0.540 mmol), and the reaction solution was stirred at 110°. After 15 hours, the reaction solution was diluted with ethyl acetate (15 mL), filtered, and concentrated to give crude (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (4.8 g), which was carried forward without further purification.

[0331] (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 2.64 mmol,...

Claims

1. Formula I 【Chemical 1】 wherein Y is CR Ｎ or N; R Ｎ is hydrogen or C １～３ alkyl; n is from 0 to 3; R １ is C １～３ alkyl; A is CH ２ or C=O; A' is NH or O; a is 1 or 2; R ２ and R ３ are each independently selected from H and C １～３ alkyl, or R ２ and R ３ and the carbon to which they are attached form a substituted or unsubstituted C ３～６ cycloalkyl; m is from 0 to 8; Each R ４ is, independently, a substituted or unsubstituted C １～３ alkyl, or two R ４ groups together with the same carbon atom or adjacent carbon atoms to which they are attached form a substituted or unsubstituted C ３～６ cycloalkyl, or two R ４ groups together with non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4- to 7-membered heterocyclyl; L is a substituted or unsubstituted -O(C １～６ alkyl)-, -(C １～６ alkyl)O-, -O(C １～６ alkyl)O-, or -(C １～９ alkyl)-; X is N or CR Ｘ wherein; R Ｘ is hydrogen, halogen, -O(C １～６ alkyl), or -(C １～９ alkyl); V is [Chemical 2] and B is N, CH, or CR Ｂ wherein; Each R Ｂ is independently selected from halogen and substituted or unsubstituted C １～６ alkyl; R Ｃ is a halogen, CF ３ or SF ５ and; R ５ and R ６ is C １～３ alkyl, or R ５ and R ６ together with the carbon atom to which they are attached form a substituted or unsubstituted C ３～６ cycloalkyl or 3- to 6-membered heterocyclyl; b is from 0 to 2) a compound of or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

2. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein n is 0.

3. Y is CR Ｎ wherein R Ｎ is H or methyl, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

4. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein A is C=O.

5. A is CH ２ The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, wherein A is CH

6. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein A' is NH.

7. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein A' is O.

8. a is 1, and R ２ and R ３ are both H, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

9. Each R ４ The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, wherein each R is a substituted or unsubstituted methyl.

10. Each R ４ is, independently, methyl and CF ３ selected from, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

11. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein m is 0, 1, 2, 3, or 4.

12. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein m is 1 or 2.

13. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein X is N.

14. X is CR Ｘ wherein; R Ｘ is hydrogen, halogen, -O(C １～６ alkyl), or -(C １～９ alkyl) and the compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1.

15. L is a substituted or unsubstituted -O(CH ２ ) ｐ -, -O(CH ２ ) ｐ O- or -(CH ２ ) ｐ - and p is 1 to 4, or a pharma- ceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

16. L is a substituted or unsubstituted -O(CH ２ ), ｐ and p is 2 or 3, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

17. L is a substituted or unsubstituted -(CH ２ ) ｐ -, and p is 3 or 4, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

18. L is -O(CH ２ )(CH ２ )-, -O(CH ２ )(CH ２ )(CH ２ )-, -O(CH ２ )(CH ２ )O-, -O(CH ２ )(CH ２ )(CH ２ )O-, -(CH ２ )(CH ２ )-, -(CH ２ )(CH ２ )(CH ２ )-, or -(CH ２ )(CH ２ )(CH ２ )(CH ２ )-, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

19. L is -O(CH ２ )(CH ２ )- or -(CH ２ )(CH ２ )(CH ２ )-, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

20. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein B is CH.

21. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein B is N.

22. The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, wherein b is 0.

23. R Ｃ is CF ３ , Cl, or SF ５ and the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

24. R Ｃ is CF ３ The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

25. R ５ and R ６ is methyl, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

26. Formula II 【Chemical 3】 The compound or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof according to claim 1, having

27. Formula IV 【Chemical Formula 4】 wherein Y is CR Ｎ or N; R Ｎ is hydrogen or methyl; a is 1 or 2; Each R ４ｍ is, independently, hydrogen or substituted or unsubstituted methyl, where the substituent, when present, is selected from 1 to 5 halos; L is a substituted or unsubstituted -O(C １～３ alkyl)-, -O(C １～３ alkyl)O-, or -(C １～４ alkyl)-; V is 【Chemical Formula 5】 and B is N or CH; R Ｃ is a halogen, CF ３ , or SF ５ ; R ５ and R ６ are C １～３ alkyl) The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof having the following.

28. Formula VI 【Chemical Formula 6】 (wherein, Y is N or CR Ｎ and; R Ｎ is hydrogen or methyl; a is 1 or 2; L is a substituted or unsubstituted -O(C １～３ alkyl)-, -O(C １～３ alkyl)O-, or -(C １～４ alkyl)-; V is 【Chemical Formula 7】 as follows, B is N or CH; R Ｃ is a halogen, CF ３ , or SF ５ ; R ５ and R ６ are C １～３ alkyl) The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof having the following.

29. Formula VIII 【Chemical 8】 (wherein, Y is N or CR Ｎ and; R Ｎ is hydrogen or methyl; a is 1 or 2; L is a substituted or unsubstituted -O(C １～３ alkyl)-, -O(C １～３ alkyl)O-, or -(C １～４ alkyl)-; V is 【Chemical Formula 9】 as follows, B is N or CH; R Ｃ is a halogen, CF ３ , or SF ５ ; R ５ and R ６ are C １～３ alkyl) The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof having the following.

30. Formula XI 【Chemical Formula 10】 (wherein, Y is CR Ｎ or N; R Ｎ is hydrogen or methyl; A' is NH or O; a is 1 or 2; Each R ４ｍ is, independently, hydrogen or substituted or unsubstituted methyl, where the substituent, when present, is selected from 1 to 5 halos; L is a substituted or unsubstituted -O(C １～３ alkyl)-, -O(C １～３ alkyl)O-, or -(C １～４ alkyl)-; V is 【Chemical 11】 as follows, B is N or CH; R Ｃ is a halogen, CF ３ , or SF ５ ; R ５ and R ６ is C １～３ alkyl). The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof having the following.

31. Formula XIII 【Chemical Formula 12】 (wherein, Y is CR Ｎ or N; R Ｎ is hydrogen or methyl; A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C １～３ alkyl)-, -O(C １～３ alkyl)O-, or -(C １～４ alkyl)-; V is 【Chemical 13】 as follows, B is N or CH; R Ｃ is a halogen, CF ３ , or SF ５ ; R ５ and R ６ are C １～３ alkyl) The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof having the following.

32. Formula XIV 【Chemical Formula 14】 (wherein, Y is CR Ｎ or N; R Ｎ is hydrogen or methyl; A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C １～３ alkyl)-, -O(C １～３ alkyl)O-, or -(C １～４ alkyl)-; V is 【Chemical Formula 15】 as follows, B is N or CH; R Ｃ is a halogen, CF ３ , or SF ５ ; R ５ and R ６ are C １～３ alkyl) The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof having the following.

33. Y is CR Ｎ wherein; R Ｎ is hydrogen or methyl, the compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

34. The compound according to claim 30 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, wherein A' is O.

35. The compound according to claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, which is selected from Compounds 1 to 30 described in Table 1 below. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】 【Table 11】 【Table 12】 【Table 13】 【Table 14】

36. A pharmaceutical composition comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

37. A therapeutic agent for androgen receptor-mediated diseases, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

38. The therapeutic agent according to claim 37, wherein the androgen-mediated disease is prostate cancer.

39. The therapeutic agent according to claim 38, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

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