Cereblon binding compounds, compositions thereof, and methods for their use in therapy

Abstract

Provided herein are piperidinedione compounds having the structure: (I), wherein R 1 , R 2 , R 3 , R 4 , L, V, X, a, and m are as defined herein; compositions comprising an effective amount of a piperidinedione compound; and methods for treating or preventing androgen receptor-mediated diseases.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 043,612, filed June 24, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This document provides compounds, compositions comprising an effective amount of such compounds, and methods for treating or preventing androgen receptor-mediated diseases, the methods comprising administering an effective amount of such compounds to a subject in need. This document also provides these compounds and compositions for use in these methods. Background Technology

[0004] Androgen receptor signaling is known to play a crucial role in the pathogenesis of prostate cancer and is involved in the development of other androgen receptor-positive cancers (Chen Y et al., Lancet Oncol, 2009, 10: 981-91; Mills IG, Nat Rev Cancer, 2014, 14: 187-98; Taplin ME, Nat ClinPract Oncol, 2007, 4: 236-44; Wirth MP et al., Eur Urol, 2007, 51(2): 306-13). Inhibition of androgen receptor signaling using antiandrogen drugs that antagonize the androgen receptor has been used or suggested for the treatment of prostate cancer.

[0005] Androgen receptors are typically located in the cytoplasm and bind to molecular chaperones such as HSP90 (Brinkmann AO et al., JSteroid Biochem Mol Biol, 1999, 69:307-13). Upon binding to dihydrotestosterone (DHT), the androgen receptor changes its conformation and translocates to the nucleus, where it binds to androgen response elements (AREs) that drive the transcription of typical targets such as KLK3 (also known as prostate-specific androgen (PSA)), TMPRSS2, and KLK2 (Tran C et al., Science, 2009, 324:787-90; Murtha P et al., Biochemistry (Mosc.), 1993, 32:6459-64).

[0006] Prostate cancer (PCa) is one of the most common non-skin cancers diagnosed in American men. More than 200,000 new cases of prostate cancer are diagnosed in the United States each year, and more than 30,000 people die from it, making it the second leading cause of cancer death.

[0007] Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer (PCa). Patients with advanced PCa undergo ADT via luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, or through bilateral orchiectomy. Although there is an initial response to ADT, disease progression is inevitable and the cancer eventually manifests as castration-resistant prostate cancer (CRPC). Up to 30% of prostate cancer patients who have received radiation or surgery as their primary therapy will develop metastatic disease within 10 years of primary therapy. Approximately 50,000 patients will develop metastatic disease (also known as metastatic CRPC (mCRPC)) each year.

[0008] There remains an urgent need for safe and effective methods to treat, prevent, and manage AR-mediated diseases, particularly those refractory to standard therapies (e.g., surgery, radiotherapy, chemotherapy, and hormone therapy), while minimizing or avoiding the toxicities and / or side effects associated with conventional therapies.

[0009] Any reference or designation in this section of this application shall not be construed as an admission that the reference is prior art. Summary of the Invention

[0010] This article provides compounds having the following formula I:

[0011]

[0012] Or its pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer, wherein R 1 R 2 R 3 R 4 L, V, X, a, and m are as defined in this document.

[0013] Compounds having Formula I or pharmaceutically acceptable salts, tautomers, isotopes or stereoisomers thereof may be used in subjects to treat or prevent androgen receptor-mediated diseases.

[0014] In one respect, this document provides compounds as described in this disclosure (e.g., as in Table 1).

[0015] In one aspect, this document provides pharmaceutical compositions comprising an effective amount of the compound as described herein, and a pharmaceutically acceptable carrier, excipient, or mediator. In some embodiments, the pharmaceutical compositions are suitable for oral, parenteral, mucosal, transdermal, or topical application.

[0016] In one aspect, this document provides methods for treating or preventing androgen receptor-mediated diseases in subjects, methods comprising administering an effective amount of a compound as described herein to a subject in need; and a pharmaceutically acceptable carrier, excipient, or mediator. In another aspect, this document provides compounds for use in the treatment of androgen receptor-mediated diseases. In yet another aspect, this document provides compounds for use in the treatment of androgen receptor-mediated diseases.

[0017] In another aspect, this document provides methods for preparing compounds as described herein.

[0018] The embodiments of the present invention can be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. Detailed Implementation

[0019] definition

[0020] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifying the presence of the stated features or components mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. Additionally, the terms “comprising” and “including” are intended to include instances covered by the term “consisting of”. Therefore, the term “consisting of” may be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0021] The term "composed of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the features or components of its declared composition. In another embodiment, the term "composed of" excludes any other features or components from any subsequently elaborated scope, except those that are not essential to the desired technical effect.

[0022] As used herein, the term "or" should be interpreted as inclusive "or," meaning either one or any combination thereof. Therefore, "A, B, or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition will only occur if the elements, functions, steps, or behaviors are inherently mutually exclusive in some way.

[0023] 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 carbons, or in some embodiments 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, etc. In some embodiments, the alkyl group is an unsaturated alkyl group (also called an alkenyl or ynyl group). An alkenyl group is an alkyl group containing one or more carbon-carbon double bonds. An ynyl group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). Alkyl groups can be substituted or unsubstituted. When the alkyl groups referred to herein are described as “substituted,” they may be substituted with: any one or more substituents as seen in the exemplary compounds and examples disclosed herein, and halogens; hydroxyl groups; alkoxy groups; cycloalkyloxy groups, aryloxy groups, heterocyclic alkyloxy groups, heterocyclic alkyloxy groups, cycloalkylalkyloxy groups, arylalkyloxy groups, heterocyclic alkyloxy groups, heterocyclic alkyloxy groups, heterocyclic alkyloxy groups; oxo (=O); amino groups, alkylamino groups, cycloalkylamino groups, arylamino groups, heterocyclic amino groups, heterocyclic alkylamino groups, heterocyclic alkylamino groups, cycloalkylalkylamino groups, cycloalkylalkylamino groups. Amino, aralkylamino, heterocyclic alkylamino, heterocyclic alkylamino, heterocyclic alkylalkylamino; imino; imino; amido; guanidinyl; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkyloxyamino; hydrazine; acylhydrazine; hydrazine; azide; nitro; thio(-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphonooxy; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2.In some embodiments, when the alkyl groups described herein are referred to as “substituted,” they may be substituted with any one or more substituents as seen in the exemplary compounds and examples disclosed herein, and halogens (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0024] A “cycloalkyl” group is a saturated or partially saturated cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple fused or bridged rings that may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms 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, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, etc., or polycyclic 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, etc. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. Cycloalkyl groups can be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol.

[0025] An "aryl" group is an aromatic carbocyclic group having 6 to 14 carbon atoms, comprising a monocyclic (e.g., phenyl) or polycyclic fused ring (e.g., naphthyl or anthracene). In some embodiments, the aryl group contains 6-14 carbons in the ring portion of the group; in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, etc. The aryl group can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.).

[0026] A "heteroaryl" group is an aromatic ring system having one to four heteroatoms as ring atoms, wherein the remaining portion of the ring atoms is carbon. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms in the ring portion of the group; in other embodiments, it contains 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolo, pyrazol, imidazo, triazol, tetrazol, oxazol, isoxazol, benzo[d]isooxazol (e.g., benzo[d]isooxazol), thiazo, pyrrolo, pyridazin, pyrimidin, pyrazin, thienyl, benzo[thienyl], furanyl, benzofuranyl, indole (e.g., indole-2-one or isoindoline-1-one), azaindole (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), inzol, benzo[d]imidazo (e.g., 1H-benzo[d]imidazo), imidazo The aryl groups can be substituted or unsubstituted. These groups include pyridyl (e.g., azirbenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-keto), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0027] A "heterocyclic group" is an aromatic cycloalkyl (also called a heteroaryl) or non-aromatic cycloalkyl group in which one to four of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some embodiments, the heterocyclic group comprises 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclic groups may also incorporate other groups at any ring atom (i.e., at any carbon atom or heteroatom in the heterocycle). Heterocyclic groups may be substituted or unsubstituted. Heterocyclic groups encompass unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazoalkyl (e.g., imidazolidin-4-one or imidazolidin-2,4-diketone) groups. The phrase "heterocyclic group" includes fused rings, including those containing fused aromatic and non-aromatic groups, such as 1- and 2-aminotetrahydronaphthalene, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxacyclopentenyl. The phrase also includes bridging polycyclic systems containing heteroatoms, such as, but not limited to, quinine cyclic groups.Representative examples of heterocyclic groups include, but are not limited to, aziridinyl, aziridine, aziridine-heptyl, oxadiazinyl, pyrrolyl, imidazoalkyl (e.g., imidazoline-4-one or imidazoline-2,4-diketone), pyrazolyl, thiazoalkyl, tetrahydrothiopheneyl, tetrahydrofuranyl, dioxacyclopentenyl, furanyl, thiopheneyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzo[d]isooxazolyl (e.g., benzo[d]isooxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorphoyl Linyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiaranyl, oxothiacyclohexyl, dioxyl, dithiaalkyl, pyranyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, dihydropyridinyl, dihydrodithiinyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decyl, periperazinesyl, quininecycloyl, indoleyl (e.g., indole-2-keto or isoindoline-1-keto), dihydroindoleyl, isoindoleyl, isoindolineyl, azaindoleyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazoleyl, indoleazinyl, benzotriazolyl ( For example, 1H-benzo[d][1,2,3]triazolyl), benzoimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazolyl-1-2(3H)-keto), benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxadiazolyl, benzooxazinyl, benzodithiacinyl, benzooxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiazolyl, benzothiazolyl, benzo[1,3]dioxacyclopentenyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H... -imidazo[4,5-b]pyridyl), triazolylpyridyl, isoxazolylpyridyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-keto), quinazinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, naphridyl, pteridine, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazoleyl, tetrahydrobenzimidazyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolylpyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolylpyridyl, tetrahydropyrimidin-2(1H)-keto and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclic groups do not include fused ring types containing fused aromatic groups.Examples of non-aromatic heterocyclic groups include aziridinyl, aziridine, aziridine-heptyl, pyrrolidinyl, imidazoalkyl (e.g., imidazoline-4-one or imidazoline-2,4-diketoyl), pyrazolyl, thiazoalkyl, tetrahydrothiopheneyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiaranyl, oxothiacyclohexyl, dithiaalkyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quininecycloyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups can be monosubstituted or polysubstituted, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted by multiple substituents (such as those listed below).

[0028] As used herein and unless otherwise stated, a "cycloalkylalkyl" group is a group having the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. A substituted cycloalkylalkyl group may be substituted at the alkyl, cycloalkyl, or both alkyl and cycloalkyl moieties of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, etc.

[0029] As used herein and unless otherwise stated, an "aralkyl" group is a group having the formula: -alkyl-aryl, where alkyl and aryl are as defined above. A substituted aralkyl group may be substituted at the alkyl, aryl, or both alkyl and aryl moieties of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and aralkyl groups where the aryl group is fused to a cycloalkyl group, such as inden-4-ylethyl.

[0030] As used herein and unless otherwise stated, a "heterocyclic alkyl" group is a group having the formula: -alkyl-heterocyclic, wherein the alkyl and heterocyclic groups are as defined above. A "heteroarylalkyl" group is a group having the formula: -alkyl-heteroaryl, wherein the alkyl and heteroaryl groups are as defined above. A "heterocyclic alkylalkyl" group is a group having the formula: -alkyl-heterocyclic alkyl, wherein the alkyl and heterocyclic alkyl groups are as defined above. A substituted heterocyclic alkyl group may be substituted at the alkyl, heterocyclic, or both the alkyl and heterocyclic moieties of the group. Representative heterocyclic alkyl groups include, but are not limited to, morpholino-4-ylethyl, morpholino-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0031] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0032] A “hydroxyalkyl” group is an alkyl group as described above that is replaced by one or more hydroxyl groups.

[0033] The "alkoxy" group is -O-(alkyl), where alkyl is defined above.

[0034] The "alkoxyalkyl" group is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0035] The "amino" group is a group with the following formula: -NH2, -NH(R) # ), or -N(R # )2, where each R # Independently defined as an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic (e.g., heteroaryl or heterocycloalkyl), or heterocyclic alkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) group, each independently being substituted or unsubstituted.

[0036] In one embodiment, the "amino" group is an "alkylamino" group, which is a group having the following formula: -NH-alkyl or -N(alkyl)2, wherein each alkyl group is independently defined above. The terms "cycloalkylamino", "arylamino", "heterocyclicamino", "heteroarylamino", "heterocyclicalkylamino", etc. are the same as those described above for "alkylamino", wherein the term "alkyl" is replaced by "cycloalkyl", "aryl", "heterocyclic", "heteroaryl", "heterocyclic alkyl", etc., respectively.

[0037] The "carboxyl" group is a group with the following formula: -C(O)OH.

[0038] As used herein and unless otherwise stated, an "acyl" group is a group having the following formula: -C(O)(R # ) or -C(O)H, where R # As defined above, the "formyl" group is a group having the following formula: -C(O)H.

[0039] As used herein and unless otherwise stated, the "amide" group is a group having the following formula: -C(O)-NH2, -C(O)-NH(R) # ), -C(O)-N(R) # )2、-NH-C(O)H、-NH-C(O)-(R # ), -N(R # -C(O)H, or -N(R)H # )-C(O)-(R # ), where each R # Defined independently above.

[0040] In one embodiment, the "amide" group is an "amino carbonyl" group, which is a group having the following formula: -C(O)-NH2, -C(O)-NH(R) # ), -C(O)-N(R) # )2, where each R # Defined independently above.

[0041] In one embodiment, the "acylamino" group is an "acylamino" group, which is a group having the following formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # -C(O)H, or -N(R)H # )-C(O)-(R # ), where each R # Defined independently above.

[0042] The "sulfonylamino" group is a group having the following formula: -NHSO2(R # ) or -N(alkyl)SO2(R # ), wherein each alkyl group and R # As defined above.

[0043] The "urea" group is a group having the following formula: -N(alkyl)C(O)N(R) # )2、-N(alkyl)C(O)NH(R) # -N(alkyl)C(O)NH2, -NHC(O)N(R) # )2、-NHC(O)NH(R # ), or -NH(CO)NH2, wherein each alkyl group and R # Independently as defined above.

[0044] When groups (other than alkyl groups) are referred to herein as “substituted,” they may be substituted by any one or more suitable substituents. Illustrative examples of substituents are those found in the exemplary compounds and examples disclosed herein, as well as halogens (chlorine, iodine, bromine, or fluorine); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; arylalkoxyamine; N-oxide; hydrazine; acylhydrazine; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may It can be a monocyclic or fused or unfused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclic group, which can be a monocyclic or fused or unfused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); a monocyclic or fused or unfused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolidinyl, indolyl, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridineyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophene, or benzofuranyl) aryloxy; aralkyloxy; heterocyclic oxy; and heterocyclic alkoxy.

[0045] 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 as well as organic acids and bases). Suitable pharmaceutically acceptable base addition salts of compounds having formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts prepared from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, viscous 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. Examples of specific salts therefore include hydrochloride salts, formate salts, and methanesulfonate salts. Others are well known in the field; see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton, PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton, PA (1995).

[0046] As used herein and unless otherwise indicated, the terms "stereoisomer" or "stereoisomer-pure" mean a stereoisomer of the compound provided herein that is substantially free of other stereoisomers of the compound. For example, a stereoisomer-pure compound having one chiral center will substantially be free of its opposite enantiomers. A stereoisomer-pure compound having two chiral centers will substantially be free of other diastereomers of the compound. Typical stereoisomer-pure compounds comprise, by weight, more than about 80% of one stereoisomer of the compound and less than about 20% of other stereoisomers of the compound, more than about 90% of one stereoisomer of the compound and less than about 10% of other stereoisomers of the compound, more than about 95% of one stereoisomer of the compound and less than about 5% of other stereoisomers of the compound, or more than about 97% of one stereoisomer of the compound and less than about 3% of other stereoisomers of the compound. These compounds may have a chiral center and may exist as racemates, single enantiomers, diastereomers, or mixtures thereof. The examples disclosed herein include all such isomers, including mixtures thereof.

[0047] The embodiments disclosed herein cover the use of pure stereoisomers of such compounds and mixtures thereof. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.See, 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 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation of Enantiomers: Synthetic Methods for Enantiomer Separation: 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).

[0048] It should also be noted that these compounds may include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In some embodiments, these compounds are isolated as either E or Z isomers. In other embodiments, these compounds are mixtures of E and Z isomers.

[0049] "Tautomers" refer to the isomers of a compound that exist in equilibrium with each other. The concentration of these isomers will depend on the environment in which the compound is present and will vary depending on, for example, whether the compound is a solid or in an organic solution or an aqueous solution. For example, in aqueous solution, pyrazole can exist in the following isomers, which are referred to as tautomers of each other:

[0050]

[0051] As will be readily understood by those skilled in the art, various functional groups and other structures can exhibit tautomerism and all tautomers of compounds having formula (I) are within the scope of this invention.

[0052] It should also be noted that the compounds presented herein may contain atomic isotopes in non-natural proportions on one or more atoms. For example, the compounds may contain radioactive isotopes such as tritium ( 3 H), Iodine-125 ( 125 I), sulfur-35( 35 S), or carbon-14 (S), or carbon-14 14 C) Radioactive labeling, or for example, using deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N) isotope enrichment. As used herein, an "isotope" is an isotope-enriched compound. The term "isotope-enriched" means having atoms composed of isotopes other than the naturally occurring isotopic composition. "Isotope-enriched" can also refer to compounds containing at least one atom composed of an isotope other than the naturally occurring isotopic composition. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotope-enriched compounds can be used as therapeutic agents such as cancer therapeutic agents, research reagents such as binding assays, and diagnostic agents such as in vivo imaging agents. All isotope variants of the compounds described herein, whether or not radioactive, are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopes of compounds are provided, for example, isotopes enriched in deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" means a compound in which at least one hydrogen (H) is replaced by deuterium (from D or 2 (H indicator), meaning that the compound is enriched in deuterium at at least one position.

[0053] It should be understood that, independent of stereoisomer or isotopic composition, each compound mentioned herein may be provided in the form of any pharmaceutically acceptable salt discussed herein. Similarly, it should be understood that isotopic composition may vary independently of the stereoisomer composition of each compound mentioned herein. Furthermore, while the isotopic composition is limited to the elements present in the compounds or their salts, it may also vary independently of the choice of pharmaceutically acceptable salts for the compounds.

[0054] It should be noted that if there is a difference between the described structure and its name, the described structure shall prevail.

[0055] As used herein, “treatment” means the complete or partial relief of a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or the slowing or cessation of the further development or worsening of these symptoms, or the relief or elimination of one or more causes of the disorder, disease, or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease as described herein, or a symptom of that disease.

[0056] As used herein, “prevention” means delaying and / or preventing the complete or partial onset, recurrence, or spread of a disorder, disease, or condition; preventing a subject from developing a disorder, disease, or condition; or a method of reducing the risk of a subject developing a disorder, disease, or condition. In one embodiment, the disorder is an androgen receptor-mediated disease as described herein, or multiple symptoms of such a disease.

[0057] The term “effective amount” in relation to compounds means the amount that is sufficient to treat or prevent the impairment, disease or ailment or its symptoms disclosed herein.

[0058] As used herein, the terms “subject” and “patient” include animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals and in another embodiment are humans. In one embodiment, a subject is a person suffering from or experiencing androgen receptor-mediated disease or its symptoms.

[0059] As used herein, the terms “androgen receptor,” “AR,” or “NR3C4” refer to nuclear hormone receptors that are activated by binding to androgens, including testosterone or dihydrotestosterone. The term “androgen receptor” may refer to the nucleotide or protein sequence of the human androgen receptor (e.g., Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeq NP_000035).

[0060] As used in this article, “AR-full-length” (AR-FL) refers to an AR protein containing all four functional domains, including the N-terminal transcription activation 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).

[0061] The term "castration-resistant prostate cancer" (CRPC) refers to advanced prostate cancer that continues to worsen or progress while the patient maintains androgen deprivation therapy or other therapies to reduce testosterone, or is considered hormone-refractory, hormone-naïve, non-androgen-dependent, or chemo- or surgically castration-resistant prostate cancer. Castration-resistant prostate cancer (CRPC) is advanced prostate cancer that continues to progress despite ongoing ADT and / or surgical castration. Castration-resistant prostate cancer is defined as prostate cancer that, despite prior surgical castration, continues to be treated with gonadotropin-releasing hormone (e.g., leuprolide) or antagonists (e.g., degarelix or abalix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, amglutethimide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, doxorubicin, mitoxantrone, estradiol mustard, cyclophosphamide), or kinase inhibitors (e.g., imatinib (Gleevec)). ) or gefitinib (Iressa Cabozantinib (Cometriq) Also known as XL184) or other prostate cancer therapies (e.g., sipuleucel-T vaccine). Treatment with herbal inhibitors (PC-SPES) and lyase inhibitors (abiraterone) has not been shown to progress or worsen or adversely affect the patient’s health, as demonstrated by elevated or higher serum prostate-specific antigen (PSA) levels, metastasis, bone metastasis, pain, lymph node involvement, increased volume or serum markers representing tumor growth, worsening of prognostic diagnostic markers, or worsening of the patient’s condition.

[0062] compound

[0063] In some embodiments, compounds having Formula I are provided herein.

[0064]

[0065] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0066] R 1 It is C 1-3 alkyl;

[0067] a is 1 or 2;

[0068] R 2 and R 3 Each is independently selected from H and C. 1-3 Alkyl, or R 2 and R 3 And the carbon attached to them forms substituted or unsubstituted C. 3-6 cycloalkyl;

[0069] m is 0-8;

[0070] Each R 4 Independently for substituted or unsubstituted C 1-3 Alkyl, or two R 4 The groups, together with the same or adjacent carbon atoms to which they are attached, form substituted or unsubstituted carbon atoms. 3-6 cycloalkyl, or two R 4 The groups together with the non-adjacent carbon atoms to which they are attached form substituted or unsubstituted 4-7 membered heterocyclic groups;

[0071] X is N or CR X ;

[0072] R X It is hydrogen, halogen, -O(C) 1-6 alkyl) or -(C 1-9 alkyl);

[0073] L is either substituted or unsubstituted -O(C) 1-6 alkyl)-, -(C 1-6 Alkyl)O-, -O(C 1-6 Alkyl)O- or -(C 1-9 alkyl)-;

[0074] V is

[0075]

[0076] in

[0077] B is N, CH, or CR. B ;

[0078] Each R B Independently selected from halogens and substituted or unsubstituted C 1-6 alkyl;

[0079] R C It is halogen, CF3 or SF5;

[0080] R 5 and R 6 It is C 1-3 Alkyl, or R5 and R 6 Together with the carbon atoms to which they are attached, they form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or 3-6 membered heterocyclic groups; and

[0081] b is 0-2.

[0082] In some embodiments, compounds having Formula I are provided herein.

[0083]

[0084] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0085] R 1 It is C 1-3 alkyl;

[0086] a is 1 or 2;

[0087] R 2 and R 3 Each is independently selected from H and C. 1-3 Alkyl, or R 2 and R 3 And the carbon attached to them forms substituted or unsubstituted C. 3-6 cycloalkyl;

[0088] m is 0-8;

[0089] Each R 4 Independently for substituted or unsubstituted C 1-3 Alkyl, or two R 4 The groups, together with the same or adjacent carbon atoms to which they are attached, form substituted or unsubstituted carbon atoms. 3-6 cycloalkyl, or two R 4 The groups together with the non-adjacent carbon atoms to which they are attached form substituted or unsubstituted 4-7 membered heterocyclic groups;

[0090] X is N or CR X ;

[0091] R X It is hydrogen, halogen, -O(C) 1-6 alkyl) or -(C 1-9 alkyl);

[0092] L is either substituted or unsubstituted -O(C) 1-6 alkyl)-, -(C 1-6 Alkyl)O- or -(C 1-9 alkyl)-;

[0093] V is

[0094]

[0095] in

[0096] B is N, CH, or CR. B ;

[0097] Each R B Independently selected from halogens and substituted or unsubstituted C 1-6 alkyl;

[0098] R C It is halogen, CF3 or SF5;

[0099] R 5 and R 6 It is C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atoms to which they are attached, they form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or 3-6 membered heterocyclic groups; and

[0100] b is 0-2.

[0101] In some embodiments of compounds having formula I, R 1 It is methyl. In some embodiments of compounds having formula I, a is 1, and R 2 and R 3 Both are H. In some embodiments of compounds having formula I, each R 4 It is a substituted or unsubstituted methyl group. In some embodiments of compounds having formula I, each R 4 It is independently selected from methyl and CF3.

[0102] In some embodiments of compounds having Formula I, m is 0, 1, 2, 3, or 4. In some embodiments of compounds having Formula I, m is 1 or 2.

[0103] In some embodiments of compounds having Formula I, X is N. In some embodiments of compounds having Formula I, X is CR. X And R X It is hydrogen, halogen, -O(C) 1-6 alkyl) or -(C 1-9 Alkyl group). In some embodiments of compounds having formula I, X is CH.

[0104] In some embodiments of compounds having formula I, L is substituted or unsubstituted -O(CH2). p -、-O(CH2) p O- or -(CH2) p - and p is 1-4.

[0105] In some embodiments of compounds having formula I, L is substituted or unsubstituted -O(CH2). p -or-(CH2) p - and p is 1-4.

[0106] In some embodiments of compounds having formula I, L is substituted or unsubstituted -O(CH2). p - and p is 2 or 3.

[0107] In some embodiments of compounds having formula I, L is substituted or unsubstituted -O(CH2). p O-, and p is 2 or 3.

[0108] In some embodiments of compounds having formula I, L is substituted or unsubstituted -(CH2). p - and p is 1, 2, 3 or 4.

[0109] In some embodiments of compounds having formula I, L is substituted or unsubstituted -(CH2). p - and p is 3 or 4.

[0110] In some embodiments of compounds having formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)- or -(CH2)(CH2)(CH2)(CH2)-.

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

[0112] In some embodiments of compounds having Formula I, B is CH. In some embodiments of compounds having Formula I, B is N.

[0113] In some embodiments of compounds having Formula I, b is 0. In some embodiments of compounds having Formula I, R C It is CF3, Cl, or SF5. In some embodiments of compounds having formula I, R C It is CF3. In some embodiments of compounds having formula I, R 5 and R 6 It is a methyl group.

[0114] In some embodiments of compounds having Formula I, the compound is

[0115]

[0116] Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof.

[0117] In some embodiments of compounds having Formula I, the compound is

[0118]

[0119] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0120] Each R 4m It is independently hydrogen or substituted or unsubstituted methyl, wherein these substituents, when present, are selected from 1 to 5 halogens;

[0121] L is either substituted or unsubstituted -O(C) 1-3 alkyl)-, -O(C 1-3 Alkyl)O- or -(C 1-4 alkyl)-;

[0122] R 1 It is methyl;

[0123] V is

[0124]

[0125] B is either N or CH;

[0126] R C It is halogen, CF3, or SF5; and

[0127] R 5 and R 6 It is C 1-3 alkyl.

[0128] In some embodiments of compounds having Formula I, the compound is

[0129]

[0130] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0131] L is either substituted or unsubstituted -O(C) 1-3 alkyl)-, -O(C 1-3 Alkyl)O- or -(C 1-4 alkyl)-;

[0132] R 1 It is methyl;

[0133] V is

[0134]

[0135] B is either N or CH;

[0136] R C It is halogen, CF3, or SF5; and

[0137] R 5 and R 6 It is C 1-3 alkyl.

[0138] In some embodiments of compounds having Formula I, the compound is

[0139]

[0140] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0141] L is either substituted or unsubstituted -O(C) 1-3 alkyl)-, -O(C 1-3 Alkyl)O- or -(C 1-4 alkyl)-;

[0142] R 1 It is methyl;

[0143] V is

[0144]

[0145] B is either N or CH;

[0146] R C It is halogen, CF3, or SF5; and

[0147] R 5 and R 6 It is C 1-3 alkyl.

[0148] In some embodiments of compounds having formulas (I), (II), (III), (IV), and (V), R 1 It is a methyl group; n is 0; X is N or CR. X R X It is hydrogen, halogen, -O(C) 1-6 alkyl) or -(C 1-9 Alkyl); L is substituted or unsubstituted -O(CH2) p -or-(CH2) p-, p is 1-4; B is CH or N; b is 0; R C It is CF3, Cl, or SF5; R C It is CF3; and R 5 and R 6 It is a methyl group.

[0149] In some embodiments of compounds having formulas (I), (II), (III), (IV) and (V), L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)- or -(CH2)(CH2)(CH2)(CH2)-.

[0150] In some embodiments of compounds having formulas (I), (II), (III), (IV) and (V), L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)- or -(CH2)(CH2)(CH2)(CH2)-.

[0151] In some embodiments of compounds having formulas (I), (II), (III), (IV) and (V), L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)- or -(CH2)(CH2)(CH2)(CH2)-.

[0152] The additional embodiments provided herein include any combination of one or more specific embodiments described above.

[0153] In some embodiments of compounds having formula (I), the compounds are those from Table 1.

[0154] The compounds listed in Table 1 were tested in the AR-mediated assays described herein, and the assays revealed that these compounds were active. In one embodiment, a concentration of 1 μM of the compounds described herein resulted in the degradation of AR proteins by at least about 50% or more.

[0155] Preparation method of piperidine dione compounds

[0156] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or the methods provided herein. For example, but not limited to, compounds having formula (I), wherein R 1 R 2 R 3 R 4R 5 R 6 R B R C L, V, X, m, a, and b, as defined herein, can be prepared as outlined in the schemes shown below and in the examples described herein. It should be noted that those skilled in the art will understand how to modify the procedures described in the illustrative schemes and examples to obtain the desired product.

[0157]

[0158] Option 1

[0159] As shown in Scheme 1, compounds having 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 groups can be prepared by reacting a piperidine derivative a with an ester intermediate b (where LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base, in a solvent (e.g., N,N-diisopropylethylamine in DMF, or K2CO3 in acetonitrile), at a high temperature (e.g., between about 40°C and about 100°C) to provide intermediate c. In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to facilitate this conversion. Removal of the ester protecting group from intermediate c (e.g., when alk = Me, Et, or other alkyl groups, by treatment with a hydroxide base in a solvent (e.g., LiOH in THF and water), or when alk = tert-butyl, by treatment with an acid in a solvent (e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane)) provides intermediate d. Intermediate d is coupled with piperidine dione 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 (e.g., DCM, DMF, NMP, or mixtures thereof) at a temperature of 0°C to about 70°C to provide a compound having 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)-). Alternatively, intermediate c(where X is N and L is -O(C) 1-3 alkyl)- or -(C 1-4The alkyl group can be prepared by reacting a derivative VL-LG (LG being a suitable leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate) with a suitable derivatized piperidinyl ester derivative f (e.g., where alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base, in a solvent (e.g., N,N-diisopropylethylamine in DMF, or K2CO3 in acetonitrile), at a high temperature (e.g., between about 40°C and about 80°C) to provide intermediate c.

[0160]

[0161] Option 2

[0162] Compounds having formula (I) (where X is N and L is -O (C 1-3 alkyl)- or -(C 1-4 The alkyl group can also be prepared according to the alternative sequence shown in Scheme 2 by reacting a derivative VL-LG (LG being a suitable leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate) with a suitably derivatized piperidinyl derivative g in the presence of a base, in a solvent (e.g., N,N-diisopropylethylamine in DMF, or K2CO3 in acetonitrile), at a high temperature (e.g., between about 40°C and about 100°C). In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to facilitate this conversion. Alternatively, compounds having 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 The alkyl group can be prepared by reacting compound e with a suitably functionalized carbonyl intermediate h (where LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, 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 of 0°C to about 60°C to provide intermediate i. Reaction of i (where LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkyl sulfonate) with amine intermediate a in the presence of a base, in a solvent (e.g., N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile), at a high temperature (e.g., between about 40°C and about 80°C) provides a compound having 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)-).

[0163]

[0164] Option 3

[0165] Intermediate g, such as amine g, can be prepared according to scheme 3. Intermediate k is provided by reacting a suitably functionalized piperazine j with an ester intermediate b (where LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base, in a solvent (e.g., N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile), at a high temperature (e.g., between about 40°C and about 100°C). In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to facilitate this conversion. Removal of the ester protecting group from intermediate k (e.g., when alk = Me, Et, or other alkyl groups, by treatment with a hydroxide base in a solvent (e.g., LiOH in THF and water), or when alk = tert-butyl, by treatment with an acid in a solvent (e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane)) provides intermediate l. Amine intermediate g is provided by coupling intermediate l with piperidine dione 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 (e.g., DCM, DMF, NMP, or mixtures thereof) at a temperature of 0°C to about 70°C. Intermediate f, such as amine f, can be obtained by removing the N-protecting group P from intermediate k. N (For example, when P) N When it is Boc, it can be treated with an acid in a solvent (e.g., HCl in dioxane or EtOAc) at room temperature, or with TFA in DCM at room temperature, or when P N When it is Bn or Cbz, it is prepared by hydrogenation in a solvent (e.g., palladium on carbon in methanol) using a metal catalyst.

[0166]

[0167] Option 4

[0168] Intermediates, for example, a (where X is N and L is -O (C 1-3 alkyl)- or -(C 1-4 Alkyl groups can be prepared according to scheme 4. VL-LG (where L is -O(C)) is used. 1-3 alkyl)- or -(C 1-4Alkyl groups (where LG is a leaving group, such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate) are treated with amine n in the presence of a base, in a solvent (e.g., N,N-diisopropylethylamine in DMF, or K₂CO₃ in acetonitrile), at a high temperature (e.g., between about 40°C and about 100°C) to provide intermediate o. In some cases, iodide salts (e.g., sodium iodide or potassium iodide) are used to facilitate this conversion. The N-protecting group P is removed from intermediate o. N (For example, when P) N When it is Boc, it can be treated with an acid in a solvent (e.g., HCl in dioxane or EtOAc) at room temperature, or with TFA in DCM at room temperature, or when P N When X is Bn or Cbz, intermediate a is provided by hydrogenation in a solvent (e.g., palladium on carbon in methanol) using a metal catalyst (where X is N and L is -O (C 1-3 alkyl)- or -(C 1-4 alkyl)-).

[0169]

[0170] Option 5

[0171] The intermediate p (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu) is treated with a suitably derivatized 4-cyanophenyl isothiocyanate or 5-isothiocyanate pyridinium q in the presence of a base (e.g., triethylamine) in a solvent (e.g., EtOAc) at a high temperature (e.g., between about 70°C and about 90°C) to provide intermediate r. An intermediate such as u (where LG is a leaving group (e.g., Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate), and L is -O (C 1-3 alkyl)- or -(C 1-4 Alkyl groups can be derived from intermediates s (where P) O It is prepared by removing the protecting group P from the alcohol (such as THP, TBS, acetate, or benzyl). O (For example, when P) O When LG is THP, treatment with a catalytic acid in a solvent (e.g., HCl in dioxane) provides the alcohol intermediate t. Activating the alcohol functional group in t to a leaving group (e.g., when LG is Br, by treating t with thionyl bromide in dichloromethane) provides the intermediate u (where LG is a leaving group (e.g., Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate), and L is -O (C 1-3 alkyl)- or -(C 1-4 Alkyl groups (-) can be further reacted to provide compounds having formula (I).

[0172]

[0173] Option 6

[0174] Intermediate p (where L is -O(C)) 1-3 alkyl)-and R Z It is a protected alcohol OP O (e.g., THP ether or TBS ether) For example, aa can be prepared according to scheme 6. From alcohol intermediate v (where P N It begins with an amine protecting group (e.g., Bn or Boc), and binds it to an electrophilic reagent w (where LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate, and P...). O The reaction, in the presence of an oxygen-protecting group (such as THP or TBS), in a solvent (e.g., KOH and tetrabutylammonium bromide in xylene), at high temperatures (e.g., between 70°C and 130°C), provides intermediate x. Removal of the protecting group P from x... N (For example, when P) N When it is Bn, it is hydrogenated on carbon with palladium in methanol, or when P N When Boc is present, treatment with HCl in dioxane provides amine intermediate y. Reacting 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, trifluoromethanesulfonate, or alkylsulfonate) in a base and possibly, in the presence of an iodide salt, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile), at a high temperature (e.g., between about 70°C and 130°C) provides intermediate aa, which can be further reacted to provide a compound having formula (I) (where L = -O(C)). 1-3 alkyl)-).

[0175]

[0176] Option 7

[0177] Intermediate p (where L is -(C 1-3 alkyl)-and R Z It is an alcohol or a protected alcohol (e.g., THP ether or TBS ether). For example, hh can be prepared according to scheme 6. From aldehyde intermediate bb (where P NStarting with an amine protecting group (e.g., Bn or Boc), reacting it with an olefinic agent in the presence of a base in a solvent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) at temperatures between 0°C and 60°C provides the olefin intermediate cc. Reduction of cc by hydrogenation in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at high pressure (e.g., between 10 and 100 psi) provides the intermediate dd. Reduction of the ester functional group is accomplished by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at temperatures between -78°C and 25°C, which provides 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 a temperature between -78°C and 25°C to provide intermediate ff. Hydrogenation of ff in the presence of a catalyst, in a solvent (e.g., palladium on carbon, in methanol, under a hydrogen atmosphere), under high pressure (e.g., between 10 and 100 psi) provides intermediate ee. Removal of the protecting group P from ee N (For example, when P) N When it is Bn, it is hydrogenated on carbon with palladium in methanol, or when P N When Boc is present, treatment with HCl in dioxane provides the amine intermediate gg. Reacting the amine gg with the 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, trifluoromethanesulfonate, or alkylsulfonate) in a base and optionally, in the presence of an iodide salt, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile), at a high temperature (e.g., between about 70°C and 130°C) provides the intermediate hh (where R... Y It is an H or alcohol protecting group (e.g., THP, TBS, or Tr), which can be further reacted to provide a compound having formula (I) (where L-(C 1-3 alkyl)-).

[0178]

[0179] Option 8

[0180] Intermediate p (where L is -(C 1-3 Alkyl)O- and R Z (If it is a heterocyclic or cycloalkyl group, for example, mm can be prepared according to scheme 8. From intermediate ii (P N’ It is an amine protecting group such as Bn or Boc, and LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate or alkylsulfonate) that begins with an alcohol (where P is a leaving group such as Cl, Br, I, trifluoromethanesulfonate or alkylsulfonate) to react with an alcohol (where P is a leaving group such as Cl, Br, I, trifluoromethanesulfonate or alkylsulfonate). NThe amine protecting group (e.g., Bn or Boc) reacts in the presence of a base and optionally a catalyst in a solvent (e.g., KOH and tetrabutylammonium bromide in xylene) at high temperatures (e.g., between 70°C and 130°C) to provide the ether intermediate kk. Removal of the protecting group P from kk... N’ (For example, when P) N’ When it is Bn, it is hydrogenated on carbon with palladium in methanol, or when P N When it is Boc, the amine intermediate ll is provided by treatment with HCl in dioxane.

[0181] Reaction of amine ll with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate) in a base and optionally, in the presence of an iodide salt, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile), at a high temperature (e.g., between about 70°C and 130°C) provides an intermediate mm, which can be further reacted to provide a compound having formula (I) (where L is -(C 1-3 Alkyl)O-).

[0182]

[0183] Option 9

[0184] For certain intermediates p (where L is -O(C)) 1-3 alkyl)-and R Z (If it is a protected heterocyclic or cycloalkyl group, for example qq, the order can be changed as shown in scheme 9.) From alcohol v (where P N It begins with an amine protecting group (e.g., Bn or Boc), causing it to react with an electrophilic intermediate nn (where LG is a leaving group such as Cl, Br, I, trifluoromethanesulfonate, or alkylsulfonate, and P...). N’ The reaction of an amine protecting group (e.g., Bn or Boc) in a base and optionally, a catalyst, in a solvent (e.g., KOH and tetrabutylammonium bromide in xylene), at a high temperature (e.g., between 70°C and 130°C), provides the ether intermediate oo. Removal of the protecting group P from oo... N (For example, when P) N’ When it is Bn, it is hydrogenated on carbon with palladium in methanol, or when P NWhen Boc is present, treatment with HCl in dioxane provides the amine intermediate pp. Reacting the amine pp with the 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, trifluoromethanesulfonate, or alkylsulfonate) in a base and optionally, in the presence of an iodide salt, in a solvent (e.g., potassium carbonate and potassium iodide in acetonitrile), at a high temperature (e.g., between about 70°C and 130°C) provides the intermediate qq, which can be further reacted to provide a compound having formula (I) (where L is -O(C)). 1-3 alkyl)-).

[0185]

[0186] Option 10

[0187] Intermediate nn (where X is CR) Z Certain instances of ) (e.g., vv) were prepared according to scheme 10. The ketone intermediate rr (where P) was prepared. N The olefin intermediate SS is provided by olefination of amine protecting groups (e.g., Bn, Boc, or Cbz) with an olefinating agent and a base in a solvent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) at temperatures between 0°C and 60°C. Hydrogenation of SS in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at high pressure (e.g., between 10 and 100 psi) provides intermediate TT. Reduction of the ester functional group in TT by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at temperatures between -78°C and 25°C provides intermediate UU. Activating alcohol uu to a leaving group LG (e.g., if LG is Br, by treatment with thionyl bromide in dichloromethane and DMF, or if LG is trifluoromethanesulfonate, by treatment with trifluoromethanesulfonic anhydride in dichloromethane) provides intermediate vv, which can be further reacted to provide a compound having formula (I) (where L is -O(C)). 1-3 alkyl)-and X is CR X ).

[0188]

[0189] Option 11

[0190] Appropriately derivatized piperidinedione e (wherein) can be prepared from an indazole derivative ww (where Hal is a halogen (e.g., Cl or Br)) by treating it under iodination conditions (e.g., iodine and potassium hydroxide in DMF, at a temperature between -40°C and 40°C) to provide an iodide intermediate xx. For intermediate e (where R 1If it is an alkyl group (e.g., Me, Et, Pr), the intermediate xx can be used with appropriate R. 1 -Hal (where Hal is a halide (e.g., Cl, Br, I)) is methylated in a solvent (e.g., iodomethane and potassium tert-butoxide in DMF) in the presence of a base to provide intermediate yy. yy is then reacted with a boric acid derivative zz (where R... W The intermediate aaa is provided by coupling H or an alkyl group (e.g., Me or pinacol) in a solvent (e.g., Pd(PPh3)4 and potassium carbonate in dioxane and water or XPhos Pd G3 and cesium carbonate in THF and water) in the presence of a palladium catalyst and a base. The intermediate bbb is provided by reacting aaa with a suitable protected ammonia equivalent (e.g., BnNH2, BocNH2, or Ph2CNH) in a solvent (e.g., Pd(dba)2·BINAP and cesium carbonate in dioxane) in the presence of a catalyst and a base at high temperatures (e.g., between 40°C and 150°C). N It is an amine protecting group (e.g., Boc, Bn, or benzophenone imine). The intermediate bbb is subjected to hydrogenation conditions using a catalyst (e.g., palladium supported on activated carbon in methanol) in a solvent under high hydrogen pressure (between 5 and 100 psi) to provide intermediate e, which is further reacted to provide a compound having formula (I).

[0191] How to use

[0192] In one embodiment, the compounds described herein have the use as a medicine to treat, prevent, or improve a condition in animals or humans. Therefore, this document provides numerous uses of the compounds, including the treatment or prevention of the diseases described below. In one embodiment, the method provided herein includes administering an effective amount of the compound to a subject in need.

[0193] The methods described herein involve administering an effective amount of one or more compounds to a subject in need.

[0194] This article provides a method for treating or preventing androgen receptor (AR)-mediated diseases in subjects, the method comprising administering an effective amount of a compound as described herein to a subject in need.

[0195] This article provides a method for treating or preventing AR-mediated diseases in subjects, the method comprising administering an effective amount of a compound as described herein to a subject in need.

[0196] On the other hand, this document provides compounds for use in treating or preventing AR-mediated diseases in subjects, including administering an effective amount of the compound as described herein to a subject in need. In some embodiments, this document provides compounds for use in treating AR-mediated diseases in subjects, including administering an effective amount of the compound as described herein to a subject in need. In some embodiments, this document provides compounds for use in preventing AR-mediated diseases in subjects, including administering an effective amount of the compound as described herein to a subject in need.

[0197] In some embodiments, the compounds used in the methods herein are compounds as described herein. In some embodiments, the compounds are compounds having formula (I). In some embodiments, the compounds are compounds having formula (II). In some embodiments, the compounds are compounds having formula (III). In some embodiments, the compounds are compounds having formula (IV). In some embodiments, the compounds are compounds from Table 1.

[0198] In some embodiments, AR-mediated disease is AR wild-type mediated disease. In other embodiments, AR-mediated disease is the result of AR amplification.

[0199] In some 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, nilumet, cyproterone acetate, ketoconazole, or spironolactone.

[0200] This document provides a method for reducing AR levels, comprising administering an effective amount of a compound to a subject. This document also provides a compound for use in a method for reducing AR levels in in vivo, in vitro, or extracellular cells, comprising contacting the cells with an effective amount of the compound. In one embodiment, the cells are in a patient. In one embodiment, the cells are not in a patient. In one embodiment, this document provides a method for reducing wild-type AR levels in a tumor, comprising administering a therapeutically effective amount of the compound to reduce wild-type AR levels in the tumor. In one embodiment, this document provides a method for reducing AR-full-length (AR-FL) levels in a tumor, comprising administering a therapeutically effective amount of the compound to reduce AR-full-length (AR-FL) levels in the tumor. In some embodiments, the AR level is reduced compared to the AR level before compound administration. In some embodiments, the AR level is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the AR level before compound administration.

[0201] This document also provides methods for modulating AR protein activity in patients in need, methods comprising administering a compound to the patient. In some such embodiments, this document also provides methods for reducing AR protein activity in patients in need, methods comprising administering a compound to the patient. In some embodiments, AR protein activity is reduced compared to AR protein activity prior to compound administration. In some embodiments, AR protein activity is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to AR protein activity prior to compound administration.

[0202] In some embodiments of the methods described herein, these methods further include administering one or more second agents selected from AR antagonists (e.g., cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (e.g., finasteride and dutasteride), CYP17A1 inhibitors (e.g., abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (e.g., leuprorelin and cetrorelix), and antigonadotropin drugs (e.g., medroxyprogesterone acetate and medroxyprogesterone acetate).

[0203] In some embodiments, the compounds provided herein may be used in any of the methods described above.

[0204] In some embodiments, the compounds provided herein may be used in any of the methods described above.

[0205] Pharmaceutical Compositions and Routes of Administration

[0206] The compounds described herein may be administered to subjects orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0207] The compound can be administered to the subject orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared using conventional organic or inorganic additives prepared by commonly used methods. These additives are, for example, excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or...). The pharmaceutical composition contains calcium citrate, lubricants (e.g., magnesium stearate, light anhydrous silicate, 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), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compounds in the pharmaceutical composition may be at a level that will exert the desired effect, for example, for oral and parenteral administration, at a unit dose of about 0.005 mg / kg of subject body weight to about 10 mg / kg of subject body weight.

[0208] The dosage range of the compound administered to subjects is quite wide and can be determined by the judgment of the healthcare practitioner. Typically, the compound can be administered one to four times daily at a dose of about 0.001 mg / kg of subject body weight to about 10 mg / kg of subject body weight, but these doses may be appropriately varied based on the subject's age, weight, medical condition, and type of administration. In one embodiment, the dose is about 0.001 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.01 mg / kg of subject body weight to about 5 mg / kg of subject body weight, about 0.05 mg / kg of subject body weight to about 1 mg / kg of subject body weight, about 0.1 mg / kg of subject body weight to about 0.75 mg / kg of subject body weight, or about 0.25 mg / kg of subject body weight to about 0.5 mg / kg of subject 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.

[0209] In another embodiment, this document provides methods for treating or preventing diseases or disorders, including administering a compound to a subject in need at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0210] In another embodiment, this document provides unit dose formulations comprising a compound between about 0.1 mg and 500 mg, between about 1 mg and 250 mg, between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, or between about 1 mg and about 10 mg.

[0211] In certain embodiments, this document provides unit dose formulations comprising about 0.1 mg or 100 mg of the compound.

[0212] In another embodiment, this document provides unit dose formulations 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 the compound.

[0213] The compound may be administered once, twice, three times, four times or more daily. In certain embodiments, a dose of 100 mg or less is administered as a once-daily dose and a dose of more than 100 mg is administered twice daily in an amount equal to half of that total daily dose.

[0214] For convenience, the compound can be administered orally. In one embodiment, when administered orally, the compound is taken with food and water. In another embodiment, the compound is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0215] The compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, or via mucosal administration, by inhalation, or topically to the ears, nose, eyes, or skin. The method of administration is determined by the healthcare practitioner and may depend in part on the site of the medical condition.

[0216] In one embodiment, this document provides a capsule containing a compound but without additional carriers, excipients, or mediators.

[0217] In another embodiment, this document provides compositions comprising an effective amount of a compound and a pharmaceutically acceptable carrier or mediator, wherein the pharmaceutically acceptable carrier or mediator may comprise excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0218] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, sugar lozenges, suppositories, and suspensions. The composition may be formulated to contain a daily dose in a single dosage unit, or a portable portion of a daily dose, and may be a single tablet or capsule or a portable volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt (e.g., hydrochloride). Typically, all compositions are prepared according to methods known in medicinal chemistry. Capsules can be prepared by mixing the compound with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances such as various types of starch, powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (e.g., fructose, mannitol, and sucrose), cereal flour, and similar edible powders.

[0219] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Their formulation typically incorporates diluents, binders, lubricants, disintegrants, and the compound itself. Typical diluents include, for example, different types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (e.g., sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, etc.). Natural and synthetic gums are also readily available, including gum arabic, alginate, methylcellulose, polyvinylpyrrolidone, etc. Polyethylene glycol, ethylcellulose, and waxes can also be used as binders.

[0220] To prevent tablets and punches from sticking together in the mold, lubricants may be necessary in tablet formulations. Lubricants can be selected from smooth solids such as talc, magnesium stearate and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon contact with moisture, causing the tablet to decompose and release compounds. Tablet disintegrants include starch, clay, cellulose, alginate, and gums. More specifically, substances such as corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginate, guar gum, citrus pomace, and carboxymethyl cellulose, as well as sodium lauryl sulfate, can be used. Tablets can be coated with sugar as flavoring and sealing agents, or film-forming protectants can be used to modify the tablet's dissolution characteristics. These compositions can also be formulated into chewable tablets, for example, by using substances such as mannitol in the formulation.

[0221] When the desired application of a compound is as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by adding waxes to slightly increase its melting point. Water-miscible suppository bases, particularly those containing polyethylene glycol of varying molecular weights, have a wide range of applications.

[0222] The action of a compound can be delayed or prolonged through proper formulation. For example, slow-dissolving microspheres of the compound can be prepared and incorporated into tablets or capsules, or used as implantable sustained-release devices. The technology also includes preparing microspheres with several different dissolution rates and filling a mixture of microspheres into capsules. Tablets or capsules can be coated with a membrane that resists dissolution for a predictable period. Even parenteral formulations can be made into long-acting formulations by dissolving or suspending the compound in an oily or emulsified medium, allowing it to disperse slowly in serum.

[0223] Listed Examples

[0224] The present invention can be defined by referring to the illustrative embodiments numbered below.

[0225] 1. A compound having Formula I

[0226]

[0227] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0228] R 1 It is C 1-3 alkyl;

[0229] a is 1 or 2;

[0230] R 2 and R 3 Each is independently selected from H and C. 1-3 Alkyl, or R 2 and R 3 And the carbon attached to them forms substituted or unsubstituted C. 3-6 cycloalkyl;

[0231] m is 0-8;

[0232] Each R 4 Independently for substituted or unsubstituted C 1-3 Alkyl, or two R 4 The groups, together with the same or adjacent carbon atoms to which they are attached, form substituted or unsubstituted carbon atoms. 3-6 cycloalkyl, or two R 4 The groups together with the non-adjacent carbon atoms to which they are attached form substituted or unsubstituted 4-7 membered heterocyclic groups;

[0233] X is N or CR X ;

[0234] R X It is hydrogen, halogen, -O(C) 1-6 alkyl) or -(C 1-9 alkyl);

[0235] L is either substituted or unsubstituted -O(C) 1-6 alkyl)-, -(C 1-6 Alkyl)O-, -O(C 1-6 Alkyl)O- or -(C 1-9 alkyl)-;

[0236] V is

[0237]

[0238] in

[0239] B is N, CH, or CR. B ;

[0240] Each R B Independently selected from halogens and substituted or unsubstituted C 1-6 alkyl;

[0241] R C It is halogen, CF3 or SF5;

[0242] R 5 and R 6 It is C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atoms to which they are attached, they form substituted or unsubstituted C atoms. 3-6 cycloalkyl, or 3-6 membered heterocyclic groups; and

[0243] b is 0-2.

[0244] 2. The compound as described in Example 1, wherein R 1 It is a methyl group.

[0245] 3. The compound as described in Example 1 or 2, wherein a is 1, and R 2 and R 3 Both are H.

[0246] 4. The compound as described in any one of Examples 1 to 3, wherein each R 4 It is a substituted or unsubstituted methyl group.

[0247] 5. The compound as described in any one of Examples 1 to 4, wherein each R 4 It is independently selected from methyl and CF3.

[0248] 6. The compound as described in any one of Examples 1 to 5, wherein m is 0, 1, 2, 3 or 4.

[0249] 7. The compound as described in any one of Examples 1 to 5, wherein m is 1 or 2.

[0250] 8. The compound as described in any one of Examples 1 to 7, wherein X is N.

[0251] 9. The compound as described in any one of Examples 1 to 7, wherein X is CR X And R X It is hydrogen, halogen, -O(C) 1-6 alkyl) or -(C 1-9 alkyl).

[0252] 10. The compound as described in any one of Examples 1 to 9, wherein L is a substituted or unsubstituted -O(CH2). p -、-O(CH2) p O- or -(CH2) p - and p is 1-4.

[0253] 11. The compound as described in any one of Examples 1 to 9, wherein L is a substituted or unsubstituted -O(CH2). p - and p is 2 or 3.

[0254] 12. The compound as described in any one of Examples 1 to 9, wherein L is a substituted or unsubstituted -O(CH2). p O-, and p is 2 or 3.

[0255] 13. The compound as described in any one of Examples 1 to 9, wherein L is substituted or unsubstituted -(CH2). p - and p is 3 or 4.

[0256] 14. The compound as described in any one of Examples 1 to 9, wherein L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0257] 15. The compound as described in any one of Examples 1 to 9, wherein L is -O(CH2)(CH2)- or -(CH2)(CH2)(CH2)-.

[0258] 16. The compound as described in any one of Examples 1 to 15, wherein B is CH.

[0259] 17. The compound as described in any one of Examples 1 to 15, wherein B is N.

[0260] 18. The compound as described in any one of Examples 1 to 17, wherein b is 0.

[0261] 19. The compound as described in any one of Examples 1 to 18, wherein R C It is CF3, Cl, or SF5.

[0262] 20. The compound as described in any one of Examples 1 to 19, wherein R C It's CF3.

[0263] 21. The compound as described in any one of Examples 1 to 20, wherein R 5 and R 6 It is a methyl group.

[0264] 22. The compound as described in Example 1, having formula II,

[0265]

[0266] Or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof.

[0267] 23. The compound as described in Example 1, having formula III,

[0268]

[0269] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0270] Each R 4m It is independently hydrogen or substituted or unsubstituted methyl, wherein these substituents, when present, are selected from 1 to 5 halogens;

[0271] L is either substituted or unsubstituted -O(C) 1-3 alkyl)-, -O(C 1-3 Alkyl)O- or -(C 1-4 alkyl)-;

[0272] R 1 It is methyl;

[0273] V is

[0274]

[0275] B is either N or CH;

[0276] R C It is halogen, CF3, or SF5; and

[0277] R 5 and R 6 It is C 1-3 alkyl.

[0278] 24. The compound as described in Example 1, having formula IV,

[0279]

[0280] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0281] L is either substituted or unsubstituted -O(C) 1-3 alkyl)-, -O(C 1-3 Alkyl)O- or -(C 1-4 alkyl)-;

[0282] R 1 It is methyl;

[0283] V is

[0284]

[0285] B is either N or CH;

[0286] R C It is halogen, CF3, or SF5; and

[0287] R 5 and R 6 It is C 1-3 alkyl.

[0288] 25. The compound as described in Example 1, having formula V,

[0289]

[0290] Or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers, wherein

[0291] L is either substituted or unsubstituted -O(C) 1-3 alkyl)-, -O(C 1-3 Alkyl)O- or -(C 1-4 alkyl)-;

[0292] R 1 It is methyl;

[0293] V is

[0294]

[0295] B is either N or CH;

[0296] R C It is halogen, CF3, or SF5; and

[0297] R 5 and R 6 It is C 1-3 alkyl.

[0298] 26. The compound as described in Example 1, wherein the compound is selected from Table 1 or its pharmaceutically acceptable salts, tautomers, isotopes, or stereoisomers.

[0299] 27. A pharmaceutical composition comprising an effective amount of a compound as described in any one of Examples 1 to 26, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or mediator.

[0300] 28. A method for treating androgen receptor-mediated diseases, the method comprising administering to a subject in need an effective amount of a compound as described in any one of Examples 1 to 26.

[0301] 29. A method for treating androgen receptor-mediated diseases, the method comprising administering to a subject in need an effective amount of the pharmaceutical composition as described in Example 27.

[0302] 30. The method as described in Example 28 or 29, wherein the androgen-mediated disease is prostate cancer.

[0303] 31. The method as described in Example 30, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

[0304] Example

[0305] The following examples are provided illustratively and not restrictively. Compound naming uses the automatic name generation tool available in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names of chemical structures supporting the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art can modify the procedures described in the illustrative examples to obtain desired products.

[0306] 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 stirring the product and an acid solution (e.g., an aqueous HCl solution) after chromatographic purification.

[0307] Abbreviations used:

[0308]

[0309]

[0310] Example 1: 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0311]

[0312] Trans-4-(dibenzylamino)cyclohexane-1-ol. Benzyl bromide (119 g, 698 mmol, 2.01 equivalents) was added to a mixture of trans-4-aminohexane-1-ol (40 g, 347 mmol, 1.0 equivalent) and cesium carbonate (339 g, 1.04 mol, 3 equivalents) in acetonitrile (900 mL), and the reaction solution was stirred at room temperature. After 48 h, the reaction mixture was filtered and concentrated. The resulting residue was diluted with dichloromethane (300 mL), washed with water (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated. Trans-4-(dibenzylamino)cyclohexane-1-ol (77 g, 261 mmol, 75% yield) was provided as a pale red solid. The crude product was used without further purification. MS (ESI) m / z 116.3 [M+1] + ; 1 H NMR400 MHz 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).

[0313] Trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl-1-amine. At 0 °C, 2-(2-bromoethoxy)tetrahydro-2H-pyran (84.9 g, 406 mmol, 61.5 mL, 2.0 equivalent) and sodium hydroxide (200 g, 5.00 mol, 24.6 equivalent) were added to a mixture of trans-4-(dibenzylamino)cyclohexane-1-ol (60 g, 203 mmol, 1.0 equivalent) and tetrabutylammonium hydrogen sulfate (13.8 g, 40.6 mmol, 0.2 equivalent) in THF (400 mL) and water (200 mL). The reaction solution was heated to 65 °C. After 12 h, the reaction solution was poured into ice water (1.0 L) and the aqueous phase was extracted with ethyl acetate (300 mL x 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 (SiO2, 2%-50% ethyl acetate in petroleum ether) to give trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl-1-amine (60 g, 142 mmol, 70% yield) as a colorless oil. 1H NMR 400MHz CDCl3δ7.37-7.39(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).

[0314] Trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl-1-amine. Under N2, 10% palladium on carbon (6.5 g) was added to a mixture of trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl-1-amine (65 g, 153 mmol, 1.0 equivalent) in MeOH (500 mL). The suspension was degassed under vacuum and purged three times with hydrogen. The reaction solution was stirred at room temperature under a hydrogen atmosphere (15 psi). After 1 h, the reaction solution was filtered and the filtrate was concentrated to give trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl-1-amine (46 g) as a grayish-white oil. The crude material was used without further purification. 1 H NMR400MHz CDCl3δ7.34-7.36(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).

[0315] Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propionate. Methyl 2-bromo-2-methylpropionate (37.2 g, 205 mmol, 26.6 mL, 2.0 equivalent), potassium carbonate (28.4 g, 205 mmol, 2.0 equivalent), and potassium iodide (1.71 g, 10.3 mmol, 0.1 equivalent) were added to a mixture of trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl-1-amine (25 g, 103 mmol, 1.0 equivalent) in acetonitrile (175 mL). The reaction solution was heated to 110 °C. After 16 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The crude material was purified by column chromatography (SiO2, 0-50% ethyl acetate in petroleum ether) to give a yellow oily methyl-2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propionate (18.6 g, 54 mmol, 53% yield). MS (ESI) m / z 344.4 [M+1] + ; 1 H NMR400 MHz CDCl3δ4.63(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).

[0316] 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile was added to a solution of methyl-2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propionate (18.6 g, 54.2 mmol, 1.0 equivalent) in ethyl acetate (130 mL). 4-isothiocyanate-2-(trifluoromethyl)benzylnitrile (24.7 g, 108 mmol, 2.0 equivalent) and N,N-diisopropylethylamine (14.0 g, 108 mmol, 2.0 equivalent) were added. The reaction solution was heated to 90 °C with stirring. After 12 hours, the reaction solution was concentrated and the 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-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (25 g, 46.3 mmol, 86% yield) as a yellow oil.

[0317] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile. HCl / dioxane (4M, 400 mL) was added dropwise to a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (42.5 g, 78.8 mmol, 1.0 equivalent) in dichloromethane (300 mL). The reaction solution was stirred at room temperature. After 1 hour, the reaction solution was concentrated and purified by silica gel column chromatography (1%–20% THF in dichloromethane) to give a bright yellow oil, 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (21 g, 46.1 mmol, 59% yield). MS (ESI) m / z 456.4 [M+1] + ; 1H NMR400 MHz CDCl3δ7.95(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),3.3 7-3.39(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).

[0318] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile. At 0 °C, N,N-dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol, 2.0 equivalent) were added to a mixture of 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (3.500 g, 7.72 mmol, 1.0 equivalent) in dichloromethane (80 mL). After 12 h, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (50 mL × 3). 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-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (4.200 g, 8.13 mmol, crude) as a yellow solid. MS (ESI) m / z 518.1 [M+1] + .

[0319] tert-Butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. A solution of tert-Butyl(3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5.g, 23.33 mmol, 1 equivalent), methyl bromoacetate (3.57 g, 23.33 mmol, 1 equivalent), and triethylamine (10.2 mL, 70 mmol, 3 equivalent) in THF (100 mL, 0.23 M) was stirred at 50 °C. After 18 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 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 hexane) to give tert-butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate as a yellow oil (6.2 g, 21.6 mmol, 92% yield). MS (ESI) m / z 287.2 [M+1] + .

[0320] Methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate. A solution of tert-butyl(3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazin-1-carboxylate (1 g, 3.49 mmol, 1 equivalent) in dichloromethane (3 mL) was reacted with 4 M HCl (in 1,4-dioxane) (8.7 mL, 34.9 mmol, 10 equivalents) and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was concentrated, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate (5 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to provide methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate as a yellow oil (510 mg, 2.72 mmol, 78% yield). MS (ESI) m / z 187.5 [M+1] + .

[0321] Methyl 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate. To 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile (208) N,N-dimethylformamide (3.2 mL, 0.13 M) and N,N-diisopropylethylamine (0.17 mL, 0.960 mmol, 2.4 equivalents) were added to a solution of methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate hydrochloride (116 mg, 0.400 mmol, 1 equivalent) and sodium iodide (79 mg, 0.5200 mmol, 1.3 equivalent). The reaction was stirred at 60 °C. After 48 h, the reaction solution was concentrated and the crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give a yellow solid methyl 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (250 mg, 0.40 mmol, 97% yield). MS (ESI) m / z 624.0 [M+1] + .

[0322] 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid. Lithium hydroxide (100 mg, 4.17 mmol, 10 equivalents) was added to a solution of methyl 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (250 mg, 0.400 mmol, 1 equivalent) in 3:1 water / THF (5 mL) and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with water and the pH was adjusted to approximately 4 by adding 1M hydrochloric acid. The solution was extracted with ethyl acetate (4 x 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (218 mg, 0.358 mmol, 90% yield) as a pale orange solid. MS (ESI) m / z 610.0 [M+1] + .

[0323] 2,6-Bis(benzyloxy)-3-bromopyridine. Cesium carbonate (369 g, 1.13 mol, 2.2 equivalents) was added to a solution of benzyl alcohol (167 g, 1.55 mol, 3 equivalents) and 3-bromo-2,6-difluoropyridine (100 g, 515 mmol) in acetonitrile (1 L). 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 x 3) was added to the residue while stirring at 0 °C for 2 h. A precipitate formed, and the mixture was filtered and the filter cake was dried under vacuum to obtain 2,6-bis(benzyloxy)-3-bromopyridine as a white solid (300 g, 405 mmol, 78% yield). 1 H NMR (400MHz, DMSO-d6) δ7.89 (d, J = 8.0 Hz, 1H), 7.42-7.32 (m, 10H), 6.44 (d, J = 8.4 Hz, 1H), 5.37 (d, J = 34.0 Hz, 4H).

[0324] 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine. Under N2, potassium acetate (71.6 g, 729 mmol, 3 equivalents) was added 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'-bis(1,3,2-dioxacyclopentaborane) (185 g, 729 mmol, 3 equivalents) in DMSO (900 mL, 0.27 M), followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]ferrocene(II) (17.8 g, 24.3 mmol, 0.1 equivalents). The reaction solution was stirred under N2 at 100 °C. After 16 h, the reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (5%-100% ethyl acetate in petroleum ether) to give 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (80 g, 192 mmol, 79% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.85 (d, J = 7.6 Hz, 1H), 7.54-7.52 (m, 2H), 7.43-7.29 (m, 8H), 6.42 (d, J = 8.0 Hz, 1H), 5.38 (d, J = 6.0 Hz, 4H), 1.28 (s, 12H).

[0325] 7-Bromo-3-iodo-1H-indazole. Two batches were run in parallel: potassium hydroxide (32.0 g, 571 mmol, 1.5 equivalents) was added to a solution of 7-bromo-1H-indazole (75.0 g, 380 mmol) and I2 (145 g, 571 mmol, 1.5 equivalents) in N,N-dimethylformamide (1.2 L, 0.3 M) at 0 °C, and the reaction solution was stirred at 15 °C. After 16 h, these batches were combined, quenched with water (15 L), and then quenched with a saturated aqueous sodium sulfate solution (1.5 L). The reaction mixture was filtered and the filter cake was dissolved in ethyl acetate (4 L). The organic solution was washed with brine (1 L), dried over anhydrous sodium sulfate, filtered, and concentrated to give 7-bromo-3-iodo-1H-indazole (233 g, 361 mmol, 94% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ13.95 (s, 1H), 7.69 (d, J = 7.2Hz, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.15 (t, J = 8.0Hz, 1H).

[0326] 7-Bromo-3-iodo-1-methyl-1H-indazole. Two batches were run in parallel: potassium tert-butoxide (80.6 g, 718 mmol, 2 equivalents) was added dropwise to a solution of 7-bromo-3-iodo-1H-indazole (116 g, 359 mmol) in THF (2.4 L, 0.15 M) at 0 °C with stirring for 1 hour. Iodomethane (91.8 g, 646 mmol, 1.8 equivalents) was added dropwise to a solution of iodomethane in THF (400 mL) at 0 °C. After the addition, the reaction mixture was stirred at 15 °C for 14 hours. The reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (2%–10% ethyl acetate in petroleum ether) to give 7-bromo-3-iodo-1-methyl-1H-indazole (138 g, 205 mmol, 57% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.69 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 4.32 (s, 3H).

[0327] 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole. Two batches were run in parallel: under N2, tripotassium phosphate (2M, 449 mL, 898 mmol, 8.3 equivalents), 7-bromo-3-iodo-1-methyl-1H-indazole (36.3 g, 108 mmol), and tetra(triphenylphosphine)palladium(0) (2.08 g, 1.80 mmol, 0.1 equivalents) were added to a solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (75 g, 180 mmol, 1.7 equivalents) in 1,4-dioxane (1.35 L, 0.08 M), and the reaction mixture was stirred at 85 °C for 16 h. The two batches were combined, the organic layer was removed, and the aqueous layer was extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (1%–10% ethyl acetate in petroleum ether) to give 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (100 g, 200 mmol, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.86(d,J=8.0Hz,1H),7.59-7.49(m,2H),7.47-7.27(m,10H ), 6.93 (t, J = 8.0Hz, 1H), 6.60 (d, J = 8.0Hz, 1H), 5.43 (d, J = 0.8Hz, 4H), 4.35 (s, 3H).

[0328] N-Benzyl-3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-7-amine. BINAP (11.2 g, 18.0 mmol, 0.15 equivalents), cesium carbonate (78.1 g, 240 mmol, 2 equivalents), and bis(dibenzylacetone)palladium(0) (6.89 g, 12.0 mmol, 0.1 equivalents) were added to a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (60 g, 120 mmol, 1 equivalent) and benzylamine (25.7 g, 240 mmol, 2 equivalents) in 1,4-dioxane (500 mL, 0.24 M). The reaction solution was stirred at 110 °C under N2 for 16 h. The solution was concentrated and purified by silica gel column chromatography (5-20% ethyl acetate in petroleum ether) to give N-benzyl-3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-7-amine (35 g, 66.5 mmol, 55% yield) as an orange solid. 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=8.0Hz,1H),7.46-7.26(m,15H),6.88(d,J=8.0Hz,1H),6.73(t,J=8.0Hz 1H), 6.56 (d, J = 8.0Hz, 1H), 6.30 (d, J = 7.6z, 1H), 6.08 (t, J = 4.0Hz 1H), 5.40 (s, 4H), 4.40 (s, 5H).

[0329] 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. Two batches were run in parallel: 10% palladium on carbon (4 g) and acetic acid (855 mg, 14.2 mmol, 1 equivalent) were added to a solution of N-benzyl-3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-7-amine (7.5 g, 14.2 mmol) in ethanol (100 mL, 0.07 M) and THF (100 mL, 0.07 M). The reaction mixture was stirred at 45 °C for 96 hours under H2 (50 psi). The two batches were combined, and the solution was filtered and concentrated. The resulting residue was ground with ethanol:THF = 1:1, 30 mL x 2 for 30 min. The mixture was filtered and the filter cake was dried to give 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (6.58 g, 12.7 mmol, 89% yield) as a gray solid. 1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),6.91(d,J=7.2Hz,1H),6.79(t,J=8.0Hz,1H),6.54(d,J=7.2Hz,1H),5.18(s,2H),4.26-4.22(m,4H),2.61-2.58(m,2H),2.49-2.26(m,1H),2.16-2.14(m,1H)。

[0330] 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy Ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (96 mg, 0.15 mmol) was combined with 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (92 mg, 0.36 mmol, 2.4 equivalences), 1-methylimidazolium (0.06 mL, 0.76 mmol, 5.1 equivalences), and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (91 mg, 0.33 mmol, 2.2 equivalences) and dissolved in acetonitrile (1.9 mL, 0.05 M) and N,N-dimethylformamide (1 mL, 0.05 M). The reaction was stirred overnight at rt. The reaction was quenched with water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by standard methods. The dried fraction was absorbed in dichloromethane / acetonitrile, treated with 10 drops of 6N hydrochloric acid aqueous solution, concentrated, and ground with hexane and dichloromethane to give 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a grayish-white solid (16 mg, 0.02 mmol, 12.2% yield).MS(ESI)m / z 850.0[M+1]+; 1H NMR(acetonitrile-d3,400MHz)δ9.50(br s,1H),8.84(s,1H),8.08(d,1H,J=8.3Hz),7.97(d,1H,J=1.6Hz),7.82(dd,1H,J=1.8 ,8.3Hz),7.64(d,1H,J=8.1Hz),7.31(d,1H,J=7.1Hz),7.14(t,1H,J=7.7Hz),4.51(br s,2H),4.30(br dd,1H,J=5.1,9.9Hz),4.24(br s,1H),4.14(s,3H),3.92(br s,2H),3.80(s,1H),3.59(br s,4H),3.41(tt,2H,J=4.0,10.1Hz),3.23(br s,2H),2.89(q,2H,J=13.7Hz),2.7-2.8(m,3H),2.46(dtd,1H,J=5.0,9.5,13.0Hz),2.10(quin,1H,J=2.6Hz),1.81(br s,2H),1.7-1.8(m,1H),1.55(s,6H),1.47(br s,6H),1.4-1.4(m,2H).

[0331] Example 2: 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0332]

[0333] tert-Butyl (trans-4-formylcyclohexyl)carbamate. IBX (352 g, 1.26 mol, 1.2 equivalent) was added to a mixture of tert-butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate (240 g, 1.05 mol, 1 equivalent) in acetonitrile (1.60 L) at 15 °C. The reaction was stirred at 65 °C for 1 h. Two batches were combined for processing and purification. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl (trans-4-formylcyclohexyl)carbamate (470 g, crude) as a white solid. The crude product was used directly for the next step without further purification. 1H NMR(400MHz CDCl3)δ9.62(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).

[0334] Ethyl(E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate. Ethyl 2-(diethoxyphosphoryl)acetate (255 g, 1.14 mol, 1.1 equivalent) was added dropwise to a mixture of sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2 equivalent) in THF (900 mL) at 0 °C. The reaction was stirred at 0 °C for 1 h. A solution of tert-butyl(trans-4-formylcyclohexyl)carbamate (235 g, 1.03 mol, 1 equivalent) in THF (500 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 2 h. The reaction solution was poured into ice water (3.0 L) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (800 mL, 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give ethyl(E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (560 g, crude) as a pale yellow solid. This material was used without further purification. 1 H NMR (400MHz CDCl3) δ6.88 (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).

[0335] tert-Butyl((trans-4-((E)-3-hydroxypropyl-1-en-1-yl)cyclohexyl)carbamate. The reaction was set as two parallel reactions. Diisobutylaluminum hydride (1M, 1.88L, 2 equivalents) was added to a solution of ethyl(E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (280 g, 942 mmol, 1 equivalent) in dichloromethane (1.12 L) under an argon atmosphere at -78 °C. The reaction was stirred at -78 °C for 1 h. The reaction was quenched with MeOH (280 mL) at -60 °C. The two reaction mixtures were combined and poured into saturated citric acid (1.0 kg citric acid in 4.0 L) below 10 °C. The mixture was extracted with ethyl acetate (2.0 L, 1.5 L). The combined organic layers were washed with aqueous sodium bicarbonate solution (2.0 L) and brine (2.0 L), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to provide tert-butyl((trans-4-((E)-3-hydroxypropyl-1-en-1-yl)cyclohexyl)carbamate as a pale yellow solid (420 g, 1.645 mol, 87% yield). 1 H NMR(400MHz CDCl3)δ5.58-5.60(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).

[0336] tert-butyl ((trans-4-(3-hydroxypropyl)cyclohexyl)carbamate. The reaction was run in parallel for four batches. A mixture of tert-butyl ((trans-4-((E)-3-hydroxypropyl-1-en-1-yl)cyclohexyl)carbamate (105 g, 411 mmol, 1 equivalent) and palladium on carbon (10.5 g, 10% purity) in MeOH (600 mL) was degassed and purged three times with H2, and then the mixture was heated at 25 °C in H2 (15 p) Stirred for 12 h under SiO2. Combined the four batches for processing and purification. Filtered and concentrated the reaction solution under reduced pressure. Purified the crude material by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 0 / 1). Tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl) carbamate (82 g, 19% yield) and tert-butyl (trans-4-(3-oxopropyl)cyclohexyl) carbamate (200 g, 48% yield) were obtained as white solids. 1H NMR(400MHz CDCl3)δ4.38(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).

[0337] 3-(trans-4-aminocyclohexyl)prop-1-ol hydrochloride. Two reactions were carried out in parallel. HCl / MeOH (4M, 500mL) was added to a solution of tert-butyl(trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (115g, 447mmol, 1 equivalent) in MeOH (200mL). The reaction was stirred at 15°C for 6h. The two batches were combined for processing and purification. The reaction solution was filtered and concentrated to give 3-(trans-4-aminocyclohexyl)prop-1-ol hydrochloride (160g, 92% yield) as a pale yellow solid. The material was used without further purification. 1 H NMR(400MHz DMSO-d6)δ8.09(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,2 H), 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).

[0338] Methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropionate. Potassium carbonate (428 g, 3.10 mol, 5 equivalents) and methyl 2-bromo-2-methylpropionate (449 g, 2.48 mol, 4 equivalents) were added to a mixture of 3-(trans-4-aminocyclohexyl)prop-1-ol hydrochloride (120 g, 619 mmol, 1 equivalent) in acetonitrile (750 mL). The mixture was stirred at 110 °C for 12 h. The reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (5%-100% ethyl acetate in petroleum ether) to give methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropionate (54 g, 210 mmol, 34% yield) as a yellow oil. MS (ESI) m / z 258.2 [M+1] + .

[0339] 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzylnitrile. N,N-diisopropylethylamine (54.2 g, 420 mmol, 2 equivalents) was added to a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropionate (54 g, 210 mmol, 1 equivalent) and 4-isothiocyanate-2-(trifluoromethyl)benzylnitrile (62.2 g, 273 mmol, 1.3 equivalents) in ethyl acetate (350 mL). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 0 / 1) to give 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (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).

[0340] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile. At 0 °C, thionyl bromide (0.752 g, 3.620 mmol, 1 equivalent) was slowly added to a solution of 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.820 g, 1.81 mmol, 1 equivalent) in N,N-dimethylformamide (0.800 mL) and dichloromethane (8 mL). After stirring at 0°C for 2 h, the reaction solution was concentrated and purified by silica gel column chromatography (15%-25% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.650 g, 1.259 mmol, 70% yield) as a brown solid. MS (ESI) m / z 516.1 [M+1] + .

[0341] Methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate. To 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl) 2,N-diisopropylethylamine (0.46 mL, 4.84 mmol, 5 equivalents) was added to a solution of methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (270 mg, 1.45 mmol, 1.5 equivalents) in N,N-dimethylformamide (4.8 mL, 0.2 M) and the reaction solution was stirred at 50 °C. After 18 h, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1%–10% methanol in dichloromethane) to give a pale yellow oil, methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate (487 mg, 0.784 mmol, 81% yield). MS (ESI) m / z 622.3 [M+1] + .

[0342] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid. LiOH (59 mg, 2.46 mmol, 3 equivalents) was added to a solution of methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (500 mg, 0.82 mmol, 1 equivalent) in 5:1 THF / water (4 mL, 0.2 M). The reaction solution was stirred at room temperature. After 12 hours, the reaction solution was diluted with water (10 mL), adjusted to pH 5 by adding 2 M HCl, and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (364 mg, 0.599 mmol, 73% yield) as a grayish-white solid. MS (ESI) m / z 608.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ8.33(d,J=8.0Hz,1H),8.19(s,1H),7.97(d,J=8.4Hz,1H),3.83(s,1H),3.37(s,2H),3.14(s,2H),2.89(s,2H),2.73(s,2H),2.40(s,2H ),2.00(s,2H),1.81(d,J=12.0Hz,2H),1.72(d,J=10.4Hz,2H),1.44-1. 54(m,8H),1.15-1.19(m,3H),1.05-1.08(m,2H),1.01(d,J=6.4Hz,6H).

[0343] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a compound containing 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine) In a flask containing 100 mg (0.16 mmol, 1 equivalent) of 1-(amino-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (51 mg, 0.20 mmol, 1.25 equivalent), N,N-dimethylformamide (1.0 mL, 0.16 M), 1-methylimidazolium (54 mg, 0.66 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (92 mg, 0.33 mmol) were added. The reaction mixture was stirred at 25 °C. After 20 min, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a white solid (108 mg, 0.119 mmol, 73% yield). MS (ESI) m / z 848.4 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.34(d,J=8.31Hz,1H),8.20(d,J=1.59Hz,1H),7.97(dd, J=1.65,8.25Hz,1H),7.64(d,J=8.07Hz,1H),7.20(d,J=7.21Hz,1H),7.06-7.15(m,1H),4.39(br dd,J=5.07,10.21Hz,1H),4.18-4.32(m,4H),4.10(s,4H),3.77-3.87(m,2H),3.48-3.60(m,2H),3.01(br s,2H),2.55-2.84(m,5H),2.30-2.43(m,1H),2.17(qd,J=5.25,13.34Hz,1H),1.84(br d,J=11.74Hz,2H),1.74(br d,J=9.41Hz,4H),1.55(s,6H),1.00-1.36(m,11H).

[0344] Example 3: 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0345]

[0346] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)benzyl nitrile was added to a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propionate (2.03 mL, 5.82 mmol, 1 equivalent) in ethyl acetate (1.3234 mL). The reaction solution was heated to 90 °C with stirring. After 18 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-50% ethyl acetate in hexane) to give 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)benzyl nitrile (2 g, 3.9521 mmol, 68% yield) as a white solid. MS (ESI) m / z 506.2 [M+1] + .

[0347] 2-Chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)benzyl nitrile. Add 4M HCl in dioxane (39.52 mL, 158.08 mmol, 20 equivalents) 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-thioimidazolidine-1-yl)benzyl nitrile (4.0 g, 7.9 mmol, 1 equivalent) in chloroform (5.7 mL) and stir the reaction solution at room temperature. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-40% ethyl acetate in hexane) to give 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)benzyl nitrile (1.5 g, 2.883 mmol, 36% yield) as a grayish-white solid. MS (ESI) m / z 422.2 [M+1] + .

[0348] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile. Thionyl bromide (0.59 mL, 7.64 mmol, 2.5 equivalences) was added to a solution of 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)benzyl nitrile (1.51 g, 3.06 mmol) in dichloromethane (38 mL) and N,N-dimethylformamide (3.8 mL), and the reaction solution was stirred at room temperature. After 1 h, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL) and 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 hexane) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile (1.171 g, 2.42 mmol, 79% yield) as a pale yellow solid. MS (ESI) m / z 484.0 [M+1]+.

[0349] Methyl 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate. To 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)- 2-Chlorobenzenenitrile (400 mg, 0.825 mmol, 1 equivalent) and methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate hydrochloride (239 mg, 1.073 mmol, 1.3 equivalent) were added to a solution of N,N-dimethylformamide, followed by N,N-diisopropylethylamine (1.03 mL, 5.94 mmol, 7 equivalent), and the reaction solution was stirred at 60 °C. After 18 h, the reaction solution was concentrated and purified by silica gel column chromatography (1%–10% methanol in dichloromethane) to give a yellow solid methyl 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetate (311 mg, 0.528 mmol, 64% yield). MS (ESI) m / z 590.0 [M+1] + .

[0350] 2-((2R,6S)-4-(2-(((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid. Lithium hydroxide (38 mg, 1.58 mmol, 3 equivalents) was added to a solution of methyl 2-((2R,6S)-4-(2-(((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid in a 4:1 solution (1 mL) of 1,4-dioxane in water. The reaction solution was stirred at room temperature. After 7 h, the reaction solution was diluted with water (10 mL) and adjusted to approximately pH 7 by adding 2 M HCl. The solution was extracted with ethyl acetate (4 x 50 mL), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (219 mg, 0.380 mmol, 72% yield) as a pale yellow solid. This material was used without further purification. MS (ESI) m / z 576.0 [M+1]+.

[0351] 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. N,N-dimethylformamide (1.2 mL, 0.2 M) was added to a solution of 4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)acetic acid (150 mg, 0.240 mmol, 1 equivalent) and 3-(7-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione (152 mg, 0.590 mmol, 2.5 equivalents), followed by 1-methylimidazolium (0.1 mL, 1.25 mmol, 5 equivalents). The reaction solution was stirred at room temperature until all solids dissolved. N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (151 mg, 0.540 mmol, 2 equivalents) was added, and the reaction was stirred at room temperature. After 2 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting 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-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a grayish-white solid (62.5 mg, 0.071 mmol, 29% yield).MS(ESI)m / z 816.0[M+1]+; 1H NMR (DMSO-d6, 400MHz) δ10.91 (s, 1H), 9.9-10.6 (m, 1H), 8.13 (d, 1H, J = 8.3Hz), 7.92 (d, 1H, J = 1.8Hz), 7.63 (d, 1H, J = 8.3Hz), 7.60(dd,1H,J=1.8,8.3Hz),7.20(d,1H,J=7.2Hz),7.11(t,1H,J=7.8Hz),4.39(dd,1H,J=5.0,10.1Hz),4.09(s,3H),3.82(br t,2H,J=4.8Hz),3.8-3.8(m,2H,J=4.3Hz),3.6-3.7(m,2H),3.47(br d,3H,J=7.3Hz),3.37(tdd,2H,J=3.6,7.3,14.5Hz),3.24(br s,2H),2.8-3.0(m,3H),2.7-2.7(m,1H),2.61(td,1H,J=4.9,17.4Hz),2.36( dddd,1H,J=4.8,10.3,13.8,15.0Hz),2.17(qd,1H,J=5.5,13.3Hz),2.10(br d,2H,J=10.3Hz),1.72(br d, 2H, J = 10.5Hz), 1.53 (s, 6H), 1.36 (q, 2H, J = 11.3Hz), 1.23 (br d, 6H, J = 4.2Hz).

[0352] Example 4: 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0353]

[0354] 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. Methyl-2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propionate (6.70 g, 19.51 mmol, 1 equivalent), 5-isothiocyanate-3-(trifluoromethyl)pyridinecarboxylonitrile (8.94 g, 39.0 mmol, 2 equivalents) and N,N-diisopropylethylamine (6.8 mL, 39.0 mmol, 2 equivalents) were combined in ethyl acetate (56 mL, 0.35 M) and heated to 90 °C for 16 h in a sealed tube. The reaction mixture was diluted with ethyl acetate (100 mL) and 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 (in hexane, 10%–100% ethyl acetate) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (3.5 g, 6.4743 mmol, 33% yield) as a brown solid. MS (ESI) m / z 457.0 [M-tetrahydropyran protecting group +1] + .

[0355] 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. Add 4M hydrochloric acid (16.2 mL, 64.7 mmol, 10 equivalents) to a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (3.50 g, 6.47 mmol, 1 equivalent) in dichloromethane (30 mL) and stir the reaction solution at room temperature. After 3 hours, the reaction solution was concentrated to provide a slightly reddish oily substance: 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (3.20 g, 6.4 mmol, 99% yield). The crude material was used without further purification. MS (ESI) m / z 457.0 [M+1] + .

[0356] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. Thionyl bromide (1.26 mL, 16.2 mmol, 2.5 equivalences) was added to a solution of 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (3.20 g, 6.49 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide (5 mL), and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated and the crude material was purified by silica gel column chromatography (5%–80% ethyl acetate in hexane) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (2.00 g, 3.85 mmol, 59% yield) as a reddish-brown oil. MS (ESI) m / z 519.8 [M+1] + .

[0357] tert-Butyl(3S,5R)-4-(2-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazin-1-carboxylate. Acetonitrile (2 mL) was added to a 20 mL vial containing 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.2 g, 0.7 mmol, 1 equivalent) and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (0.5 g, 1.6 mmol, 2.2 equivalents), followed by the addition of 1-methylimidazole (0.30 mL, 3.7 mmol, 5 equivalents). The reaction solution was stirred at room temperature for 10 min. Then, a solution of 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.2 g, 0.88 mmol, 1.2 equivalents) in acetonitrile (1 mL) was added, and the reaction solution was stirred at room temperature. After 16 h, the reaction solution was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was removed and washed with 100 mL of brine, dried over magnesium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (50 g column, 1%–10% methanol in dichloromethane) to give tert-butyl(3S,5R)-4-(2-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (0.16 g, 0.31 mmol, 42% yield). MS (ESI) m / z 513.3 [M+1] + .

[0358] 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide hydrochloride. Add 2 mL of dichloromethane to a 20 mL vial containing tert-butyl(3S,5R)-4-(2-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazin-1-carboxylate (0.16 g, 0.29 mmol), followed by 4 M hydrochloric acid in dioxane (1.35 mL, 5.41 mmol, 20 equivalences). Stir the reaction mixture at room temperature. After 20 h, the reaction solution was concentrated to provide 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.1 g, 0.26 mmol, 83% yield) as a yellow solid, which was used without further purification. MS (ESI) m / z 413.2 [M+1] + .

[0359] 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a compound containing 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3- Acetonitrile (2 mL) was added to a 1-duralumin vial containing (trifluoromethyl)pyridinecarboxylonitrile (0.1 g, 0.18 mmol, 1 equivalent), 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.1 g, 0.23 mmol, 1.3 equivalent), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equivalent). N,N-diisopropylethylamine (0.19 mL, 1.08 mmol, 6 equivalent) was then added. The reaction vial was heated to 60 °C with stirring. After 16 h, 3 mL of the solution was purified using dimethyl sulfoxide and standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.06 g, 0.07 mmol, 38% yield). MS (ESI) m / z 851.0 [M+1] + ; 1 H NMR(DMSO-d6,500MHz)δ10.7-11.0(m,1H),9.0-9.3(m,1H),8.5-8.9(m,1H),7.5-7.8(m,1 H),7.0-7.3(m,3H),6.6-6.8(m,1H),4.3-4.5(m,1H),4.0-4.2(m,4H),3.8-3.9(m,3H),3.6 -3.8(m,3H),3.4-3.5(m,2H),3.3-3.4(m,1H),3.2-3.3(m,2H),2.8-2.9(m,2H),2.6-2.8( m,2H),2.3-2.4(m,1H),2.1-2.2(m,3H),1.7-1.8(m,4H),1.5-1.7(m,6H),1.3-1.5(m,7H).

[0360] Example 5: 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0361]

[0362] Trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl-1-amine was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran (113.28 g, 507.75 mmol, 2.5 equivalents), tetrabutylammonium bromide (13.09 g, 40.62 mmol, 0.2 equivalents), and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 equivalents) in xylene (450 mL, 0.45 M). The reaction solution was stirred at room temperature. After 24 h, the reaction solution was diluted with ethyl acetate (500 mL), washed with water (200 mL) and 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)cyclohexyl-1-amine (40.0 g, 91.4 mmol, 45% yield), a pale yellow oil. MS (ESI) m / z 438.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.38-7.32(m,4H),7.31-7.28(m,4H),7.24-7.22(m,2 H),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)

[0363] Trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl-1-amine. 10% palladium on carbon (10.0 g, 9.39 mmol) was added to a solution of trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl-1-amine (20.0 g, 45.7 mmol, 1 equivalent) in methanol (100 mL). The reaction flask was evacuated and purged three times with hydrogen, then stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 h, the reaction solution was filtered and the filtrate concentrated to provide trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl-1-amine (11.00 g, 42.74 mmol, 94% yield) as a pale yellow oil. This material was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ4.52(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).

[0364] Methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propionate. Potassium iodide (0.451 g, 2.72 mmol, 0.1 equivalent) and potassium carbonate (7.518 g, 54.4 mmol, 2 equivalent) were added to a solution of trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl-1-amine (7.00 g, 27.2 mmol, 1 equivalent) and methyl 2-bromo-2-methyl-propionate (12.5 mL, 108.79 mmol, 4 equivalent) in acetonitrile (10 mL). 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)propionate as a pale yellow oil (8.00 g, 22.4 mmol, 82% yield). MS (ESI) m / z 358.4 [M+1] + .

[0365] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolidine-1-yl)benzylnitrile. 2-Chloro-4-cyanophenyl isothiocyanate (10.9 g, 56.0 mmol, 2 equivalents) and triethylamine (7.8 mL, 56.0 mmol, 2 equivalents) were added to a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propionate (10.0 g, 28.0 mmol, 1 equivalent) in ethyl acetate (100 mL, 0.28 M) and the reaction solution was stirred at 80 °C. After 8 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (9%–20% ethyl acetate in petroleum ether) to give a red oily substance, 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolidine-1-yl)benzyl nitrile (8.50 g, 16.3 mmol, 58% yield). MS (ESI) m / z 542.2 [M+23] + .

[0366] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile. 1M hydrochloric acid (5 mL, 13.07 mmol) was added to a solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolium-1-yl)benzyl nitrile (6.80 g, 13.1 mmol) in methanol (50 mL), and the reaction solution was stirred at 25 °C. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 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 (20%-70% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (5.60 g, 12.8 mmol, 98% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=8.4Hz,1H),7.92(d,J=1.6Hz,1H),7.61(dd,J=2.0,8.4Hz,1H),3.89-3.76(m,1H),3.48-3.42(m,4H),3. 24-3.16(m,1H),2.79(d,J=11.2Hz,2H),2.04(d,J=10.8Hz,2H),1.70(d,J=10.8Hz,2H),1.65-1.59(m,2H),1.53(s,6H),1.34-1.25(m,2H).

[0367] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile. At 0 °C, 5.8 g (13.3 mmol) of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (2.1 mL, 26.6 mmol, 2 equivalents) was added to a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (5.8 g, 13.3 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL). After 8 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile (4.8 g, 9.6 mmol, 72% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.14-8.11(m,1H),7.93(d,J=1.6Hz,1H),7.61(dd,J=1.6,8.0Hz,1H),3.84(s,1H),3.58-3.51(m, 4H), 3.27-3.21 (m, 1H), 2.81 (d, J = 11.6Hz, 2H), 2.06 (m, 2H), 1.71 (d, J = 11.6Hz, 2H), 1.53 (s, 6H), 1.33 (d, J = 13.2Hz, 2H).

[0368] 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl) A mixture of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.148 g, 0.300 mmol, 1.5 equivalents) and N,N-diisopropylethylamine (0.17 mL, 1.000 mmol, 5 equivalents) was prepared by adding 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.148 g, 0.300 mmol, 1.5 equivalents) to N,N-diisopropylethylamine (0.17 mL, 1.000 mmol, 5 equivalents). The reaction solution was stirred at 50 °C. After 14 hours, the reaction solution was filtered and purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a white solid (0.082 g, 0.097 mmol, 49% yield). MS (ESI) m / z 830.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),8.13(d,J=8.4Hz,1H),7.93(d,J=1.6Hz,1H),7.67-7.59(m,2H),7.22( d,J=7.2Hz,1H),7.16-7.09(t,J=7.6Hz,1H),4.40(dd,J=4.8,10.0Hz,1H),4.11(s,3H),3.87-3.80(m,2H),3 .68-3.58(m,2H),3.52(t,J=5.6Hz,2H),3.33-3.18(m,2H),3.10(s,4H),2.82(m,2H),2.76-2.56(m,6H),2.4 6-2.31(m,2H),2.07(d,J=10.0Hz,2H),2.01-1.94(m,2H),1.71(d,J=11.2Hz,2H),1.54(s,6H),1.32(s,6H).

[0369] Example 6: 2-((2R,6S)-4-(2-((trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0370]

[0371] 3-Chloro-5-isothiocyanate-pyridin-2-carboxylonitrile. Thiophanate (5.96 mL, 78.14 mmol, 1 equivalent) was added to a solution of 5-amino-3-chloro-pyridin-2-carboxylonitrile (10.00 g, 65.12 mmol, 1 equivalent) in toluene (20 mL). The mixture was stirred at 110 °C. After 16 h, the reaction solution was concentrated and purified by silica gel chromatography (20%–50% ethyl acetate in petroleum ether) to give 3-chloro-5-isothiocyanate-pyridin-2-carboxylonitrile (8.000 g, 40.89 mmol, 63% yield) as a red solid.

[0372] Triethylamine (5.7 mL, 40.89 mmol, 2 equivalents) was added to a mixture of methyl 3-chloro-5-isothiocyanate-pyridin-2-carboxylonitrile (4.000 g, 20.45 mmol, 1 equivalent) and methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propionate (7.720 g, 22.49 mmol, 1.1 equivalents) in ethyl acetate (100 mL, 0.2 M). The reaction solution was stirred at 90 °C. Six hours later, the reaction solution was concentrated and purified by silica gel chromatography (10%–50% ethyl acetate in petroleum ether) to give 3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)pyridinecarboxylate (4.000 g, 7.89 mmol, 39% yield) as a yellow solid. MS (ESI) m / z = 507.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ8.92-8.72(m,1H),8.62-8.31(m,1H),4.68-4.50(m,1H),3.91-3.63(m,4H),3.62-3.52(m ,3H),3.50-3.39(m,3H),2.91-2.73(m,3H),2.10-2.03(m,2H),1.75-1.68(m,3H),1.55(s,6H),1.50-1.43(m,4H).

[0373] 3-Chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)pyridinecarboxylonitrile. 2M hydrochloric acid (3 mL, 15.78 mmol, 2 equivalents) was added to a solution of 3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioimidazolidine-1-yl)pyridinecarboxylonitrile (4.000 g, 7.89 mmol, 1 equivalent) in methanol (30 mL, 0.27 M). The reaction solution was stirred at 25 °C. After 2 h, the pH of the mixture was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (33-100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)pyridinecarboxylate (2.400 g, 0.01 mmol, 69% yield) as a yellow solid. MS (ESI) m / z 423.3 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.59 (s, 1H), 7.43-7.33 (m, 2H), 7.15 (br d, J = 7.0Hz, 1H), 6.57 (br s,1H),4.40(t,J=6.7Hz,2H),2.98(s,3H),2.70-2.55(m,2H),1.53(s,5H), 1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H).

[0374] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-chloropyridinecarboxylonitrile. At 0 °C, thionyl bromide (0.65 mL, 10.17 mmol, 2 equivalents) was added to a solution of 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)pyridinecarboxylonitrile (2.150 g, 5.08 mmol, 1 equivalent) in dichloromethane (5 mL, 1 M) and N,N-dimethylformamide (0.50 mL). The mixture was stirred at 25 °C for 16 h. The pH of the mixture was adjusted to 8 using saturated sodium carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (150 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (50%–100% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-chloropyridinium carbide as a red solid (2.3 g, 4.73 mmol, 93% yield). MS (ESI) m / z 485.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.90-8.72(m,1H),8.60-8.44(m,1H),3.93-3.81(m,1H),3.79-3.72(m,2H),3.61-3.53(m,2H),3.34(br s,1H),2.90-2.74(m,2H),2.12-2.02(m,2H),1.76-1.67(m,2H),1.59-1.52(m,6H),1.44-1.28(m,2H).

[0375] 2-((2R,6S)-4-(2-((trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-chloropyridinecarboxylate (0.100) N,N-diisopropylethylamine (0.14 mL, 0.820 mmol, 4 equivalents) and sodium iodide (0.031 mg, 0.210 mmol, 1 equivalent) were added to a mixture of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.122 g, 0.250 mmol, 1.2 equivalents) in N,N-dimethylformamide (1.5 mL, 0.14 M) and N,N-diisopropylethylamine (0.14 mL, 0.820 mmol, 4 equivalents) and sodium iodide (0.031 mg, 0.210 mmol, 1 equivalent). The reaction solution was stirred at 50 °C. After 12 h, the reaction solution was poured into water (20 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.054 g, 0.066 mmol, 32% yield). MS (ESI) m / z 817.2 [M+1] + ; 11H NMR (400MHz, DMSO-d6) δ = 10.92 (s, 1H), 10.55-9.56 (m, 1H), 8.82 (d, J = 2.0Hz, 1H), 8.53 (d, J = 2.0Hz, 1H), 7.63 (d,J=7.6Hz,1H),7.24-7.16(m,1H),7.14-7.08(m,1H),4.43-4.36(m,1H),4.09(s,3H),3.86-3.79(m,3H),3. 61-3.54(m,2H),3.30-3.18(m,3H),2.98-2.77(m,4H),2.76-2.68(m,1H),2.65-2.55(m,2H),2.54-2.52(m,4H ),2.34-2.32(m,1H),2.20-2.08(m,3H),1.76-1.68(m,2H),1.56(s,6H),1.43-1.34(m,2H),1.25-1.17(m,6H).

[0376] Example 7: 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0377]

[0378] N,N-diisopropylethylamine (4.62 mL, 28.0 mmol, 2 equivalents) was added to a solution of methyl-2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. 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 give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (7.00 g, 12.6 mmol, 90% yield) as a brown oil. 1 H NMR(400MHz, CDCl3)δ8.95(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),3.4 8-3.45(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).

[0379] 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. 1M hydrogen chloride (5.0 mL, 5 mmol) was added to a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (7.00 g, 12.6 mmol, 1 equivalent) in methanol (50 mL), 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 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a brown oily substance: 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (5.00 g, 10.6 mmol, 84% yield). MS (ESI) m / z 471.2 [M+1] + .

[0380] 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. At 0 °C, thionyl bromide (1.7 mL, 21.3 mmol, 2 equivalents) was added to a solution of 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (5.00 g, 10.6 mmol, 1 equivalent) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL). After stirring for 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2 x 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-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate as a pale yellow solid. (ESI) m / z 535.1 [M+1] + ; 1H NMR (400MHz, CDCl3) δ8.98(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).

[0381] 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(tri... A solution of fluoromethyl pyridinium nitrile (0.150 g, 0.28 mmol, 1 equivalent) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.208 g, 0.42 mmol, 1.5 equivalent) in N,N-dimethylformamide (1 mL, 0.28 M) was added to N,N-diisopropylethylamine (0.49 mL, 2.81 mmol, 0.1 M), and the mixture was stirred at 50 °C. After 12 hours, the reaction solution was filtered and the filtrate was purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (145.57 mg, 0.17 mmol, 60% yield), as a yellow solid. MS (ESI) m / z 865.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.29-10.08(m,1H),9.14(d,J=1.2Hz,1H),8.74(d,J=1.6Hz,1H),7.64(d,J=7 .6Hz,1H),7.20(d,J=7.2Hz,1H),7.13-7.09(m,1H),4.41-4.40(m,1H),4.09(s,3H),3.82-3.79(m,2H),3.51(m,3H), 3.32-3.21(m,2H),3.08(d,J=3.6Hz,2H),2.97-2.76(m,4H),2.75-2.65(m,2H),2.62(d,J=5.2Hz,1H),2.42-2.34(m, 1H),2.23-2.14(m,1H),2.12-2.04(m,2H),2.01-1.90(m,2H),1.72(d,J=10.0Hz,2H),1.57(s,6H),1.34-1.25(m,8H).

[0382] Example 8: 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0383]

[0384] N,N-diisopropylethylamine (4.6 mL, 28.0 mmol, 2 equivalents) was added to a solution of methyl-2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile in ethyl acetate (50 mL), 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 give a brown oily substance, 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile (6.5 g, 11.7 mmol, 84% yield). MS (ESI) m / z 554.4 [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,1 H),4.60-4.58(m,1H),3.84-3.82(m,2H),3.71-3.61(m,1H),3.60-3.52(m,2H),3.5 0-3.49(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).

[0385] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile. 1M hydrogen chloride (5.0 mL, 5 mmol) was added to a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile (6.5 g, 11.7 mmol) in methanol (50 mL), and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a brown oily substance, 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile (5.0 g, 10.7 mmol, 91% yield). MS (ESI) m / z 470.2 [M+1] + .

[0386] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile. At 0 °C, a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (5.0 g, 10.7 mmol, 1 equivalent) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added to thionyl bromide (1.7 mL, 21.3 mmol, 4 equivalents), and the reaction solution was gradually heated to room temperature. After 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2 x 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 to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (5.0 g, 9.4 mmol, 88% yield), a pale yellow oil. MS (ESI) m / z 534.1 [M+1] + ; 1H 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).

[0387] 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)- 2-(trifluoromethyl)benzyl nitrile (0.150 g, 0.28 mmol, 1 equivalent) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.208 g, 0.42 mmol, 1.5 equivalent) in a solution of N,N-dimethylformamide (1 mL, 0.28 M) were added to N,N-diisopropylethylamine (0.49 mL, 2.81 mmol, 10 equivalent). The reaction solution was stirred at 50 °C. After 12 hours, the reaction solution was filtered and purified by standard methods to provide 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide as a yellow solid (103 mg, 0.12 mmol, 43% yield). MS (ESI) m / z 864.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.48-9.92(m,1H),8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.98-7.95(m ,1H),7.63(d,J=8.0Hz,1H),7.20(d,J=7.6Hz,1H),7.18-7.09(m,1H),4.41-4.37(m,1H),4.09(s,3H),3.94-3.78(m, 2H),3.51(t,J=5.6Hz,4H),3.33-3.21(m,2H),3.08(d,J=2.0Hz,2H),2.92-2.78(m,3H),2.75-2.57(m,3H),2.43-2.3 4(m,1H),2.23-2.13(m,1H),2.11-2.03(m,2H),2.00-1.91(m,2H),1.73-1.70(m,2H),1.55(s,6H),1.34-1.25(m,8H).

[0388] Example 9: 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0389]

[0390] 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. N,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equivalents) was added to a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropionate (1.47 g, 5.71 mmol, 1 equivalent) and 5-isothiocyanate-3-(trifluoromethyl)pyridinecarboxylonitrile (1.44 g, 6.28 mmol, 1.1 equivalents) in ethyl acetate (15 mL, 0.38 M). The reaction solution was stirred at 80 °C. After 16 hours, the reaction solution was concentrated under reduced pressure and the crude material was purified by standard methods to give 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (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) δ8.99-8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.72(m,1H),3.67-3.64(t,J=6.4Hz,2H),2.7 2-2.70(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).

[0391] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. At 0 °C, thionyl bromide (1.650 g, 7.92 mmol, 2 equivalents) was slowly added to a solution of 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (1.80 g, 3.96 mmol, 1 equivalent) in dichloromethane (18 mL, 0.22 M) and N,N-dimethylformamide (1.8 mL). The reaction solution was stirred at 0 °C. After 12 h, the reaction solution was diluted with water (30 mL) and extracted with dichloromethane (25 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (5%–80% ethyl acetate in hexane) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (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) δ8.99-8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.71(m,1H),3.43

[0392] -3.40(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).

[0393] 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl) Pyridine carboxynitrile (0.100 g, 0.190 mmol) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.143 g, 0.290 mmol, 1.5 equivalents) were added to a solution of N,N-dimethylformamide (2 mL, 0.1 M) and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to provide 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide as a yellow solid (0.062 g, 0.073 mmol, 38% yield). MS (ESI) m / z 849.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),10.24(s,1H),9.15(s,1H),8.75(s,1H),7.6 5-7.63(d,J=8.0Hz,1H),7.21-7.19(d,J=6.8Hz,1H),7.13-7.09(m,1H),4.41-4.3 8(m,1H),4.10(s,3H),3.84(s,2H),3.01-2.89(m,5H),2.73-2.63(m,6H),2.38-2. 33(m,4H),2.19-2.15(m,2H),1.86-1.74(m,5H),1.57(s,6H),1.27-1.09(m,10H).

[0394] Example 10: 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0395]

[0396] 3-Chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)pyridinecarboxylonitrile. Triethylamine (2.28 mL, 16.36 mmol, 2 equivalents) was added to a mixture of methyl 3-chloro-5-isothiocyanate-pyridine-2-carboxylonitrile (1.600 g, 8.18 mmol, 1 equivalent) and methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropionate (2.320 g, 9 mmol, 1.1 equivalents) in ethyl acetate (100 mL), and the reaction solution was stirred at 90 °C. After 6 hours, the reaction solution was concentrated and purified by silica gel column chromatography (10%–100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)pyridinecarboxylate (2.000 g, 4.75 mmol, 58% yield) as a yellow solid. MS (ESI) m / z 421.2 [M+1] + ; 1 ¹H NMR (400MHz, chloroform-d) δ 8.67–8.50 (m, 1H), 7.98–7.83 (m, 1H), 3.80–3.48 (m, 4H), 2.75–2.52 (m, 2H), 1.93–1.60 (m, 6H), 1.51–1.28 (m, 3H), 1.27–1.15 (m, 5H), 1.06–0.89 (m, 3H).

[0397] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-chloropyridinecarboxylonitrile. At 0 °C, thionyl bromide (0.61 mL, 9.5 mmol, 2 equivalents) was added to a solution of 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)pyridinecarboxylonitrile (2.000 g, 4.75 mmol, 1 equivalent) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (0.50 mL). The reaction solution was stirred at 25 °C. After 16 h, the pH of the reaction solution was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (50%–100% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-chloropyridinium carboxylate as a red solid (1.600 g, 3.31 mmol, 70% yield). MS (ESI) m / z 483.1 [M+1] + ; 1 ¹H NMR (400MHz, chloroform-d) δ 8.73–8.50 (m, 1H), 7.98–7.82 (m, 1H), 3.78–3.65 (m, 1H), 3.37–3.29 (m, 2H), 2.77–2.49 (m, 2H), 1.93–1.80 (m, 4H), 1.57–1.52 (m, 6H), 1.30 (br t, J = 5.6 Hz, 3H), 1.08–0.97 (m, 2H).

[0398] 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl) A mixture of 3-chloropyridinium carboxynitrile (0.150 g, 0.319 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.280 mmol, 4 equivalents) in N,N-dimethylformamide (2 mL, 1.6 M) was supplemented with 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.198 mg, 0.480 mmol, 1.5 equivalents). The mixture was stirred at 50 °C. After 12 h, the reaction solution was poured into water (20 mL), stirred for 1 min, and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide hydrochloride (95 mg, 0.12 mmol, 37% yield), as a yellow solid. MS (ESI) m / z 815.3 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.80 (s, 1H), 8.82 (d, J = 2.0Hz, 1H), 8. 52(d,J=2.0Hz,1H),8.15(d,J=1.2Hz,1H),7.63-7.50(m,1H),7.39-7.26(m,1 H),7.08(t,J=8.0Hz,1H),4.38(dd,J=4.8,10.0Hz,1H),4.12(s,3H),3.87-3 .79(m,1H),2.82-2.59(m,9H),2.44-2.31(m,2H),2.26-2.12(m,3H),1.81(br d,J=10.8Hz,4H),1.71(br d,J=11.6Hz,2H),1.55(s,6H),1.49-1.39(m,2H),1.29-1.15(m,3H),1.08(br d,J=6.0Hz,6H).

[0399] Example 11: 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0400]

[0401] 2-Chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)benzyl nitrile. N,N-diisopropylethylamine (2.51 mL, 15.18 mmol, 3 equivalents) was added to a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropionate (1.31 g, 5.1 mmol, 1 equivalent) and 2-chloro-4-cyanophenyl isothiocyanate (1.08 g, 5.57 mmol, 1.1 equivalents) in ethyl acetate (25 mL), and the reaction mixture was stirred at 80 °C. After 18 hours, the reaction solution was concentrated and purified by column chromatography (15%-50% ethyl acetate in petroleum ether) to give 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)benzyl nitrile (1.26 g, 3.01 mmol, 59% yield), a brown oil. MS (ESI) m / z 420.1 [M+1] + .

[0402] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile. At 0 °C, thionyl bromide (1.88 g, 9.03 mmol, 3 equivalents) was slowly added to a solution of 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)benzyl nitrile (1.26 g, 3.01 mmol) in N,N-dimethylformamide (0.30 mL) and dichloromethane (3 mL). After 12 hours, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (15%–30% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile (1.21 g, 2.50 mmol, 83% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=8.4Hz,1H),7.58(d,J=2.0Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),3.87(m,1H) ,3.43(t,J=6.8Hz,2H),2.70(s,2H),1.94-1.82(m,6H),1.59(s,6H),1.39-1.36(m,3H),1.12-1.03(m,2H).

[0403] 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide. To 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole- N,N-diisopropylethylamine (0.14 mL, 0.830 mmol, 4 equivalents) was added to a mixture of 7-yl)acetamide (0.128 g, 0.310 mmol, 1.5 equivalents) and 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-chlorobenzyl nitrile (0.100 g, 0.207 mmol, 1 equivalent) in N,N-dimethylformamide (2 mL, 0.1 M), and the mixture was stirred at 50 °C. After 12 h, the reaction solution was poured into water (30 mL) and stirred for 1 min, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide as a white solid (75.4 mg, 0.093 mmol, 45% yield). MS (ESI) m / z 814.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.62-9.71(m,1H),8.13(d,J=8.4Hz,1H),7.92(d,J=1.6Hz,1H),7.67-7.59(m,2H),7.20(br d,J=7.2Hz,1H),7.14-7.08(m,1H),4.39(dd,J=5.2,10.4Hz,1H),4.10(s,3H),3.64-3.45(m,3H),3.00(br s,2H),2.85-2.58(m,8H),2.46-2.27(m,2H),2.17(td,J=5.2,13.2Hz,1H),1.87-1.71(m,6H),1.53(s,6H),1.36-1.02(m,12H).

[0404] Example 12: 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0405]

[0406] (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one. Acetaldehyde (150.8 g, 1368.9 mmol, 2 equivalents) was added to a solution of 3-oxoglutaric acid (100.0 g, 684.5 mmol, 1 equivalent) in water (200 mL) at 20 °C. The reaction was stirred at 20 °C for 20 min, then cooled to 0 °C and benzylamine (74.61 mL, 684.5 mmol, 1 equivalent) was added dropwise. The reaction solution was heated to room temperature and stirred for 48 h. The reaction solution was extracted with 3000 mL of ethyl acetate (1000 mL × 3), and the combined organic layers were washed with 500 mL of brine. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (27.70 g, 127.5 mmol, 19% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.42 (d, J = 7.2Hz, 2H), 7.37-7.29 (m, 2H), 7.27-7.20 (m, 1H), 3.8 6(s,2H),3.17-3.09(qd,J=6.4,13.2Hz,2H),2.42-2.28(m,4H),1.16(d,J=6.4Hz,6H).

[0407] Ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)acetate. Ethyl 2-(diethoxyphosphoryl)acetate (40.23 g, 179.5 mmol, 1.3 equivalents) in THF (100 mL) was added dropwise to a solution of sodium hydride (8.283 g, 207.1 mmol, 1.5 equivalents) in THF (50 mL). The mixture was stirred at 0 °C for 30 min. (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (30.00 g, 138.1 mmol, 1 equivalent) in THF (200 mL) was added dropwise to the above solution, and the reaction solution was heated to room temperature. After 12 h, the reaction solution was neutralized by adding saturated ammonium chloride solution and poured into ice water (200 mL). The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by rapid silica gel chromatography (2.0% ethyl acetate in petroleum ether) (petroleum ether:ethyl acetate = 3:1, Rf: 0.65) and further purified by semi-preparative reversed-phase HPLC (55%-85% acetonitrile + 0.05% ammonium hydroxide in water, over 20 min). The collected fractions were concentrated, and the aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)acetate as a yellow oil (11.7 g, 40.7 mmol, 30% yield). MS (ESI) m / z 288.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.45-7.35(m,2H),7.30(t,J=7.6Hz,2H),7.26-7.16(m,1H),5.63(s,1H),4.15(q,J=7.2Hz,2H),3.82( s,2H),3.57(dd,J=2.8,14.0Hz,1H),2.84-2.62(m,2H),2.29-2.08(m,3H),1.33-1.23(m,3H),1.14(dd,J=6.4,16.4Hz,6H).

[0408] tert-Butyl(2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidin-1-carboxylate. Under nitrogen, 10% palladium on carbon (1.500 g, 1.84 mmol, 10 mol%) was added to a solution of ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-yl)acetate (5.300 g, 18.44 mmol, 1 equivalent) and di-tert-butyl dicarbonate (6.037 g, 27.66 mmol, 1.5 equivalent) in THF (80 mL, 0.23 M). The reaction mixture was stirred at room temperature for 12 hours under hydrogen (50 psi). The reaction mixture was filtered and concentrated to give the residue, which was purified by rapid silica gel chromatography (1% ethyl acetate in petroleum ether, petroleum ether:ethyl acetate = 5:1) to give tert-butyl(2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate as a yellow oil (2.630 g, 8.784 mmol, 48% yield). 1 H NMR(400MHz, CDCl3)δ4.26(s,1H),4.21(m,1H),4.17-4.10(m,2H),2.26-2.18(m,2H),2.13-2.05(m,1H),1.99-1.84 (m,1H),1.66-1.55(m,1H),1.47(s,9H),1.36-1.29(m,1H),1.29-1.25(m,3H),1.24-1.19(m,6H),1.15-1.02(m,2H).

[0409] tert-Butyl(2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate. At 0 °C, a solution of tert-butyl(2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.780 mmol, 1 equivalent) in THF (40 mL) was added to a solution of lithium aluminum hydride (0.500 g, 13.18 mmol, 1.5 equivalent) in THF (10 mL). The reaction solution was slowly heated to room temperature over 1 h. The reaction solution was quenched by adding 0.5 mL of water, 1 mL of 15% sodium hydroxide solution, and 1.5 mL of water. The slurry was stirred for 0.5 h, filtered, and concentrated under vacuum. The crude material was diluted with 100 mL of water and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to provide tert-butyl(2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate as a yellow solid (2.180 g, 8.470 mmol, 96% yield). 1 H NMR (400MHz, CDCl3) δ4.40-4.25(m,1H),4.24-4.07(m,1H),3.77-3.65(m,2H),2.12-2.03(m,1H),1.68 -1.56(m,2H),1.55-1.49(m,2H),1.49-1.42(m,9H),1.33-1.26(m,1H),1.25-1.17(m,6H),1.05(m,1H).

[0410] tert-Butyl(2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate. A solution of tert-butyl(2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 1 equivalent) and triphenylphosphine (3.332 g, 12.71 mmol, 1.5 equivalent) in dichloromethane (40 mL, 0.21 M) was added to the reaction solution at 0 °C. The reaction mixture was slowly heated to room temperature. After 2 h, the reaction solution was poured into a saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to provide tert-butyl(2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate as a clear, colorless oil (2.160 g, 6.744 mmol, 80% yield). 1 H NMR (400MHz, CDCl3) δ4.45-4.27(m,1H),4.26-4.06(m,1H),3.51-3.29(m,2H),2.18-1.96(m,2H),1.89-1. 75(m,2H),1.73-1.53(m,2H),1.48-1.39(m,9H),1.33-1.25(m,1H),1.24-1.19(m,6H),1.13-0.97(m,1H).

[0411] tert-Butyl(2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate was added to a solution of trans-4-(dibenzylamino)cyclohexanol (12.18 g, 41.22 mmol, 2 equivalents) and tert-Butyl(2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (6.600 g, 20.61 mmol, 1 equivalent) in xylene (120 mL, 0.17 M) with potassium hydroxide (5.318 g, 94.80 mmol, 4.6 equivalents) and tetrabutylammonium bromide (1.328 g, 4.120 mmol, 0.2 equivalents). The reaction was stirred at 30 °C. After 24 hours, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by rapid silica gel column chromatography (2.5%–3% ethyl acetate in petroleum ether) to provide tert-butyl(2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate as a yellow oil (2.800 g, 5.236 mmol, 25% yield). 1 H NMR (400MHz, CDCl3) δ7.42-7.33(m,4H),7.33-7.27(m,4H),7.24-7.17(m,2H),4.36-4.23(m,2H),4.22 -4.15(m,1H),3.62(s,4H),3.48(t,J=6.4Hz,1H),3.45-3.37(m,1H),3.19-3.06(m,1H),2.53(m,1H),2 .09-2.04(m,3H),2.01-1.86(m,3H),1.63-1.59(m,1H),1.57-1.51(m,2H),1.47-1.46(m,9H),1.43-1. 33(m,2H),1.28-1.24(m,2H),1.21(s,2H),1.17(d,J=7.0Hz,6H),1.14-1.08(m,1H),1.07-0.92(m,1H).

[0412] tert-Butyl(2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. Under nitrogen atmosphere, palladium on carbon (2.000 g) was added to a solution of tert-butyl(2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.240 mmol, 1 equivalent) in methanol (60 mL). The reaction was stirred at room temperature under hydrogen atmosphere (15 psi) for 12 hours. The reaction mixture was filtered and concentrated to give a yellow oily tert-butyl(2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 98% yield), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ4.23-4.08(m,2H),4.08-3.93(m,1H),3.50-3.40(m,2H),3.40-3.33(m,1H),3.18-3.04(m,1H),2.55-2.51(m,2H),2.49(br s,1H),2.05-1.83(m,4H),1.82-1.68(m,2H),1.67-1.47(m,2H),1.46- 1.32(m,16H),1.29-1.15(m,2H),1.15-1.07(m,9H),1.07-0.87(m,3H).

[0413] Tert-butyl(2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. Potassium iodide (0.086 g, 0.520 mmol, 10 mol%), potassium carbonate (2.148 g, 15.54 mmol, 3 equivalents), and methyl 2-bromo-2-methylpropionate (3.75 mL, 25.91 mmol, 5 equivalents) were added to a solution of tert-butyl(2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 1 equivalent) in acetonitrile (10 mL, 0.5 M) to form 2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 1 equivalent). The reaction was stirred at 110 °C. After 48 hours, the reaction solution was filtered and concentrated to give tert-butyl(2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 5.279 mmol, crude), which was used without further purification. MS (ESI) m / z 455.5 [M+1] + .

[0414] tert-butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate and tert-butyl(2R,4r,6S)-4-(2-(((1r,4R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate Ester. A solution of tert-butyl(2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 4.750 mmol, 1 equivalent) and 4-isothiocyanate-2-(trifluoromethyl)benzyl nitrile (1.084 g, 4.750 mmol, 1 equivalent) in ethyl acetate (10 mL, 0.47 M) was reacted with N,N-diisopropylethylamine (1.660 mL, 9.500 mmol, 2 equivalents). The reaction was stirred at 90 °C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by rapid silica gel column chromatography to obtain a mixture of diastereomers, which was then purified by SFC (DAICEL CHIRAL PAK IG: 250mm*30mm, 10µm, 20% methanol + 0.1%). NH3.H2O) was used to separate tert-butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.060 g, 1.629 mmol, 34% yield) and tert-butyl(2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.553 mmol, 12% yield). tert-Butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1H NMR (400MHz, CDCl3) δ7.95(d,J=8.0Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0Hz,1H),4.38- 4.22(m,2H),3.72-3.59(m,1H),3.54(t,J=6.4Hz,2H),3.37-3.24(m,1H),3.03-2.75(m,2H),2.21(br d,J=12.4Hz,2H), 2.03-1.90(m,1H), 1.89-1.77(m,2H), 1.61(s,6H), 1.58(m,2H), 1.54-1.48(m,2H), 1.47(s,9H), 1.40-1.26(m,4H), 1.19(d,J=7.2Hz,6H). tert-Butyl(2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1 H NMR (400MHz, CDCl3) δ7.95(d,J=8.4Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),4. 28-4.10(m,2H),3.76-3.58(m,1H),3.49(t,J=6.0Hz,2H),3.30(m,1H),3.03-2.76(m,2H),2.19(br d,J=12.0Hz,2H),2.12-1.98(m,2H),1.89-1.76(m,2H),1.61(s,6H),1.52(br t,J=6.4Hz,2H),1.47(s,9H),1.40-1.25(m,3H),1.22(d,J=6.8Hz,6H),1.03(m,2H).

[0415] 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile. To a solution of tert-butyl(2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-carboxylate (1.060 g, 1.630 mmol, 1 equivalent) in dichloromethane (5 mL) was mixed with 4 M hydrochloric acid (in 1,4-dioxane) (20 mL, 80.00 mmol) and the reaction solution was stirred at room temperature. After 2 hours, the reaction solution was concentrated. The resulting yellow solid was absorbed in saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to provide a yellow solid of 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.920 g, 1.67 mmol, 99% yield), which was used without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.0, 8. 0Hz,1H),3.74-3.59(m,1H),3.51(t,J=6.8Hz,2H),3.31(m,1H),2.92(m,4H),2.20(br d,J=12.0Hz,2H),2.02-1.92(m,1H),1.82(br d,J=12.0Hz,2H),1.70(q,J=6.8Hz,2H),1.64-1.56(s,6H),1.51(br d,J=12.8Hz,2H),1.40-1.27(m,4H),1.09(br d,J=6.0Hz,6H).

[0416] 2-Chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide. Triethylamine (1.62 mL, 11.62 mmol, 3 equivalents) and 2-chloroacetyl chloride (0.46 mL, 5.810 mmol, 1.5 equivalents) were added in a single step to a solution of 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (1.000 g, 3.870 mmol, 1 equivalent) in dichloromethane (20 mL, 0.2 M) under nitrogen atmosphere. After 2 h, the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (4 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by rapid silica gel column chromatography (0-100% ethyl acetate in dichloromethane) to provide 2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide as a gray solid (0.750 g, 2.240 mmol, 58% yield). MS (ESI) m / z 335.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 10.27 (s, 1H), 7.65 (d, J = 7.6Hz, 1H), 7.18-7.08 (m, 2H), 4 .39(s,2H),4.21(m,1H),4.06(s,3H),2.71-2.61(m,2H),2.43-2.32(m,1H),2.21-2.14(m,1H).

[0417] 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo N,N-diisopropylethylamine (0.13 mL, 0.730 mmol, 4 equivalents) and sodium iodide (0.027 g, 0.180 mmol, 1 equivalent) were added to a solution of 2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.079 g, 0.240 mmol, 1.3 equivalents) in N,N-dimethylformamide (2 mL, 0.09 M). The reaction solution was stirred at 80 °C. After 22 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to give 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a yellow solid (0.068 g, 0.080 mmol, 44% yield). MS (ESI) m / z 849.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ11.14-10.67(m,1H),10.24-9.68(m,1H),9.10(br s,1H),8.33(d,J=8.4Hz,1H),8.19(s,1H),7.97(br d,J=8.4Hz,1H),7.67(m,1H),7.22(t,J=7.6Hz,1H),7.13(m,1H),4.47-4.2 8(m,3H),4.12(s,3H),3.99-3.74(m,6H),3.53-3.38(m,2H),3.30-3.16(m, 1H),2.92-2.71(m,2H),2.68-2.60(m,1H),2.44-2.33(m,1H),2.23-2.11(m ,1H),2.11-1.85(m,4H),1.82-1.61(m,6H),1.54(d,J=4.4Hz,6H),1.39(br d,J=6.4Hz,3H),1.32(m,1H),1.29-1.18(m,3H).

[0418] Example 13: 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0419]

[0420] 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile. Add 4M hydrochloric acid (in 1,4-dioxane) (12 mL, 48 mmol) to a solution of tert-butyl(2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-carboxylate (0.360 g, 0.550 mmol, 1 equivalent) in dichloromethane (3 mL, 0.12 M) (12 mL, 48 mmol) and stir the reaction solution at 15 °C. After 14 hours, the reaction solution was concentrated. The resulting solid was diluted to pH 8-9 with saturated bicarbonate solution (20 mL), and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid of 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.330 g, 0.56 mmol), which was used without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),3.73-3.59(m ,1H),3.52(t,J=6.4Hz,2H),3.30(m,1H),3.03-2.80(m,2H),2.74(m,2H),2.20(brd,J=12.4Hz,2H),1.82(br d,J=11.6Hz,2H),1.68(br d,J=13.2Hz,2H),1.61(s,6H),1.54-1.48(m,2H),1.41-1.27(m,3H),1.14(br d,J=6.4Hz,6H),0.92-0.76(m,2H).

[0421] 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo (-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.060 g, 0.110 mmol, 1 equivalent) and 2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.055 g, 0.160 mmol, 1.5 equivalent) were added to a solution of N,N-dimethylformamide (1 mL, 0.1 M), along with N,N-diisopropylethylamine (0.09 mL, 0.540 mmol, 5 equivalent) and sodium iodide (0.016 g, 0.110 mmol, 1 equivalent). The reaction solution was stirred at 80 °C. After 24 h, the reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 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-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a white solid (0.030 g, 0.035 mmol, 32% yield). MS (ESI) m / z 849.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.92(s,1H),10.87-10.72(m,1H),9.99-9.76(m,1H),9.12(br s,1H),8.34(d,J=8.4Hz,1H),8.19(s,1H),7.97(d,J=8.4Hz,1H),7.67( m,1H),7.30-7.19(m,1H),7.18-7.06(m,1H),4.45-4.35(m,2H),4.28(br d,J=3.2Hz,1H),4.12(s,3H),3.93-3.76(m,1H),3.72-3.59(m,1H),3.57-3. 53(m,1H),3.47-3.40(m,2H),3.29-3.16(m,1H),2.92-2.74(m,2H),2.59(br s,2H),2.40-2.30(m,1H),2.23-2.12(m,1H),2.11-1.99(m,2H),1.91-1.66(m,5H),1.59-1.53(m,6H),1.52-1.44(m,2H),1.41(br d,J=6.4Hz,3H),1.37-1.28(m,2H),1.26(br d,J=6.4Hz,3H),1.25-1.14(m,2H).

[0422] Example 14: 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride

[0423]

[0424] tert-Butyl(R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. Add tert-Butyl(R)-3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol), N,N-diisopropylethylamine (0.69 mL, 3.93 mmol, 2 equivalents), methyl bromoacetate (1.09 mL, 11.8 mmol, 6 equivalents), and THF (20 mL, 0.1 M) to a 40 mL vial. Stir the reaction solution at room temperature. After 18 minutes, dilute the solution with 100 mL of ethyl acetate and 100 mL of water. Remove the organic layer and extract the aqueous layer with ethyl acetate (2 x 50 mL). Then, dry the combined organic layers with magnesium sulfate and concentrate. The crude material was purified by silica gel column chromatography (1%–50% ethyl acetate in hexane) to provide tert-butyl(R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate as a yellow oil (0.557 g, 1.71 mmol, 88% yield). MS (ESI) m / z 227 [M-99] + .

[0425] Methyl(R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate. Tert-butyl(R)-3-(trifluoromethyl)piperazin-1-carboxylate (250 mg, 0.7 mmol) and trifluoroacetic acid (0.58 mL, 7.6 mmol, 10 equivalences) were combined in dichloromethane (7.6 mL, 1 M) and stirred at room temperature in a screw-capped scintillation flask. After 1 h, the solution was concentrated to give methyl(R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (255 mg, 0.75 mmol, 98% yield) as a yellow oil, which was used without further purification. MS (ESI) m / z 227 [M+1] + .

[0426] Methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate. To contain 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2- Acetonitrile (5 mL) was added to a 1-duralumin vial containing (trifluoromethyl)benzyl nitrile (0.5 g, 0.96 mmol, 1 equivalent), methyl(R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (0.33 g, 0.96 mmol, 1 equivalent), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equivalent). N,N-diisopropylethylamine (0.8 mL, 4.82 mmol, 5 equivalent) was then added. The reaction vial was heated to 60 °C with stirring. After 16 h, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (0.6 g, 0.89 mmol, 91% yield). MS (ESI) m / z 664.2 [M+1]+.

[0427] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid. At 0°C, to methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl) Lithium hydroxide monohydrate (0.58 g, 1.3 mmol, 1.5 equivalent) was added in a single step to a cooled solution of 5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (0.6 g, 0.9 mmol, 1 equivalent) in a mixture of tetrahydrofuran / methanol / water (3:1:1, 5 mL). The resulting solution was stirred at room temperature. After 3 h, the reaction solution was diluted with water (20 mL) and extracted with 10% methanol (4 x 50 mL) in dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.33 g, 0.46 mmol, 51% yield), which was used without further purification. MS (ESI) m / z 650.2 [M+1]+.

[0428] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To contain 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. Acetonitrile (1.5 mL) and N,N-dimethylformamide (1.5 mL) were added to a two-duralumin vial containing methyl(dimethylamino)methylene)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.12 g, 0.19 mmol, 1 equivalent) and 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (0.06 g, 0.22 mmol, 1.2 equivalent). The reaction solution was stirred until all solids dissolved. 1-Methylimidazole (0.07 mL, 0.84 mmol, 5 equivalent) was added, followed by N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (0.12 g, 0.41 mmol, 2.2 equivalent), and the reaction solution was stirred at room temperature. After 1 hour, the reaction solution was diluted with dimethyl sulfoxide to a total volume of 3 ml, filtered, and purified by standard methods to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.13 g, 0.14 mmol, 78% yield). MS (ESI) m / z 890.2 [M+1]+; 1H NMR(DMSO-d6,400MHz)δ10.8-10.9(m,1H),9.9-10.1(m,1H),8.2-8.3(m,1H),8.0-8.2(m,1 H),7.8-8.0(m,1H),7.5-7.6(m,1H),7.0-7.1(m,2H),4.3-4.4(m,2H),4.0-4.0(m,3H),3.6 -3.9(m,11H),3.4-3.5(m,1H),3.1-3.2(m,2H),2.7-2.9(m,2H),2.5-2.7(m,2H),2.2-2.4( m,1H),2.1-2.2(m,1H),2.0-2.1(m,2H),1.6-1.7(m,2H),1.4-1.5(m,6H),1.2-1.4(m,2H).

[0429] Example 15: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0430]

[0431] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 5-(3-((trans)-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4- A mixture of dimethyl-5-oxo-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (0.090 g, 0.16 mmol) and N-ethyl-N-isopropylpropyl-2-amine (0.042 g, 0.33 mmol) in N,N-dimethylformamide (4 mL) was added to 2-chloro-N-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]acetamide (0.109 g, 0.33 mmol) and sodium iodide (0.002 g, 0.02 mmol), and the reaction solution was stirred at 80 °C. After 16 h, the reaction solution was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by standard methods to provide 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.042 g, 0.05 mmol, 30% yield) as a yellow solid. MS (ESI) m / z: 850.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ: 10.92 (d, J = 4.4Hz, 1H), 10.79 (s, 1H), 9.19-9.11 (m, 1H), 8. 75(s,1H),7.68(dd,J=4.8,8.0Hz,1H),7.32-7.06(m,2H),4.47-4.35(m,2H),4.26(br d,J=3.2Hz,1H),4.12(s,3H),3.96-3.77(m,1H),3.49(br dd,J=6.0,11.6Hz,3H),3.34-3.16(m,1H),2.84(br d,J=10.4Hz,2H),2.75-2.56(m,3H),2.42-2.32(m,1H),2.23-2.14(m,1H),2.08(br s,2H),1.94-1.66(m,5H),1.57(d,J=4.0Hz,6H),1.53-1.31(m,7H),1.30-1.20(m,5H).

[0432] Example 16: 2-((2R,4s,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0433]

[0434] 2-((2R,4s,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 5-(3-((trans)-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-di A mixture of methyl-5-oxo-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (0.120 g, 0.22 mmol) and N-ethyl-N-isopropylpropyl-2-amine (0.056 g, 0.44 mmol) in N,N-dimethylformamide (4 mL) was added to 2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.146 g, 0.44 mmol) and sodium iodide (0.002 g, 0.02 mmol), and the reaction solution was stirred at 80 °C. After 16 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by standard methods to provide 2-((2R,4s,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.080 g, 0.09 mmol, 43% yield) as a yellow solid. MS (ESI) m / z: 850.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ: 11.14-10.82 (m, 2H), 9.19-9.07 (m, 1H), 8.75 (d, J = 2.0Hz, 1H), 7.68(dd,J=4.4,8.0Hz,1H),7.34-7.04(m,2H),4.48-4.29(m,3H),4.13(s,3H),3.84(br s,2H),3.62(br dd,J=2.0,5.2Hz,1H),3.54-3.48(m,2H),3.27-3.19(m,1H),2.89-2.80(m,2H),2.72-2.62(m,3H),2.41-2.33(m,1H),2.18(br dd,J=5.6,12.4Hz,1H),2.13-1.86(m,5H),1.75-1.65(m,5H),1.57(d,J=4.4Hz,6H),1.43-1.24(m,8H).

[0435] Example 17: 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0436]

[0437] (3R)-tert-butyl-4-(2-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate.

[0438] To a solution of (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.460 g, 1.470 mmol) in pyridine (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.04 mL, 2.95 mmol) was added, followed by the addition of 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidine-2,6-dione (0.400 g, 1.550 mmol), and the reaction mixture was stirred at 60 °C. After 12 hours, the reaction solution was concentrated and purified by standard methods to provide (3R)-tert-butyl-4-(2-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate as a brown solid (0.650 g, 1.176 mmol, 80% yield). MS (ESI) m / z 497.1 [M-55] + .

[0439] N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide. A solution of (3R)-tert-butyl 4-(2-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazin-1-carboxylate (0.650 g, 1.18 mmol) in dichloromethane (6 mL) was added to acetic acid (2.0 mL, 1.180 mmol), and the reaction mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.750 g, crude), which was used as a brown solid without further purification. MS (ESI) m / z 453.2 [M+1] + .

[0440] 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride.

[0441] To a solution of 5-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (0.100 g, 0.190 mmol) in DMF (1 mL), N-ethyl-N-isopropylpropyl-2-amine (0.1 mL, 0.580 mmol) and N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.144 g, 0.270 mmol) were added and the reaction mixture was stirred at 50 °C. After 12 hours, the reaction solution was concentrated and purified by standard methods to provide 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.083 g, 0.092 mmol, 48% yield), as a white solid. MS (ESI) m / z 889.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),10.91(s,1H),10.05-9.98(m,1H),9.16-9.15(d,J=2.0Hz,1 H),8.76-8.75(d,J=2.0Hz,1H),7.64-7.62(d,J=8.0Hz,1H),7.19-7.08(m,2H),4.41-4.35(m,2H), 4.07(s,3H),3.90-3.77(m,2H),3.71-3.65(m,2H),3.55-3.52(m,2H),3.24-3.11(m,5H),2.78-2.5 9(m,4H),2.38-2.34(m,1H),2.20-2.15(m,1H),1.86-1.72(m,6H),1.57(s,6H),1.27-1.06(m,5H).

[0442] Example 18: 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0443]

[0444] 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 4-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium A mixture of alkyl(1-yl)-2-(trifluoromethyl)benzyl nitrile (0.093 g, 0.180 mmol) and N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.115 g, 0.220 mmol) in DMF (1 mL) was added to N,N-diisopropylethylamine (0.05 mL, 0.300 mmol), and the reaction solution was stirred at 50 °C. After 8 hours, the reaction solution was concentrated and purified by standard methods to provide 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide as a yellow solid (0.093 g, 0.104 mmol, 58% yield). MS (ESI) m / z: 888.5 [M+1] + ; 1 HNMR(400MHz,DMSO-d6)δ10.91(s,1H),10.70-10.51(m,1H),10.04-9.83(m,1H),8.34(d,J=8.4Hz,1H),8.19( s,1H),7.99-7.93(m,1H),7.62(d,J=7.6Hz,1H),7.20-7.07(m,2H),4.39(dd,J=5.2,10.4Hz,1H),4.31(dd,J= 2.8,6.4Hz,1H),4.06(s,3H),3.87-3.64(m,4H),3.56-3.51(m,1H),3.22-3.07(m,4H),2.83-2.58(m,5H),2.4 3-2.33(m,1H),2.22-2.11(m,1H),1.83(d,J=10.8Hz,2H),1.79-1.67(m,4H),1.54(s,6H),1.38-0.98(m,6H).

[0445] Example 19: 2-((2S,6R)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0446]

[0447] 2-((2S,6R)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 4-(3-((trans)-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine) 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.150 g, 0.280 mmol) and N-ethyl-N-isopropylpropyl-2-amine (0.3 mL, 1.890 mmol) were added to a solution of 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide in DMF (0.5 mL) and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was diluted with DMSO, filtered, and purified by standard methods to provide 2-((2S,6R)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a yellow solid (0.118 g, 0.134 mmol, 47% yield). MS (ESI) m / z: 862.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 10.57-9.72 (m, 1H) 8.34 (d, J = 8.4Hz, 1H),8.20(d,J=1.24Hz,1H),7.97(dd,J=8.19,1.6Hz,1H),7.64(d,J=8.4Hz, 1H),7.23-7.09(m,2H),4.40(dd,J=10.15,4.8Hz,1H),4.10(s,3H),4.01-3. 88(m,2H),3.69-3.60(m,2H),3.57-3.46(m,2H),3.36-3.22(m,1H),3.01(br d,J=7.6Hz,2H),2.80-2.69(m,3H),2.68-2.59(m,2H),2.44-2.34(m,1H),2.22-2.14(m,1H),1.86-1.78(m,2H),1.73(br d,J=12Hz,4H),1.55(s,6H),1.44-1.14(m,12H),1.13-1.02(m,2H).

[0448] Example 20: 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0449]

[0450] 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 5-(3-(((trans)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl) N-ethyl-N-isopropylprop-2-amine (0.073 g, 0.56 mmol) was added to a mixture of N-(2,6-dioxadiazin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.100 g, 0.19 mmol) in N,N-dimethylformamide (2 mL), and the reaction solution was stirred at 50 °C. After 16 h, the reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 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 provide 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.049 g, 0.05 mmol, 28% yield) as a yellow solid. MS (ESI) m / z: 905.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ: 10.91 (s, 1H), 10.54-10.22 (m, 1H), 10.10-9.78 (m, 1H), 9.14 (d, J = 1.6Hz, 1H), 8.74 (d, J = 2.0Hz, 1H), 7.63 (br d,J=7.6Hz,1H),7.26-6.99(m,2H),4.47-4.26(m,2H),4.06(s,3H),3.88-3.72(m,3H),3.50(br s,3H),3.30-3.25(m,2H),2.83(br d,J=12.4Hz,3H),2.75-2.58(m,6H),2.42-2.29(m,2H),2.24-2.14(m,1H),2.07(br d,J=7.2Hz,2H),1.94(br d,J=6.8Hz,2H),1.78-1.67(m,2H),1.57(s,6H),1.33(q,J=11.2Hz,2H).

[0451] Example 21: 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0452]

[0453] 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 4-(3-(((trans)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolium) A solution of alkyl-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.080 g, 0.150 mmol) in DMF (2 mL) was mixed with N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.082 g, 0.180 mmol) and N-ethyl-N-isopropylpropyl-2-amine (0.097 g, 0.750 mmol) and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was diluted with DMSO and purified by standard methods to provide 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.048 g, 0.049 mmol, 33% yield) as a yellow solid. MS (ESI) m / z: 904.1 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ10.91(s,1H),10.10-9.20(m,1H),8.35(d,J=8.26Hz,1H),8.20(d,J=1. 25Hz,1H),7.97(dd,J=8.4Hz,1H),7.63(d,J=7.50Hz,1H),7.26-7.06(m,2H),4.42-4.27(m,2H),4 .07(s,3H),3.32-3.10(m,6H),2.93-2.74(m,3H),2.71-2.61(m,3H),2.41-2.30(m,1H),2.24-2. 13(m,1H),2.07(d,J=9.2Hz,2H),1.97(s,2H),1.78-1.66(m,2H),1.55(s,6H),1.40-1.24(m,2H).

[0454] Example 22: 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0455]

[0456] 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride.

[0457] Add N-ethyl-N-isopropylpropyl-2-amine (0.23 mL, 1.29 mmol) to a solution of 5-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (0.097 g, 0.19 mmol) and N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)-2-((R)-2-(trifluoromethyl)piperazin-1-yl)acetamide (0.100 g, 0.19 mmol) in DMF (1 mL) and stir the reaction solution at 50 °C. After 12 hours, the reaction solution was adjusted to pH 7 by adding formic acid and purified by standard methods to provide 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperazin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (73.67 mg, 0.0816 mmol, 44% yield). MS (ESI) m / z: 891.0 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.91(s,2H),10.08-9.94(m,1H),9.14(d,J=1.6Hz,1H),8.74(d,J=1.6Hz,1H),7 .62(d,J=7.6Hz,1H),7.15(d,J=6.8Hz,1H),7.12-7.07(m,1H),4.42-4.32(m,2H),4.06(s,3H),3.95-3.79 (m,4H),3.77-3.69(m,2H),3.40-3.32(m,4H),3.27-3.12(m,3H),2.96-2.79(m,2H),2.75-2.56(m,3H),2. 41-2.29(m,1H),2.23-2.14(m,1H),2.13-2.05(m,2H),1.79-1.67(m,2H),1.57(s,6H),1.45-1.28(m,2H).

[0458] Example 23: 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0459]

[0460] 2S,4r,6S)-tert-butyl-4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. Tetrabutylammonium bromide (0.840 g, 2.620 mmol) and potassium hydroxide (3.5 mL, 65.41 mmol) were added 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)cyclohexylamine (6.290 g, 15.70 mmol) in xylene (45 mL), 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 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to provide (2R,4r,6S)-tert-butyl-4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate as a white solid (5.300 g, 9.657 mmol, 74% yield). 1H NMR (400MHz, DMSO-d6) δ7.34-7.26(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).

[0461] (2R,4r,6S)-tert-butyl4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. Under a nitrogen atmosphere, 10% palladium supported on activated carbon (3.000 g, 28.19 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(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). The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at 25 °C under hydrogen (15 Psi) for 12 h. The reaction mixture was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum 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 used without further purification. 1 H NMR(400MHz, DMSO-d6)δ4.17-4.03(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).

[0462] (2R,4r,6S)-tert-butyl-4-(3-((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. Sodium iodide (0.060 g, 0.410 mmol) and potassium carbonate (1.690 g, 12.21 mmol) were added 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-methylpropionate (3.680 g, 20.35 mmol) in acetonitrile (5 mL). The mixture was stirred at 110 °C. After 12 hours, the reaction solution was filtered and concentrated to provide crude (2R,4r,6S)-tert-butyl-4-(3-((1r,4R)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.054 mmol, 99.6% yield), which was used without further purification. MS (ESI) m / z 469.4 [M+1] + .

[0463] (2R,4r,6S)-tert-butyl4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-carboxylate. 2-(yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.050 mmol) and 4-isothiocyanate-2-(trifluoromethyl)benzyl nitrile (0.930 g, 4.050 mmol) were added to a solution of ethyl acetate (10 mL) and N,N-diisopropylethylamine (2.11 mL, 12.16 mmol) was added, and the reaction solution was stirred at 90 °C. After 12 hours, the reaction solution was filtered and concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 3.610 mmol, 89% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.97(d d,J=1.6,8.4Hz,1H),4.14-4.06(m,2H),3.90-3.74(m,1H),3.59-3.54(m,1H) ),3.40-3.37(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).

[0464] 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile hydrobromide. 33% hydrogen bromide (20 mL, 3.610 mmol) in acetic acid was added to a solution of (2R,4r,6S)-tert-butyl4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-carboxylate (2.400 g, 3.610 mmol) in dichloromethane (20 mL), and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to provide crude 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile hydrobromide (2.000 g, 3.542 mmol, 98% yield), which was used without further purification. MS (ESI) m / z 565.3 [M+1] + .

[0465] Benzyl 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetate. To 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethyl) Piperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile and benzyl 2-bromoacetate (1.220 g, 5.310 mmol) were added to a solution of acetonitrile (20 mL) and N,N-diisopropylethylamine (3.080 mL, 17.71 mmol) was added and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated and purified by a standard method to provide benzyl 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.800 g, 1.122 mmol, 32% yield). 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.4Hz,1H),8.20(d,J=2.0Hz,1H),7.97(d d,J=1.6,8.4Hz,1H),7.38-7.32(m,5H),5.09(s,2H),3.83(s,1H),3.53(s,2H ),3.23-3.15(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).

[0466] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. Benzyl 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl) Lithium hydroxide (0.135 g, 5.610 mmol) was added to a solution of fluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.800 g, 1.120 mmol) in THF (3 mL), methanol (3 mL), and water (3 mL) and the mixture was stirred at room temperature. After 12 hours, the reaction solution was adjusted to pH 7 by adding aqueous HCl and concentrated to provide crude 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (1.000 g, 1.606 mmol), which was used without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.34(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).

[0467] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride.

[0468] To a solution of 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.250 g, 0.400 mmol) and 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (0.124 g, 0.480 mmol) in pyridine (3 mL), N-((ethylimino)methylene)-N,N-dimethylpropane-1,3-diamine hydrochloride (0.153 g, 0.800 mmol) was added and the reaction solution was stirred at 50 °C. After 12 hours, the reaction solution was concentrated, absorbed into DMSO, and purified by standard methods to provide 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride as a white solid (48.81 mg, 0.054 mmol, 14% yield). MS (ESI) m / z 863.5 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ11.11-10.88(m,2H),10.28-9.18(m,1H),8.35-8.33(d,J=8.0Hz,1H),8.20-8.19(d,J=8.0Hz, 1H),7.99-7.96(dd,J=8.4,1.6Hz,1H),7.69-7.66(m,1H),7.24-7.21(m,1H),7.16-7.11(m,1H),4.43-4.37(m,3H),4.1 3(s,3H),3.85-3.81(m,1H),3.60-3.53(m,2H),3.45-3.39(m,2H),2.75-2.60(m,4H),2.43-2.33(m,1H),2.19-2.10(m, 3H),1.83-1.80(m,2H),1.74-1.66(m,3H),1.55-1.51(m,8H),1.45-1.35(m,4H),1.29-1.21(m,7H),1.09-1.06(m,2H).

[0469] Example 24: 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0470]

[0471] (2R,4r,6S)-tert-butyl4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-carboxylate. N,N-diisopropylethylamine (2.11 mL, 12.16 mmol) was added to a solution of 2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.054 mmol) and 5-isothiocyanate-3-(trifluoromethyl)pyridinecarboxylonitrile (0.929 g, 4.054 mmol) in ethyl acetate (10 mL) 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 provide (2R,4r,6S)-tert-butyl4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2.500 g, 3.755 mmol, 92% yield). 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),4.15-4.06(m,2H),3.83(s,1H),3.60-3.55(m,1H),3.40-3.37(m,2H) ),2.84-2.63(m,2H),1.80(d,J=13.2Hz,2H),1.76-1.65(m,6H),1.57-1.45(m,8H),1.39(s,9H),1.26(d,J=7.2Hz,9H),1.11-1.02(m,2H).

[0472] 5-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate. Add 33% hydrogen bromide (20 mL, 3.755 mmol) in acetic acid to a solution of (2R,4r,6S)-tert-butyl4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-carboxylate (2.500 g, 3.755 mmol) in dichloromethane (20 mL). The mixture was stirred at 25 °C for 12 h. The pH of the reaction mixture was adjusted to 7 by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude material was purified by standard methods to provide 5-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (0.550 g, 0.972 mmol, 26% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ9.15(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.34(s,1H),3 .84(s,1H),3.41-3.34(m,3H),2.87(dd,J=6.0,10.0Hz,2H),2.72(d,J=10.4Hz,2H), 1.99(d,J=11.6Hz,2H),1.81(d,J=12.0Hz,2H),1.71(d,J=10.4Hz,2H),1.56(s,6H) ,1.52-1.45(m,2H),1.21(d,J=7.2Hz,3H),1.12(d,J=6.4Hz,6H),1.07-0.97(m,4H).

[0473] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. To 5-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl A mixture of 2-chloro-N-(3-(2,6-dioxopiridin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.118 g, 0.35 mmol) in N,N-dimethylformamide (2 mL) was reacted with N-ethyl-N-isopropylpropyl-2-amine (0.114 g, 0.88 mmol) and sodium iodide (0.053 g, 0.35 mmol), and the reaction solution was stirred at 80 °C. After 16 h, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude material was purified by standard methods to provide 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide as a yellow solid (0.053 g, 0.06 mmol, 33% yield). MS (ESI) m / z: 864.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ: 10.99-10.74 (m, 2H), 10.21-9.06 (m, 2H), 8.76 (d, J = 2.0Hz, 1H), 7.77-7.61 (m, 1H), 7.28-7.08 (m, 2H), 4.45-4.30 (m ,3H),4.12(s,3H),3.92-3.55(m,6H),2.81-2.64(m,5H),2.43-2.31(m ,2H),2.23-2.09(m,3H),1.86-1.70(m,5H),1.63-1.51(m,8H),1.43(br d,J=6.4Hz,4H),1.28(br d,J=6.4Hz,5H),1.16-1.06(m,2H).

[0474] Example 25: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0475]

[0476] (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Potassium hydroxide (3.080 g, 54.95 mmol) and tetra-n-butylammonium bromide (0.790 g, 2.440 mmol) were added to a solution of (trans)-N,N-dibenzyl-4-(2-bromoethyl)cyclohexylamine (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), and the reaction mixture was stirred at 15 °C. After 12 hours, the reaction solution was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate as a white solid (3.500 g, 6.545 mmol, 53.6% yield). 1 H NMR(400MHz, CDCl3)δ7.43-7.36(m,5H),7.30-7.26(m,4H),7.22-7.18(m,1H), 4.28-4.20(m,2H),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,2H),1.47(s,9H),1.44-1.38(m,4H),1.32-1.30(m,6H),0.90-0.82(m,2H).

[0477] (2R,4r,6S)-tert-butyl4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Ammonium hydroxide (0.23 g, 6.54 mmol) and palladium supported on activated carbon (0.350 g, 0.330 mmol) were added to a solution of (2R,4r,6S)-tert-butyl4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.540 mmol) in methanol (40 mL). The reaction mixture was stirred at 20 °C under a molecular hydrogen atmosphere (15 Psi) for 12 h. The reaction mixture was poured into methanol (50 mL) and filtered. 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)δ4.12-4.08(m,2H),3.57-3.55(m,1H),3.41-3.38(m,5H),2.45-2.3 9(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).

[0478] (2R,4r,6S)-tert-butyl4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Potassium carbonate (2.220 g, 16.08 mmol) and sodium iodide (0.080 g, 0.540 mmol) were added to a solution of (2R,4r,6S)-tert-butyl4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 5.360 mmol) and methyl 2-bromo-2-methylpropionate (3.880 g, 21.44 mmol) in acetonitrile (6 mL), 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 provide crude (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (4.8 g), which was used without further purification.

[0479] (2R,4r,6S)-tert-butyl4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-carboxylate. N-ethyl-N-isopropylprop-2-amine (1.38 mL, 7.920 mmol) was added to a solution of 2,6-dimethylpiperidine-1-carboxylate (2.400 g, 2.64 mmol, 50%) and 5-isothiocyanate-3-(trifluoromethyl)pyridinecarboxylate (0.730 g, 3.170 mmol) in ethyl acetate (15 mL) and the reaction mixture was stirred at 80 °C. After 3 hours, the reaction solution was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-carboxylate (1.200 g, 1.841 mmol, 70% yield), as a brown oil. MS (ESI) m / z 552.2 [M-99] + ; 1 H NMR(400MHz,DMSO-d6)δ8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),4.29-4.2 1(m,2H),3.82(m,1H),3.59-3.54(m,1H),3.48-3.45(t,J=6.4Hz,2H),2.68-2.5 9(m,2H),1.97-1.89(m,4H),1.85-1.82(m,2H),1.73-1.67(m,2H),1.63(s,6H), 1.54-1.49(m,3H),1.47(s,9H),1.34-1.32(d,J=7.2Hz,6H),1.14-1.05(m,2H).

[0480] 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile. Trifluoroacetic acid (5 mL) was added to a solution of (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-carboxylate (1.200 g, 1.840 mmol) in dichloromethane (15 mL), and the reaction mixture was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the residue. Water (30 mL) was added and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 4). The organic phase was concentrated under reduced pressure to give 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (1.010 g, 1.831 mmol, 99% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.85(m,1H),3.51-3.49(m,2H),3.36-3.28(m,1H),2.78 -2.59(m,4H),2.03-1.92(m,5H),1.86(m,2H),1.63(s,6H),1.54-1.50(m,3H),1.17-1.16(d,J=6.4Hz,6H),1.10-1.00(m,4H).

[0481] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. Under nitrogen, to 5-(3-((trans-4-(2-( ((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxynitrile (0.120 g, 0.220 mmol) and 2-chloro-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.109 g, 0.330 mmol) in DMF (5 mL) N,N-diisopropylethylamine (0.11 mL, 0.650 mmol) was added to the solution in a single addition, and the reaction solution was stirred at 80 °C. After 12 h, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to provide 2-((2R,4r,6S)-4-(2-((trans-)) as a white solid. 4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.055 g, 0.062 mmol, 28% yield). MS (ESI) m / z 850.5 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.93-10.75(m,2H),10.10-9.09(m,2H),8.74(d,J=2.0Hz,1H),7.70-7.65( m,1H),7.24-7.20(m,1H),7.16-7.10(m,1H),4.45-4.34(m,2H),4.32(brs,1H),4.11(s,3H),3.84(br s,1H),3.68(br s,1H),3.52-3.47(m,2H),2.90-2.56(m,5H),2.43-2.34(m,1H),2.22-2.09(m,3H),1.81(br s,2H),1.76-1.66(m,3H),1.57(d,J=1.9Hz,6H),1.45-1.33(m,7H),1.27(d,J=6.4Hz,4H),1.13(br d,J=11.2Hz,2H).

[0482] Example 26: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0483]

[0484] (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Potassium hydroxide (3.080 g, 54.95 mmol) and tetra-n-butylammonium bromide (0.790 g, 2.440 mmol) were added to a solution of (trans)-N,N-dibenzyl-4-(2-bromoethyl)cyclohexylamine (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), and the reaction mixture was stirred at 15 °C. After 12 hours, the reaction solution was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate as a white solid (3.500 g, 6.545 mmol, 53.6% yield). 1H NMR(400MHz, CDCl3)δ7.43-7.36(m,5H),7.30-7.26(m,4H),7.22-7.18(m,1H), 4.28-4.20(m,2H),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,2H),1.47(s,9H),1.44-1.38(m,4H),1.32-1.30(m,6H),0.90-0.82(m,2H).

[0485] (2R,4r,6S)-tert-butyl4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Ammonium hydroxide (0.23 g, 6.54 mmol) and palladium supported on activated carbon (0.350 g, 0.330 mmol) were added to a solution of (2R,4r,6S)-tert-butyl4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.540 mmol) in methanol (40 mL). The reaction mixture was stirred at 20 °C under a molecular hydrogen atmosphere (15 Psi) for 12 h. The reaction mixture was poured into methanol (50 mL) and filtered. 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)δ4.12-4.08(m,2H),3.57-3.55(m,1H),3.41-3.38(m,5H),2.45-2.3 9(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).

[0486] (2R,4r,6S)-tert-butyl4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Potassium carbonate (2.220 g, 16.08 mmol) and sodium iodide (0.080 g, 0.540 mmol) were added to a solution of (2R,4r,6S)-tert-butyl4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 5.360 mmol) and methyl 2-bromo-2-methylpropionate (3.880 g, 21.44 mmol) in acetonitrile (6 mL), 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 provide crude (2R,4r,6S)-tert-butyl-4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (4.8 g), which was used without further purification.

[0487] (2R,4r,6S)-tert-butyl4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. N-ethyl-N-isopropylprop-2-amine (1.38 mL, 7.920 mmol) was added to a solution of 2,6-dimethylpiperidine-1-carboxylate (2.400 g, 2.640 mmol) and 4-isothiocyanate-2-(trifluoromethyl)benzyl nitrile (1.200 g, 5.280 mmol) in ethyl acetate (1 mL) and the reaction mixture was stirred at 80 °C. After 12 hours, the reaction solution 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-thioimidazolidine-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] + ; 1H NMR (400MHz, CDCl3) δ7.97-7.95(d,J=8.0Hz,1H),7.87(d,J=1.6Hz,1H),7.76-7.73(dd ,J=8.0,1.6Hz,1H),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).

[0488] 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile. 2,2,2-trifluoroacetic acid (5. mL, 65.34 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-carboxylate (1.150 g, 1.770 mmol) in dichloromethane (15 mL), and the reaction mixture was stirred at room temperature. After 2 hours, the reaction solution was concentrated, and the resulting material was absorbed in a saturated aqueous sodium bicarbonate solution 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-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.870 g, 1.580 mmol, 90% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ7.96-7.95(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).

[0489] Benzyl 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate. To 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy) Benzyl 2-bromoacetate (0.723 g, 3.160 mmol) and N-ethyl-N-isopropylprop-2-amine (0.83 mL, 4.740 mmol) were added to a solution of 4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.870 g, 1.580 mmol) in acetonitrile (9 mL) and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated and purified by standard methods to provide benzyl 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (1.100 g, 1.574 mmol), as a brown solid. MS (ESI) m / z 699.3 [M+1] + .

[0490] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. Benzyl 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (1.100 g, 1.570 mmol) was added to a solution of lithium hydroxide (0.189 g, 7.870 mmol) in THF (12 mL) and water (1.5 mL), and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was concentrated and extracted with 10:1 DCM / methanol (3 x 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-thioimidazolidine-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 used without further purification. MS (ESI) m / z 609.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.34-8.32(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).

[0491] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. Under nitrogen, to 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. N,N-diisopropylethylamine (0.071 g, 0.460 mmol) was added in a single reaction to a solution of 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (0.059 g, 0.230 mmol) in pyridine (5 mL), and the reaction solution was stirred at 50 °C. After 12 h, the reaction solution was diluted with water (80 mL) and washed with ethyl acetate (4 x 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 provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide as a yellow solid (0.127 g, 0.138 mmol, 60% yield). MS (ESI) m / z: 849.5 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.88(s,1H),8.33(d,J=8.0Hz,1H),8.19(s,1H),7.98-7.94(m,1H),7.57(d,J=8.4Hz,1H),7. 30(d,J=7.2Hz,1H),7.08(t,J=7.6Hz,1H),4.37(dd,J=5.2,10.4Hz,1H),4.40-4.34(m,1H),4.10(s,3H),3.93-3.74(m,1H),3.45(br t,J=6.0Hz,2H),3.26(s,2H),2.78-2.56(m,7H),2.39-2.31(m,1H),2.16(br dd,J=5.2,13.2Hz,1H),1.88(br d,J=13.2Hz,2H),1.81(br d,J=13.2Hz,2H),1.71(br d,J=11.6Hz,2H),1.54(s,6H),1.40(br d,J=5.6Hz,3H),1.23(s,1H),1.20(br s, 1H), 1.16 (d, J = 6.0Hz, 6H), 1.12-1.03 (m, 2H).

[0492] Example 27: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0493]

[0494] (2R,4r,6S)-tert-butyl-4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol) were added 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)cyclohexylamine (3.680 g, 9.157 mmol) in xylene (30 mL), 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 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 standard methods to provide (2R,4r,6S)-tert-butyl-4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate as a white solid (2.600 g, 4.721 mmol, 77% yield). 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).

[0495] (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Under a nitrogen atmosphere, 10% palladium supported on activated carbon (0.115 g, 1.089 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(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). The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at 25 °C under hydrogen (15 Psi) for 12 h. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to give a 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 used without further purification. MS (ESI) m / z 371.3 [M+1] + .

[0496] (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Potassium carbonate (0.448 g, 3.239 mmol) and sodium iodide (0.016 g, 0.108 mmol) were added to a solution of (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) and methyl 2-bromo-2-methylpropionate (0.977 g, 5.400 mmol) in acetonitrile (1 mL). The reaction solution was stirred at 110 °C. After 12 hours, the reaction solution was filtered and concentrated to provide crude (2R,4r,6S)-tert-butyl-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol), which was used without further purification. MS (ESI) m / z 471.4 [M+1] + .

[0497] (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. N,N-diisopropylethylamine (0.55 mL, 3.19 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol) and 4-isothiocyanate-2-(trifluoromethyl)benzyl nitrile (0.242 g, 1.062 mmol) in ethyl acetate (5 mL), 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 provide (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.470 g, 0.705 mmol, 66% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.33(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),3.31-3.2 5(m,1H),2.81(d,J=12.8Hz,2H),2.04(d,J=10.8Hz,2H),1.89(d,J=11.2Hz,2H ),1.75-1.72(m,5H),1.54(s,6H),1.39(s,9H),1.26(s,6H),1.20-1.15(m,4H).

[0498] 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzylnitrile. Trifluoroacetic acid (2.0 mL, 25.78 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-carboxylate (0.470 g, 0.705 mmol) in dichloromethane (5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum 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-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.400 g, 0.706 mmol), which was used without further purification.

[0499] tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate. To 4-(3-(((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl) N,N-dimethylformamide (0.61 mL, 3.530 mmol) was added to a solution of 4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-2-(trifluoromethyl)benzyl nitrile (0.400 g, 0.706 mmol) and tert-butyl 2-bromoacetate (0.206 g, 1.059 mmol) in acetonitrile (5 mL), and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated and purified by standard methods to provide tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.150 g, 0.220 mmol, 31% yield). 1H 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).

[0500] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. Trifluoroacetic acid (1.0 mL, 12.89 mmol) was added 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-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.220 mmol) in dichloromethane (5 mL) and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to provide crude 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.240 mmol), which was used without further purification.

[0501] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. Under nitrogen, to 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.122 g, 0.640 mmol) was added in a single step to a solution of 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (0.050 g, 0.190 mmol) in pyridine (4 mL). The reaction solution was stirred at 50 °C. After 12 h, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to provide 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide as a yellow solid (0.047 g, 0.052 mmol, 41% yield). MS (ESI) m / z 865.5 [M+1] + ; 1HNMR (400MHz, DMSO-d6) δ10.90(s,1H),9.87(s,1H),8.33(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1 H),7.57(d,J=8.0Hz,1H),7.31(d,J=7.2Hz,1H),7.08(t,J=7.6Hz,1H),4.38(dd,J=5.2,10.0Hz,1H),4.11(s,3H),3.83(br s,1H),3.52(s,4H),3.27(s,3H),2.81(br d,J=11.6Hz,2H),2.70-2.60(m,4H),2.43-2.35(m,1H),2.16(br dd,J=5.2,13.5Hz,1H),2.05(br d,J=14.4Hz,2H),1.89(br d,J=10.4Hz,2H),1.71(br d,J=10.4Hz,2H),1.54(s,6H),1.32(br d,J=14.4Hz,2H),1.28-1.21(m,2H),1.20(br s,1H),1.16(d,J=6.4Hz,6H).

[0502] Example 28: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0503]

[0504] 2R,4r,6S)-tert-butyl-4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol) were added 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)cyclohexylamine (3.680 g, 9.157 mmol) in xylene (30 mL), 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 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 standard methods to provide (2R,4r,6S)-tert-butyl-4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate as a white solid (2.600 g, 4.721 mmol, 77% yield). 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).

[0505] (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Under a nitrogen atmosphere, 10% palladium supported on activated carbon (0.115 g, 1.089 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(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). The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at 25 °C under hydrogen (15 Psi) for 12 h. The reaction mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to give a 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 used without further purification. MS (ESI) m / z 371.3 [M+1] + .

[0506] (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. Potassium carbonate (0.448 g, 3.239 mmol) and sodium iodide (0.016 g, 0.108 mmol) were added to a solution of (2R,4r,6S)-tert-butyl4-(2-((((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) and methyl 2-bromo-2-methylpropionate (0.977 g, 5.400 mmol) in acetonitrile (1 mL). The reaction solution was stirred at 110 °C. After 12 hours, the reaction solution was filtered and concentrated to provide crude (2R,4r,6S)-tert-butyl-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol), which was used without further purification. MS (ESI) m / z 471.4 [M+1] + .

[0507] (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-carboxylate. A solution of 2,6-dimethylpiperidine-1-carboxylate (0.300 g, 0.637 mmol) and 5-isothiocyanate-3-(trifluoromethyl)pyridinecarboxylate (0.146 g, 0.637 mmol) in ethyl acetate (5 mL) was mixed with N,N-diisopropylethylamine (0.33 mL, 1.910 mmol). The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under vacuum to give a crude product. The residue was purified by rapid silica gel chromatography (0-27% ethyl acetate in petroleum ether) to provide (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.340 g, 0.509 mmol, 80% yield). 1 H NMR (400MHz, DMSO-d6) δ9.14(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),3.3 2-3.25(m,1H),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).

[0508] 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylate. Trifluoroacetic acid (2.0 mL, 25.78 mmol) was added to a solution of (2R,4r,6S)-tert-butyl4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-carboxylate (0.340 g, 0.509 mmol) in dichloromethane (5 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under vacuum 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-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxynitrile (0.290 g, 0.511 mmol), which was used without further purification. MS (ESI) m / z 568.3 [M+1] + .

[0509] tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate. To 5-(3-(((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4- N,N-dimethylformamide (0.44 mL, 2.55 mmol) was added to a solution of 4,4-dimethyl-5-oxo-2-thioimidazolium-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile (0.290 g, 0.511 mmol) and tert-butyl-2-bromoacetate (0.149 g, 0.766 mmol) in acetonitrile (5 mL), 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 provide tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.270 g, 0.396 mmol, 78% yield). 1H NMR (400MHz, DMSO-d6) δ9.14(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,4 H),2.04(d,J=10.4Hz,2H),1.88(d,J=12.0Hz,2H),1.70(d,J=11.2Hz,2 H), 1.56 (s, 6H), 1.40 (s, 9H), 1.32 (d, J = 12.8Hz, 2H), 1.08-0.91 (m, 8H).

[0510] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To tert-butyl2-((2R,4r,6S)-4-(2-(((trans)-4-(3-( 6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.270 g, 0.396 mmol) was added to a solution of dichloromethane (5 mL) and the reaction solution was stirred at room temperature. After 12 hours, the reaction solution was concentrated to provide crude 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.250 g, 0.400 mmol), which was used without further purification. MS (ESI) m / z 626.3 [M+1] + .

[0511] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide. Under nitrogen, to 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl) A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.040 mmol) was prepared by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.198 g, 1.040 mmol) to a solution of 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (0.064 g, 0.250 mmol) in pyridine (5 mL) and stirring the solution at 50 °C. After 12 h, the solution was diluted with water (80 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to provide 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide as a grayish-white solid (0.060 g, 0.066 mmol, 32% yield). MS (ESI) m / z 866.4 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),9.87(s,1H),9.14(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),7.57(d,J=8.0Hz,1H),7.31(d,J= 7.2Hz,1H),7.08(t,J=8.0Hz,1H),4.38(dd,J=5.2,10.3Hz,1H),4.11(s,3H),3.92-3.75(m,1H),3.52(s,4H),3.27(s,3H),2.82(br d,J=12.8Hz,2H),2.70-2.61(m,3H),2.41-2.31(m,1H),2.20-2.13(m,1H),2.06(br d,J=12.0Hz,2H),1.89(br d,J=12.0Hz,2H),1.71(br d,J=10.4Hz,2H),1.56(s,6H),1.37-1.27(m,3H),1.23(s,1H),1.21-1.12(m,8H).

[0512] Example 29: 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0513]

[0514] Tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. To a solution of tert-butyl 3,3-difluoro-4-(2-(((methanesulfonyl)oxy)ethyl)piperidine-1-carboxylate (1.81 g, 5.27 mmol) in xylene (30 mL), (1r,4r)-4-(dibenzylamino)cyclohexane-1-ol (3.11 g, 10.54 mmol), tetrabutylammonium bromide (0.340 g, 1.054 mmol), and potassium hydroxide (1.479 g, 26.4 mmol) were added. The reaction mixture was heated to 30 °C for 24 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was collected and volatile organic compounds were removed under reduced pressure to give a pale yellow solid. The solid was absorbed in ethyl acetate and purified on a silica gel column using 0-75% ethyl acetate in hexane (to a flow rate of 2000 mL). Fractions containing the desired product were combined and volatile organic compounds were removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate as a colorless oil (1.79 g, 3.30 mmol, 63% yield). MS (ESI) m / z 543.2 [M+1] + .

[0515] tert-Butyl 4-(2-((((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate. Palladium on carbon (500 mg, 4.70 mmol) was added to a solution of tert-butyl 4-(2-((((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (2.65 g, 4.88 mmol) in methanol (50 mL). The air in the flask was evacuated and replaced with hydrogen (3x, 15 psi, gasket). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with more methanol. The filtrate was collected and volatile organic compounds were removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol, 97% yield), a pale yellow oil. MS (ESI) m / z 363.2 [M+1] + .

[0516] Tert-butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-(2-((((trans)-4-aminocyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.72 g, 4.75 mmol) in acetonitrile (20 mL), methyl 2-bromo-2-methylpropionate (1.718 g, 9.49 mmol), potassium iodide (0.079 g, 0.475 mmol), and potassium carbonate (1.312 g, 9.49 mmol) were added. The reaction mixture was stirred at 110 °C for 20 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was collected and volatile organic compounds were removed under reduced pressure to yield a yellow oily substance, tert-butyl-3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (2.20 g, 4.76 mmol), which was used without further purification. MS (ESI) m / z 463.2 [M+1] + .

[0517] tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate was added to a solution of tert-butyl 3,3-difluoro-4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropane-2-yl)amino)cyclohexyl)oxy)ethyl)piperidine-1-carboxylate (1.47 g, 3.18 mmol) in ethyl acetate (14 mL). 5-Isothiocyanate-3-(trifluoromethyl)pyridinecarboxylonitrile (0.728 g, 3.18 mmol) and diisopropylethylamine (1.665 mL, 9.53 mmol) were added. The reaction vial was sealed and stirred at 90 °C for 18 h. The reaction mixture was partitioned between water and ethyl acetate. A few mL of brine was added to reduce emulsification. The organic layer was removed and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was collected and the volatile organic compounds were removed under reduced pressure to give a foamy, deep orange semi-solid. The solid was absorbed in ethyl acetate and purified on a silica gel column using 0-100% ethyl acetate in hexane (to 1800 mL). The fractions containing the desired product were combined and the volatile organic compounds were removed under reduced pressure to give tert-butyl 4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidine-1-carboxylate (1.10 g, 1.667 mmol, 52% yield) as a foamy, light orange semi-solid. MS(ESI) m / z 560.2 [M-99] + .

[0518] 5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxylonitrile hydrochloride. HCl (5.0 ml, 20.00 mmol) (4.0 M in dioxane) was added to a solution of tert-butyl 4-(2-(((1r,4r)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-carboxylate (1.10 g, 1.667 mmol) in 1,4-dioxane (5.0 ml). The reaction was stirred at ambient temperature for 90 min. Volatile organic compounds were removed under reduced pressure to give 5-(3-((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxynitrile hydrochloride (1.08 g, 1.812 mmol), which was used without further purification. MS (ESI) m / z 560.2 [M+1] + .

[0519] 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate. Add triethylamine (0.758 mL, 5.44 mmol) and tert-butyl-2-bromoacetate (1.338 mL, 9.06 mmol) to a solution of 5-(3-(((trans)-4-(2-(3,3-difluoropiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxynitrile, HCl (1.08 g, 1.812 mmol) in acetonitrile (15 mL). The reaction vessel was sealed and stirred at 70 °C for 18 h. Volatile organic compounds were removed under reduced pressure to give an orange solid. The solid was absorbed in dichloromethane and purified on a silica gel column using 0-100% ethyl acetate (to 2200 mL) in hexane. Fractions containing the desired product were combined, and volatile organic compounds were removed under reduced pressure to give tert-butyl 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate (0.997 g, 1.480 mmol, 82% yield) as a foamy orange semi-solid. MS (ESI) m / z 674.2 [M+1]+ .

[0520] 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate hydrochloride. HCl (10.0 mL, 40.0 mmol) (4.0 M in dioxane) was added to a flask containing tert-butyl 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate (1.0 g, 1.484 mmol). The reaction mixture was stirred at ambient temperature for 3 h. Volatile organic compounds were removed under reduced pressure to give 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetate hydrochloride (1.14 g, 1.743 mmol), as a light brown solid, which was used without further purification. MS (ESI) m / z 618.2 [M+1] + .

[0521] 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine- 1-(1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)acetic acid hydrochloride (100 mg, 0.153 mmol) was added to a solution of acetonitrile (1.0 mL) with 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (47.4 mg, 0.183 mmol), 1-methyl-1H-imidazolium (0.049 mL, 0.612 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (86 mg, 0.306 mmol) and 1 mL DMF. The reaction solution was stirred at room temperature. After 18 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to provide 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (27 mg, 0.030 mmol, 20% yield) as a white solid. MS (ESI) m / z 858.2 [M+1] + ; 1 H NMR (DMSO-d6, 400MHz) δ10.91 (s, 1H), 9.14 (d, 1H, J = 1.8Hz), 8.74 (d, 1H, J = 2.0Hz), 7.63 (d, 1H, J = 8.2Hz),7.27(d,1H,J=7.3Hz),7.11(t,1H,J=7.8Hz),4.39(dd,2H,J=5.1,10.2Hz),4.10(s,4H),3. 8-3.9(m,2H),3.5-3.6(m,3H),3.2-3.3(m,2H),2.8-2.9(m,3H),2.6-2.7(m,3H),2.3-2.4(m,1H),2 .1-2.2(m,1H),2.0-2.1(m,4H),1.8-2.0(m,1H),1.7-1.8(m,2H),1.5-1.6(m,7H),1.3-1.5(m,3H).

[0522] Cell-based assays

[0523] VCAP AR Degradation Assay. Test compounds were pre-dispensed into Corning CellBind 96-well clear plates (catalog number 3300) using an acoustic dispenser, producing a 10-point concentration series for each compound at a 1:3 dilution. The final maximum concentration for each compound was 5 μM. 0.1% DMSO was used as a control. VCaP cells cultured in DMEM with 8% fetal bovine serum (FBS) were seeded at 50 k cells / well in 200 μL volumes onto the compound plates and incubated at 37°C in a CO2 incubator for 24 h. The culture medium was carefully removed from the cells, and the plates were placed on ice. One hundred μL of ice-cold 1x cell lysis buffer (from Cell Signaling Technologies, catalog number 9803) was added to the cells in each well, and the plates were incubated at 4°C on a shaker for 1 h. Fifteen μL of cell lysate was used for ARELISA assays using the PathScan Total Sandwich AR ELISA kit (Cell Signaling Technologies, catalog number 12580). The AR levels in the wells treated with the compound were normalized relative to the DMSO control level and expressed as a percentage of the control (PoC)(y). A four-parameter logistic model (S-type dose-response model) was used to determine the DC of the compound. 50 and EC 50 Use the following equation:

[0524] y=(A+((BA) / (1+((C / x)^D))))

[0525] A = Y Min (The lowest AR level normalized relative to the DMSO control in response to compound treatment, as determined by curve fitting)

[0526] B = Y Max (Highest AR level, as determined by curve fitting)

[0527] C = EC 50

[0528] D = Hill's slope

[0529] x = compound concentration

[0530] EC 50 =When y=(Y Max -Y Min When ) / 2, the concentration of the compound

[0531] DC 50= the concentration of the compound when y = 50% DMSO control (50% AR degradation)

[0532] y = AR protein level normalized to the DMSO control

[0533] The efficiency of compound-mediated AR degradation was characterized using the lowest measured AR level (referred to as the Y value) that responded to compound treatment and was normalized to the DMSO control.

[0534] Each compound in Table 1 was tested in the VCAP AR degradation assay and found to be active. All compounds in Table 1 showed: DC 50 < 1 μM and Y < 50% of the DMSO control.

[0535] Prostate cancer cell proliferation assay. VCAP or ENZR cells were plated at 10K cells / well in a 96-well CellBind (Costar) plate using DMEM + 8% FBS medium. The cells were incubated overnight at 37 °C and the test compounds were serially diluted and added to the wells. After seven days of incubation, the assay medium was removed by inversion and the plate was frozen at -80 °C overnight. The plate was thawed at room temperature and 100 μL of deionized water (ddH2O) was added to each well. The plate was incubated at 37 °C in a non-CO2 incubator for 1 h and then frozen at -80 °C overnight. The plate was thawed to room temperature and 100-μL TNE buffer (NaCl, Tris, EDTA) + Hoescht dye (1.0 mg / ml, 1:400) was added to each well. The fluorescence signal was measured at 460 nm. All data were normalized to the percentage of the DMSO control. A four-parameter logistic model (S-shaped dose-response model) was used to determine the GI 50 value, using the following equation:

[0536] y = (A + ((B - A) / (1 + ((C / x)^D))))

[0537] A = Y Min (the lowest cell viability (in luminescence units) that responded to compound treatment and was normalized to the DMSO control, as determined by curve fitting)

[0538] B = Y Max (the maximum cell viability measured in luminescence units and normalized to the DMSO control, as determined by curve fitting)

[0539] C = EC 50

[0540] D = Hill slope

[0541] GI 50=When Y=(Y Max When +Yt0) / 2, the concentration of the compound

[0542] EC 50 =When y=(Y Max -Y Min When ) / 2, the concentration of the compound

[0543] IC 50 =When Y = 50% of the DMSO control, the concentration of the compound

[0544] y = percentage of cell viability measured in luminescent units and normalized to the DMSO control.

[0545] t0 = Time when the compound was added

[0546] Yt0 = the value of y at time t0

[0547] The compounds described herein have been or will be tested in prostate cancer cell proliferation assays and have shown or will show activity.

[0548] In vivo assay

[0549] AR degradation assay. In vivo AR degradation was measured in NSG mice carrying VCaP-bearing prostate cancer xenografts. Male NSG mice were inoculated with VCaP cells in the flank region above the right leg. Following inoculation, tumors were allowed to grow to approximately 500 mm before randomization. 3 The test compound, prepared in 20% Labrasol, 80% 25 mM citrate buffer, pH 3, was administered to randomized animals. The compound was administered orally once daily for 3 days. After the last dose, plasma and tumor samples were collected and processed for AR degradation assays. Intratumoral AR levels were measured using Western blot analysis. Statistical analysis was performed using one-way ANOVA.

[0550] The compounds described herein have been or will be tested in in vivo AR degradation assays and have shown or will show activity.

[0551] VCaP prostate cancer xenograft model. Xenograft studies were conducted using male NSG mice carrying VCaP-bearing prostate cancer xenografts. Male NSG mice were subcutaneously inoculated with VCaP cells in the upper right flank region. Following inoculation, tumors were allowed to grow to approximately 200 mm before randomization. 3 During randomization, the payload will be in the range of 75 and 250 mm. 3Mice with VCaP tumors were pooled together and randomized to different treatment groups. The test compound formulated in 20% Labrasol, 80% 25 mM citrate buffer pH 3 was administered at a dose volume of 5 mL / kg. During the study, the compound was administered orally once daily. Tumors were measured twice a week using calipers and the tumor volume was calculated using the formula W 2 x L / 2. Statistical analysis was performed using one-way ANOVA or two-way ANOVA.

[0552] The compounds provided herein have been or will be tested in the VCAP prostate cancer xenograft model and have been shown or will be shown to be effective in treating prostate cancer in the model.

[0553] Activity table

[0554] Each compound in Table 1 was tested in one or more of the AR degradation assays shown above (e.g., VCAP AR degradation assay) and was found to be active.

[0555] All compounds in Table 1 were shown to have: DC 50 < 0.1 μM and Y < 50% of the DMSO control, where some compounds have DC 50 value D: DC 50 ≤ 0.002 μM, some have DC 50 value C: 0.002 μM < DC 50 ≤ 0.005 μM, some have DC 50 value B: 0.005 μM < DC 50 ≤ 0.020 μM, and some have DC 50 value A: 0.020 μM < DC 50 ≤ 0.1 μM.

[0556] In addition, the compounds were shown to have: AR degradation efficiency Y value < 50% of the DMSO control, where some compounds have: 0 < Y ≤ 25% (shown as *), some compounds have: 25% < Y ≤ 30% (shown as **), and other compounds have: 30% < Y < 50% (shown as ***). [[ID=**]]

[0557] [[ID=**]] [[ID=**]] [[ID=**]]

[0558] [[ID=**]] [[ID=**]] [[ID=**]]

[0559] [[ID=**]] [[ID=**]] [[ID=**]]

[0560] [[ID=**]] [[ID=**]] [[ID=**]]

[0561] [[ID=**]]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571] Numerous references have been cited, and the contents of these references have been incorporated into this paper in their entirety through citation.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-3 alkyl; a is 1 or 2; R 2 and R 3 is H; m is 0-2; Each R 4 Independently halogen-substituted C1 alkyl or unsubstituted C 1-3 alkyl; X is N or CH; L is -O(CH2) p - or -O(CH2) p O- or -(CH2) p - and p is 1-4; V is wherein B is N or CH; R C is halogen or CF3; R 5 and R 6 are C 1-3 alkyl; and b is 0.

2. The compound of claim 1, wherein R 1 is methyl.

3. The compound of claim 1, wherein a is 1, and R 2 and R 3 are both H.

4. The compound of claim 1, wherein each R 4 is independently selected from methyl and CF3.

5. The compound of claim 1, wherein L is -O(CH2) p - and p is 2 or 3.

6. The compound of claim 1, wherein L is -O(CH2) p O-, and p is 2 or 3.

7. The compound of claim 1, wherein L is -(CH2) p - and p is 3 or 4.​ 8. The compound of claim 1, wherein L is -0(CH2)(CH2)-, -0(CH2)(CH2)(CH2)-, -0(CH2)(CH2)0-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

9. The compound of claim 1, wherein L is -0(CH2)(CH2)- or -(CH2)(CH2)(CH2)-.

10. The compound of claim 1, wherein R 5 and R 6 are methyl.

11. The compound of claim 1, having Formula II, or a pharmaceutically acceptable salt thereof.

12. A compound, wherein the compound is selected from the following compounds, 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,6S)-4-(2-((trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1 -yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1 -yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1 -yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1 -yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2R,6S)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1 -yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1 -yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1 -yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1 -yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1 -methyl-1 H-indol-7-yl)acetamide; 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,4s,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((R)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((R)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2S,6R)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,6S)-4-(4-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-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)-N-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H-indazol-7-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)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H-indazol-7-yl)acetamide; 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-l-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-l-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-l-methyl-lH-indol-7-yl)acetamide; 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-l-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-l-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-l-methyl-lH-indol-7-yl)acetamide; 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-l-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-l-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-l-methyl-lH-indol-7-yl)acetamide; 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-l-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-l-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-l-methyl-lH-indol-7-yl)acetamide; or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. Use of a compound of any one of claims 1-12 in the manufacture of a medicament for the treatment of an androgen receptor mediated disease, wherein the disease is prostate cancer.

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

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