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

Abstract

As used herein, the following structure: TIFF2023531495000109.tif38161 (in the formula, R 1 , R 2 , R 3 , R 4 , L, V, X, A, A', a and m are as defined herein. and compositions comprising an effective amount of the piperidinedione compound, and methods for treating or preventing androgen receptor-mediated diseases.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 043,650, filed June 24, 2020, the disclosure of which is incorporated herein by reference in its entirety.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0021] A "cycloalkyl" group is a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0051] "Treatment," as used herein, means the total or partial alleviation of a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or the slowing or halting of further progression or worsening of such symptoms, or the alleviation or eradication of one or more causes of the disorder, disease, or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease or symptom thereof, as described herein.

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

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

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

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

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

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

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

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

[0060] In some embodiments of the compound of Formula I, R 1 is methyl. In some embodiments of the compound of Formula I, a is 1 and R 2 and R 3 are both H. In some embodiments of the compound of Formula I, a is 2 and R2 and R 3 are both H. In some embodiments of the compound of Formula I, each R 4 is substituted or unsubstituted methyl. In some embodiments of the compound of Formula I, each R 4 is independently selected from methyl and CF3.

[0061] In some embodiments of the compound of Formula I, A is C=O. In some embodiments of the compound of Formula I, A is CH2.

[0062] In some embodiments of the compound of Formula I, A' is NH. In some embodiments of the compound of Formula I, A' or O.

[0063] In some embodiments of the compound of Formula I, m is 0, 1, 2, 3, or 4. In some embodiments of the compound of Formula I, m is 1 or 2.

[0064] In some embodiments of the compound of Formula I, X is N. In some embodiments of the compound of Formula I, X is CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 In some embodiments of the compound of Formula I, X is CH.

[0065] In some embodiments of the compound of Formula I, L is substituted or unsubstituted —O(CH) p -, -(C 1~6 alkyl)O-, -O(C 1~6 alkyl)O- or -(CH2) p - and p is 1 to 4.

[0066] In some embodiments of the compound of Formula I, L is substituted or unsubstituted —O(CH) p - and p is 2 or 3.

[0067] In some embodiments of the compound of Formula I, L is substituted or unsubstituted —O(CH)p O- and p is 2 or 3.

[0068] In some embodiments of the compound of Formula I, L is a substituted or unsubstituted —(CH) p - and p is 3 or 4.

[0069] In some embodiments of the compound of Formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0070] In some embodiments of the compound of Formula I, L is -O(CH)(CH)-, -O(CH)(CH)(CH)-, -(CH)(CH)-, -(CH)(CH)(CH)-, -(CH)(CH)(CH)-, or -(CH)(CH)(CH)(CH)(CH)-. In some embodiments of the compound of Formula I, L is -O(CH)(CH)-, -O(CH)(CH)O-, or -(CH)(CH)(CH)-. In some embodiments of the compound of Formula I, L is -O(CH)(CH)- or -(CH)(CH)(CH)-.

[0071] In some embodiments of the compound of Formula I, B is CH. In some embodiments of the compound of Formula I, B is N.

[0072] In some embodiments of the compound of Formula I, b is 0. In some embodiments of the compound of Formula I, R C is CF3, Cl, or SF5. In some embodiments of the compound of Formula I, R C is CF. In some embodiments of the compound of Formula I, R 5 and R 6 is methyl.

[0073] In some embodiments of the compound of Formula I, the compound is [ka] wherein the variables are as described elsewhere herein. or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0074] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R 1 is methyl; A is CH2 or C=O; Each R 4m are independently hydrogen or substituted or unsubstituted methyl, the substituents, when present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0075] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R 1 is methyl; A is CH2 or C=O; L is a substituted or unsubstituted -O(C1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0076] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R 1 is methyl; A is CH2 or C=O; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0077] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R 1 is methyl; A' is NH or O; a is 1 or 2; Each R 4m are independently hydrogen or substituted or unsubstituted methyl, the substituents, when present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0078] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R 1 is methyl; A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0079] In some embodiments of the compound of Formula I, the compound is [ka] (In the formula, R 1 is methyl; A is CH2 or C=O; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0080] In certain embodiments of compounds of Formula I, II, III, IV and V, A is C=O. In certain embodiments of compounds of Formula I, II, III, IV and V, A is CH2.

[0081] In certain embodiments of compounds of Formula VI, VII and VIII, A' is O. In certain embodiments of compounds of Formula VI, VII and VIII, A' is NH.

[0082] In some embodiments of the compounds of Formula I, II, III, IV, V, VI, VII, and VIII, R 1 is methyl; X is N or CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(CH) p -, -O(CH2) p O- or -(CH2) p -, p is 1 to 4; B is CH or N; b is 0; R C is CF3, Cl or SF5; R C is CF3; and R 5 and R 6 is methyl.

[0083] In some embodiments of the compounds of Formula I, II, III, IV, V, VI, VII, and VIII, R 1 is methyl; X is N or CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); L is a substituted or unsubstituted -O(CH) p -or-(CH2) p -, p is 1 to 4; B is CH or N; b is 0; R C is CF3, Cl or SF5; R C is CF3; and R 5 and R 6 is methyl.

[0084] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, and VIII, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)O-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0085] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, and VIII, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)(CH2)-.

[0086] Further embodiments provided herein include any combination of one or more of the detailed embodiments set forth above.

[0087] In some embodiments of the compound of Formula I, the compound is a compound of Table 1.

[0088] The compounds shown in Table 1 have been tested in the AR mediation assays described herein and found to be active therein. In one embodiment, a compound described herein leads to at least about 50% or more degradation of AR protein at a concentration of 1 μM.

[0089] Method for producing piperidinedione compounds The compounds described herein can be made using conventional organic synthesis and commercially available starting materials, or using the methods provided herein. By way of example and not limitation, compounds of formula I (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R B , R C, L, V, X, m, a, and b are as defined herein) can be prepared as outlined in the schemes shown below and in the examples provided herein. It should be noted that one of ordinary skill in the art would know how to modify the procedures shown in the illustrative schemes and examples to obtain the desired products.

[0090] [ka] As shown in Scheme 1, a compound of formula (I) (wherein X is N or CR X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 The preparation of (A' is NH) can begin by reacting piperidine derivative a with ester intermediate b (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) in a solvent at elevated temperature (e.g., about 40° C. to about 100° C.) to provide intermediate c. Optionally, an iodide salt can be used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the ester protecting group from intermediate c (e.g., by treatment with a hydroxide base in a solvent, such as LiOH in THF and water when alk=Me, Et, or other alkyl, or by treatment with an acid in a solvent, such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane when alk=tert-butyl) provides intermediate d. Coupling of intermediate d with piperidinedione intermediate e in the presence of a coupling agent (e.g., HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent, such as DCM, DMF, NMP, or mixtures thereof, at a temperature between 0°C and about 70°C, affords compounds of formula (I) (wherein X is N or CRX and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 Alternatively, there is provided a compound in which X is N and L is —O(C alkyl)-, A is CO, and A′ is NH. 1~3 alkyl)- or -(C 1~4 Preparation of intermediate c, wherein X is N and L is —O(C alkyl), can begin by reacting the derivative VL-LG (where LG is a suitable leaving group such as Cl, Br, I, triflate or alkyl sulfonate) with a suitably derivatized piperidyl ester derivative f (where alk is, for example, an alkyl group such as Me, Et, Bn or tert-Bu) at elevated temperature (e.g., about 40° C. to about 80° C.) in a solvent in the presence of a base (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) to provide intermediate c, which can be further reacted to give compounds of formula (I) (where X is N and L is —O(C 1~3 alkyl)- or -(C 1~4 alkyl)-, A is CO, and A' is NH).

[0091] [ka] Compounds of formula (I) wherein X is N and L is —O(C 1~3 alkyl)- or -(C 1~4 The compounds of formula (I) (where X is N or CR)- can also be prepared by reacting the derivative VL-LG (where LG is a suitable leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) with the appropriately derivatized intermediate g at elevated temperatures (e.g., about 40°C to about 100°C) in a solvent in the presence of a base (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile). Optionally, the use of an iodide salt facilitates this transformation (e.g., sodium iodide or potassium iodide). Alternatively, compounds of formula (I) (where X is N or CR)- can be prepared by reacting the derivative VL-LG (where LG is a suitable leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) with the appropriately derivatized intermediate g at elevated temperatures (e.g., about 40°C to about 100°C) in a solvent in the presence of a base (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile). X and L is -O(C 1~3 alkyl)-, -(C1~3 alkyl)O- or -(C 1~4 The preparation of compounds of formula (I) (where X is N or CR) can be carried out by reacting compound e with an appropriately functionalized carbonyl intermediate h (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DCM or triethylamine in pyridine) at a temperature between 0° C. and about 60° C. to provide intermediate i. Reaction of i (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) with amine intermediate a in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at an elevated temperature (e.g., about 40° C. to about 80° C.) can provide compounds of formula (I) (where X is N or CR). X and L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 alkyl)-, A is CO, and A' is NH).

[0092] [ka] Intermediates such as amine g (where L is -O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4alkyl)-, A is CO, and A' is NH) can be prepared according to Scheme 3, starting with the reaction of an appropriately functionalized piperazine j with an ester intermediate b (where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or KCO in acetonitrile) at elevated temperatures (e.g., about 40°C to about 100°C) to provide intermediate k. Optionally, an iodide salt can be used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the ester protecting group from intermediate k (e.g., by treatment with a hydroxide base in a solvent, such as LiOH in THF and water when alk=Me, Et, or other alkyl, or by treatment with an acid in a solvent, such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane when alk=tert-butyl) provides intermediate l. Coupling of intermediate l with piperidinedione intermediate e in the presence of a coupling agent (e.g., HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt) and a base (e.g., N,N-diisopropylethylamine, triethylamine, or N-methylimidazole) in a solvent, such as DCM, DMF, NMP, or a mixture thereof, at a temperature between 0° C. and about 70° C., provides amine intermediate g, which upon further reaction affords compounds of formula (I) (wherein L is —O(C 1~3 alkyl)-, -(C 1~3 alkyl)O- or -(C 1~4 The preparation of intermediates such as amine f can be achieved by the addition of an N-protecting group P from intermediate k. N (e.g., P N When P is Boc, by treatment with an acid in a solvent such as HCl in dioxane or EtOAc at room temperature, or TFA in DCM at room temperature, or N is Bn or Cbz by hydrogenation with a metal catalyst in a solvent such as palladium on carbon in methanol).

[0093] [ka] Intermediates such as a (wherein X is N and L is —O(C 1~3 alkyl)- or -(C 1~4 VL-LG (where L is -O(C alkyl)-) can be prepared according to Scheme 4. In the presence of a base (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) in a solvent at elevated temperature (e.g., about 40°C to about 100°C), VL-LG (where L is -O(C alkyl)-) can be prepared according to Scheme 4. 1~3 alkyl)- or -(C 1~4 Treatment of amine n with amine n, where LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate, provides intermediate o. Optionally, an iodide salt can be used to facilitate this transformation (e.g., sodium iodide or potassium iodide). Removal of the N-protecting group P from intermediate o can be achieved by the addition of an iodide salt. N When removing (for example, P N When P is Boc, by treatment with an acid in a solvent such as HCl in dioxane or EtOAc at room temperature, or TFA in DCM at room temperature, or N is Bn or Cbz, by hydrogenation with a metal catalyst in a solvent such as palladium on carbon in methanol, to intermediate a (wherein X is N and L is —O(C 1~3 alkyl)- or -(C 1~4 alkyl)-) is provided.

[0094] [ka] VLR Z Intermediates such as (e.g., intermediate r) (wherein R Zwhere alk is an alkyl group such as Me, Et, Bn, or tert-Bu) with an appropriately derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile q in the presence of a base such as triethylamine in a solvent such as EtOAc at elevated temperatures, for example, about 70°C to about 90°C, to provide intermediate r. Intermediates such as u, where LG is a leaving group (such as Cl, Br, I, triflate, or alkyl sulfonate), and L is -O(C 1~3 alkyl)- or -(C 1~4 alkyl)-) can be reacted with intermediate s, where P O is an alcohol protecting group such as THP, TBS, acetate or benzyl. O When removing (for example, P O When LG is THP, by treatment with catalytic acid in a solvent, e.g., HCl in dioxane, provides the alcohol intermediate t. Activation of the alcohol functionality of t to a leaving group (e.g., by treating t with thionyl bromide in dichloromethane when LG is Br) provides intermediate u, where LG is a leaving group (e.g., Cl, Br, I, triflate, or alkyl sulfonate, etc.), and L is —O(C 1~3 alkyl)- or -(C 1~4 alkyl)-) which can be further reacted to provide compounds of formula (I).

[0095] [ka] Intermediate p (wherein L is -O(C 1~3 alkyl)-, and R Z is a protected alcohol OP O (e.g., THP ether or TBS ether), such as aa, can be prepared according to Scheme 6. Alcohol intermediate v (wherein P Nis an amine protecting group such as Bn or Boc, an electrophile w (where LG is a leaving group such as Cl, Br, I, triflate or alkyl sulfonate, and P O is an oxygen protecting group such as THP or TBS) to provide intermediate x. N When removing (for example, P N When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc, by treatment with HCl in dioxane provides amine intermediate y. Reaction of amine y with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides intermediate aa, which can be further reacted to give compounds of formula (I) (where L=—O(C 1~3 alkyl)-).

[0096] [ka] Intermediate p (wherein L is -(C 1~3 alkyl)-, and R Z is an alcohol or a protected alcohol (e.g., a THP ether or a TBS ether), such as hh, can be prepared according to Scheme 6. The aldehyde intermediate bb (wherein P NStarting from R (where R is an amine protecting group such as Bn or Boc), reaction with an olefinating reagent in the presence of a base (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) in a solvent at temperatures between 0°C and 60°C provides the olefin intermediate cc. Reduction of cc by hydrogenation in the presence of a catalyst (e.g., palladium on carbon in methanol under a hydrogen atmosphere) in a solvent at elevated pressure (e.g., 10-100 psi) provides the intermediate dd. Reduction of the ester functionality can be achieved by treatment with a reducing agent (e.g., diisobutylaluminum hydride in DCM) in a solvent at temperatures between -78°C and 25°C to provide the intermediate ee (where R Y is H). Alternatively, intermediate ee can be prepared by treating intermediate cc with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at temperatures between -78°C and 25°C to provide intermediate ff. Hydrogenation of ff at elevated pressure (e.g., 10-100 psi) in a solvent in the presence of a catalyst (e.g., palladium on carbon in methanol under a hydrogen atmosphere) provides intermediate ee. Removal of the protecting group P of ee N When removing (for example, P N When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc), by treatment with HCl in dioxane provides the amine intermediate gg. Reaction of amine gg with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or an alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides intermediate hh (where R Y is H or an alcohol protecting group (e.g., THP, TBS, or Tr), which upon further reaction provides a compound of formula (I), 1~3 alkyl)-).

[0097] [ka] Intermediate p (wherein L is -(C 1~3 alkyl)O—, and R Z is a heterocycle or cycloalkyl group), such as mm, can be prepared according to Scheme 8. Intermediate ii (wherein P N’ is an amine protecting group, e.g., Bn or Boc, and LG is a leaving group, e.g., Cl, Br, I, triflate, or alkyl sulfonate, to afford alcohol jj, where P N is an amine protecting group, e.g., Bn or Boc), to provide the ether intermediate kk. N’ When removing (for example, P N’ When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc), by treatment with HCl in dioxane provides the amine intermediate ll. Reaction of amine ll with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or an alkyl sulfonate) at elevated temperature (e.g., about 70°C to 130°C) in a solvent, in the presence of a base, optionally in combination with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides intermediate mm, which can be further reacted to give compounds of formula (I) (where L is -(C 1~3 alkyl)O—).

[0098] [ka] Particular intermediate p (wherein L is -O(C 1~3 alkyl)-, and R Z For groups such as qq, the modified sequence shown in Scheme 9 can be used. Nis an amine protecting group such as Bn or Boc, is converted to an electrophilic intermediate nn (where LG is a leaving group such as Cl, Br, I, triflate or alkyl sulfonate, and P N’ is an amine protecting group such as Bn or Boc) to provide the ether intermediate oo. N When removing (for example, P N’ When is Bn, by hydrogenation with palladium on carbon in methanol, or by P N is Boc), by treatment with HCl in dioxane provides the amine intermediate pp. Reaction of the amine pp with an ester (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or an alkyl sulfonate) at elevated temperature (e.g., about 70° C. to 130° C.) in a solvent, optionally in the presence of a base together with an iodide salt (e.g., potassium carbonate and potassium iodide in acetonitrile) provides the intermediate qq, which can be further reacted to give compounds of formula (I) (where L is —O(C 1~3 alkyl)-).

[0099] [ka] Intermediate nn (wherein X is CR Z Specific examples of intermediates such as vv were prepared according to Scheme 10. The ketone intermediate rr (wherein P Nis olefinated with an amine protecting group (e.g., Bn, Boc, or Cbz) using a base (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) in an olefinating reagent and solvent at temperatures between 0°C and 60°C to provide the olefin intermediate ss. Hydrogenation of ss in a solvent in the presence of a catalyst (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at elevated pressure (e.g., 10-100 psi) provides intermediate tt. Reduction of the ester functionality of tt is achieved by treatment with a reducing agent (e.g., diisobutylaluminum hydride in DCM) in a solvent at temperatures between -78°C and 25°C to provide intermediate uu. Activation of alcohol uu to leaving group LG (e.g., by treatment with thionyl bromide in dichloromethane and DMF when LG is Br, or by treatment with triflic anhydride in dichloromethane when LG is a triflate) provides intermediate vv, which upon further reaction gives compounds of formula (I), where L is —O(C 1~3 alkyl)-, and X is CR X ) can be provided.

[0100] [ka] Piperidine dihydrouracil e can be prepared from indazole derivative ww by treatment with acrylic acid in the presence of a Lewis acid catalyst (e.g., aluminum oxide in dioxane) in a solvent at elevated temperature (e.g., 60°C-150°C) to provide intermediate xx. Methylation of the carboxylic acid of xx (e.g., by treatment with diazomethane in toluene and methanol or catalytic sulfuric acid in methanol) provides the methyl ester yy, which is reacted with an isocyanate (e.g., potassium isocyanate or sodium isocyanate) in a solvent (e.g., acetic acid) to give the urea intermediate zz. Cyclization of aaa (by treatment with a strong acid such as concentrated aqueous hydrochloric acid) followed by reduction of the nitro group (e.g., by treatment with a reducing agent, e.g., H2, in the presence of a catalyst such as Pd / C in a solvent such as EtOH or MeOH; or EtOH and HO in the presence of a catalyst such as Fe and NH4Cl) provides intermediate e, which can be further reacted to provide compounds of formula (I) where A is CO and A' is NH.

[0101] [ka] Amine intermediate g (where A is CH2 and A' is NH) can be prepared according to Scheme 12. Reduction of the nitro group of intermediate zz by treatment with a reducing agent (e.g., Pd / C in a solvent such as EtOH or MeOH; or H2 in the presence of a catalyst such as Fe and NH4Cl in a solvent such as EtOH and HO) provides intermediate bbb. At elevated temperatures (e.g., 50°C to about 120°C) in a solvent, in the presence of a base, optionally with an iodide salt (e.g., N,N-diisopropylethylamine and sodium iodide in acetonitrile), bbb can be converted to the appropriately derivatized piperazine intermediate ccc (where P N is an amine protecting group (e.g., Bn or Cbz), A is CH2, and R Yis coupled with a leaving group (e.g., Cl, Br, I, OTf, or OMs) to provide intermediate ddd. Cyclization of intermediate ddd to intermediate eee can be achieved by treatment with a strong acid (e.g., concentrated aqueous hydrochloric acid), followed by P N Upon removal of the protecting group, (e.g., P N When is Cbz, hydrogenation in the presence of a catalyst in a solvent (e.g., palladium on carbon in ethyl acetate) provides intermediate g, which can be further reacted to provide compounds of formula (I) where A is CH and A' is NH.

[0102] [ka] Intermediate ccc (wherein, P N is an amine protecting group (e.g., Bn or Cbz), A is CH2, and R Y is a leaving group (e.g., Cl, Br, I, OTf, or OMs), an alcohol, or a protected alcohol (e.g., OTBS, OPiv, or OTHP) can be prepared according to Scheme 13. In a solvent at elevated temperature (e.g., 40°C to about 100°C), in the presence of a base, optionally together with an iodide salt (e.g., N,N-diisopropylethylamine and sodium iodide in DMF), piperazine intermediate j (wherein P N is an amine protecting group (e.g., Bn or Cbz) to intermediate fff (where LG is a leaving group (e.g., Cl, Br, I, OTf, or OMs), A is CH, and R Y is reacted with a leaving group (e.g., Cl, Br, I, OTf, or OMs), an alcohol, or a protected alcohol (e.g., OTBS, OPiv, or OTHP) to give intermediate ccc, where P N is an amine protecting group (e.g., Bn or Cbz), A is CH2, and R Y is a leaving group (e.g., Cl, Br, I, OTf, or OMs), an alcohol, or a protected alcohol (e.g., OTBS, OPiv, or OTHP). Yis an alcohol or a protected alcohol) can be treated under alcohol activation conditions to give intermediate ccc (where R Y is a leaving group (e.g., Cl, Br, I, OTf, or OMs) (e.g., where R Y Formation of ccc where R is Br is by treatment under bromination conditions, for example, with thionyl bromide in dichloromethane and DMF; or Y When is OTf, this can be achieved by treatment under triflating conditions, for example by treatment with triflic anhydride in dichloromethane).

[0103] [ka] ddd, etc. (wherein P N is an amine protecting group (e.g., Boc, Cbz, or Bn), A is CH2, and A' is O) can be prepared according to Scheme 14. Indazole ggg is reacted with electrophile ccc (where P N is an amine protecting group (e.g., Boc, Cbz, or Bn), A is CH2, and R Y is a leaving group (e.g., Cl, Br, I, OTf, or OMs) to provide intermediate hhh. Coupling of hhh with methyl acrylate in a solvent in the presence of a catalyst (e.g., aluminum oxide in methyl acrylate) provides intermediate iii, which can be reacted with an isocyanate (e.g., sodium isocyanate or potassium isocyanate) in a solvent (e.g., potassium isocyanate in acetic acid) to provide intermediate ddd, where A' is O.

[0104] How to use In one embodiment, the compounds described herein have utility as pharmaceuticals for treating, preventing, or ameliorating a pathological condition in an animal or human. The compounds described herein have utility as pharmaceuticals for treating, preventing, or ameliorating a pathological condition in an animal or human. Accordingly, numerous uses of the compounds are provided herein, including the treatment or prevention of the diseases described below. In one embodiment, the methods provided herein comprise administering an effective amount of the compound to a subject in need thereof.

[0105] The methods provided herein include administering to a subject in need thereof an effective amount of one or more compounds.

[0106] Provided herein are methods for treating or preventing an androgen receptor (AR)-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0107] Provided herein are methods for treating or preventing an AR-mediated disease in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0108] In another aspect, provided herein is a compound for use in treating or preventing AR-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.In some embodiments, provided herein is a compound for use in treating AR-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.In some embodiments, provided herein is a compound for use in preventing AR-mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound as described herein.

[0109] In some embodiments, the compound used in the methods herein is a compound as described herein. In some embodiments, the compound is a compound of Formula I. In some embodiments, the compound is a compound of Formula II. In some embodiments, the compound is a compound of Formula III. In some embodiments, the compound is a compound of Formula IV. In some embodiments, the compound is a compound of Formula V. In some embodiments, the compound is a compound of Formula VI. In some embodiments, the compound is a compound of Formula VII. In some embodiments, the compound is a compound of Formula VIII. In some embodiments, the compound is a compound of Table 1.

[0110] In some embodiments, the AR-mediated disease is an AR wild-type mediated disease. In other embodiments, the AR-mediated disease is the result of AR amplification.

[0111] In certain embodiments, the AR-mediated disease is prostate cancer. In some such embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some such embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In yet another embodiment, the prostate cancer is non-metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is hormone-refractory. In some embodiments, the prostate cancer is resistant to treatment with an AR antagonist. For example, the prostate cancer is resistant to treatment with enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole, or spironolactone.

[0112] Provided herein are methods for reducing AR levels, comprising administering an effective amount of a compound to a subject. Also provided herein are compounds for use in methods for reducing AR levels in cells in vivo, ex vivo, or in vitro, comprising contacting the cells with an effective amount of a compound. In one embodiment, the cells are cells of a patient. In one embodiment, the cells are not cells of a patient. In one embodiment, provided herein are methods for reducing wild-type AR levels in tumors, comprising administering a therapeutically effective amount of a compound, thereby reducing wild-type AR levels in the tumor. In one embodiment, provided herein are methods for reducing AR full-length (AR-FL) levels in tumors, comprising administering a therapeutically effective amount of a compound, thereby reducing AR full-length (AR-FL) levels in the tumor. In some embodiments, the AR levels are reduced compared to the AR levels before administration of the compound. In some embodiments, AR levels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to AR levels before administration of the compound.

[0113] Also provided herein is a method for regulating AR protein activity in a patient in need thereof, comprising administering an amount of a compound to the patient. In some such embodiments, provided herein is a method for reducing AR protein activity in a patient in need thereof, comprising administering an amount of a compound to the patient. In some embodiments, the AR protein activity is reduced compared to the AR protein activity before administration of the compound. In some embodiments, the AR protein activity is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% compared to the AR protein activity before administration of the compound.

[0114] In some embodiments of the methods described herein, the methods additionally include administering one or more second agents selected from AR antagonists (such as cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (such as finasteride and dutasteride), CYP17A1 inhibitors (such as abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (such as leuprorelin and cetrorelix), and antigonadotropins (such as megestrol acetate and medroxyprogesterone acetate).

[0115] In some embodiments, the compounds provided herein can be used in any of the methods described above.

[0116] In some embodiments, the compounds provided herein can be used in any of the methods described above.

[0117] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional dosage forms such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0118] The compounds can be administered to a subject orally, topically, or parenterally in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations may contain an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), a disintegrant (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silica, The pharmaceutical compositions can be prepared by conventional methods using conventional organic or inorganic additives such as citric acid, talc, or sodium lauryl sulfate, flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound in the pharmaceutical composition is a level that will produce the desired effect; for example, for both oral and parenteral administration, the unit dosage can be from about 0.005 mg / kg to about 10 mg / kg of subject's body weight.

[0119] The dose of the compound administered to a subject may vary widely and be at the discretion of a medical professional. Generally, the compound may be administered at a dose of about 0.001 mg / kg to about 10 mg / kg of subject's body weight, once to four times daily; however, this dosage may be varied as appropriate depending on the subject's age, body weight, and medical condition, as well as the type of administration. In one embodiment, the dose is about 0.001 mg / kg to about 5 mg / kg of subject's body weight, about 0.01 mg / kg to about 5 mg / kg of subject's body weight, about 0.05 mg / kg to about 1 mg / kg of subject's body weight, about 0.1 mg / kg to about 0.75 mg / kg of subject's body weight, or about 0.25 mg / kg to about 0.5 mg / kg of subject's body weight. In one embodiment, one dose is given daily. In any given case, the amount of compound administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration.

[0120] In another embodiment, provided herein is a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof from about 0.01 mg / day to about 750 mg / day, from about 0.1 mg / day to about 375 mg / day, from about 0.1 mg / day to about 150 mg / day, from about 0.1 mg / day to about 75 mg / day, from about 0.1 mg / day to about 50 mg / day, from about 0.1 mg / day to about 25 mg / day, or from about 0.1 mg / day to about 10 mg / day of a compound.

[0121] In another embodiment, provided herein is a unit dosage formulation comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound.

[0122] In particular embodiments, provided herein are unit dosage formulations containing about 0.1 mg or 100 mg of compound.

[0123] In another embodiment, provided herein is a unit dosage formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound.

[0124] The compound can be administered once, twice, three times, four or more times daily, hi particular embodiments, doses of 100 mg or less are administered as a single daily dose, and doses above 100 mg are administered twice daily in an amount equal to half the total daily dose.

[0125] The compound can be administered orally for convenience. In one embodiment, when administered orally, the compound is administered with food and water. In another embodiment, the compound is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0126] The compounds may also be administered to the ear, nose, eye or skin, intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation or topically. The mode of administration is left to the discretion of the health-care practitioner, and may depend in-part on the site of the medical condition.

[0127] In one embodiment, provided herein is a capsule containing the compound but no additional carriers, excipients, or vehicles.

[0128] In another embodiment, provided herein is a composition comprising an effective amount of a compound and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0129] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or a convenient fraction of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, any composition is prepared according to known methods in pharmaceutical chemistry. Capsules may be prepared by mixing the compound with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0130] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Such preparations usually contain diluents, binders, lubricants, and disintegrants in combination with the compound. Typical diluents include, for example, various starches, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums are also useful, including acacia, alginic acid, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0131] Tablet formulations may require lubricants to prevent the tablet and tablet punches from adhering to the die. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, causing the tablet to break apart and release the compound. These include starch, clay, cellulose, algin, and gums. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose can be used, as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavoring and sealant, or with film-forming protective agents to modify the dissolution properties of the tablet. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0132] When it is desired to administer the compound as a suppository, typical bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding waxes to slightly raise its melting point. Water-miscible suppository bases, especially those containing polyethylene glycols of various molecular weights, are widely used.

[0133] The effect of a compound can be delayed or prolonged by appropriate formulation.For example, slowly dissolving pellets of the compound can be prepared and incorporated into tablets or capsules or as sustained-release implantable devices.This technique also includes making pellets with several different dissolution rates and filling capsules with a mixture of these pellets.Tablets or capsules can be coated with a film that resists dissolution for a predictable duration.Even parenteral preparations can be made long-acting by dissolving or suspending the compound in an oily or emulsion-like medium that allows the compound to slowly disperse in serum.

[0134] Enumerated Embodiments The invention can be defined by reference to the following enumerated exemplary embodiments.

[0135] 1. Formula I [ka] (In the formula, R 1 is C 1~3 is alkyl; A is CH2 or C=O; A' is NH or O; a is 1 or 2; R 2 and R 3 are each independently H and C 1~3 alkyl, or R 2 and R 3 and the carbon to which they are attached may be substituted or unsubstituted C 3~6 Forming a cycloalkyl; m is 0 to 8; Each R 4 are independently substituted or unsubstituted C 1~3 alkyl or two R 4 The groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, may form a substituted or unsubstituted C 3~6 Form a cycloalkyl or two R 4 groups, taken together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4- to 7-membered heterocyclyl; L is a substituted or unsubstituted -O(C 1~6 alkyl)-, -(C 1~6 alkyl)O-, -O(C 1~6 alkyl)O- or -(C 1~9 alkyl)-; X is N or CR X and; R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 alkyl); V is [ka] wherein: B is N, CH or CR B and; Each R B are independently selected from halogen and substituted or unsubstituted C 1~6 alkyl; R C is a halogen, CF3 or SF5; R 5 and R 6 is C 1~3 alkyl or R 5 and R 6 together with the carbon atoms to which they are attached, form a substituted or unsubstituted C 3~6 forming a cycloalkyl or a 3- to 6-membered heterocyclyl; and b is 0 to 2) or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0136] 2.R 1 is methyl.

[0137] 3. a is 1 and R 2 and R 3 and R are both H.

[0138] 4. The compound of any one of embodiments 1-3, wherein A is C=O.

[0139] 5. The compound of any one of embodiments 1-3, wherein A is CH2.

[0140] 6. The compound of any one of embodiments 1-5, wherein A' is NH.

[0141] 7. A' or O, a compound according to any one of embodiments 1 to 5.

[0142] 8.Each R 4The compound of any one of embodiments 1-7, wherein is substituted or unsubstituted methyl.

[0143] 9.Each R 4 is independently selected from methyl and CF3.

[0144] 10. The compound of any one of embodiments 1 to 9, wherein m is 0, 1, 2, 3, or 4.

[0145] 11. The compound according to any one of embodiments 1 to 10, wherein m is 1 or 2.

[0146] 12. The compound of any one of embodiments 1-11, wherein X is N.

[0147] 13.X is CR X and R X is hydrogen, halogen, -O(C 1~6 alkyl) or -(C 1~9 The compound of any one of embodiments 1-11, wherein R is 1 or 2;

[0148] 14. L is a substituted or unsubstituted -O(CH2) p -, O(CH2) p O- or -(CH2) p - and p is 1-4.

[0149] 15. L is a substituted or unsubstituted -O(CH2) p - and p is 2 or 3.

[0150] 16. L is a substituted or unsubstituted -O(CH2) p The compound of any one of embodiments 1 to 13, wherein p is O— and p is 2 or 3.

[0151] 17. L is a substituted or unsubstituted -(CH2) p- and p is 3 or 4.

[0152] 18. The compound of any one of embodiments 1-13, wherein L is -O(CH2)(CH2)-, -O(CH2)(CH2)O-, or -(CH2)(CH2)(CH2)-.

[0153] 19. The compound according to any one of embodiments 1-18, wherein B is CH.

[0154] 20. The compound according to any one of embodiments 1-19, wherein B is N.

[0155] 21. The compound of any one of embodiments 1-20, wherein b is 0.

[0156] 22.R C The compound of any one of embodiments 1-21, wherein is CF3, Cl, or SF5.

[0157] 23.R C The compound of any one of embodiments 1-22, wherein is CF3.

[0158] 24.R 5 and R 6 The compound of any one of embodiments 1-23, wherein is methyl.

[0159] 25.Formula II [ka] or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0160] 26.Formula III [ka] (In the formula, R 1 is methyl; A is CH2 or C=O; Each R 4m are independently hydrogen or substituted or unsubstituted methyl, the substituents, when present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0161] 27.Formula IV [ka] (In the formula, L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; R 1 is methyl; A is CH2 or C=O; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0162] 28.Formula V [ka] (In the formula, R 1 is methyl; A is CH2 or C=O; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0163] 29. Formula VI [ka] (In the formula, R 1 is methyl; A' is NH or O; a is 1 or 2; Each R 4m are independently hydrogen or substituted or unsubstituted methyl, the substituents, when present, being selected from 1 to 5 halo; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3alkyl)- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0164] 30.Formula VII [ka] (In the formula, R 1 is methyl; A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0165] 31.Formula VIII [ka] (In the formula, A' is NH or O; a is 1 or 2; L is a substituted or unsubstituted -O(C 1~3 alkyl)-, -O(C 1~3 alkyl)O- or -(C 1~4 alkyl)-; R 1 is methyl; V is [ka] and B is N or CH; R C is a halogen, CF3 or SF5; and R 5 and R 6 is C 1~3 alkyl) or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, of the compound of embodiment 1,

[0166] 32. A compound according to embodiment 1 selected from Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof.

[0167] 33. A pharmaceutical composition comprising an effective amount of a compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt, tautomer, isotopologue or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0168] 34. A method for treating an androgen receptor mediated disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-32.

[0169] 35. A method for treating an androgen receptor-mediated disease, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of embodiment 33.

[0170] 36. The method of embodiment 34 or 35, wherein the androgen-mediated disease is prostate cancer.

[0171] 37. The method of embodiment 36, wherein the prostate cancer is castration-resistant prostate cancer (CRPC). [Example]

[0172] The following examples are presented by way of illustration, not limitation. Compound names were assigned using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic chemical structure names adhering to the Cahn-Ingold-Prelog stereochemical rules. Those skilled in the art can modify the procedures shown in the illustrative examples to obtain the desired products.

[0173] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product with a solution of an acid (e.g., aqueous HCl) after chromatographic purification.

[0174] [Table 1]

[0175] The following examples are presented by way of illustration, not limitation. Compound names were assigned using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic chemical structure names adhering to the Cahn-Ingold-Prelog stereochemical rules. Those skilled in the art can modify the procedures shown in the illustrative examples to obtain the desired products.

[0176] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product with a solution of an acid (e.g., aqueous HCl) after chromatographic purification.

[0177] [Table 2]

[0178] Example 1: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] trans-4-(Dibenzylamino)cyclohexan-1-ol. To a mixture of trans-4-aminocyclohexan-1-ol (40 g, 347 mmol, 1.0 equiv.) and cesium carbonate (339 g, 1.04 mol, 3 equiv.) in acetonitrile (900 mL) was added benzyl bromide (119 g, 698 mmol, 2.01 equiv.) dropwise. The reaction was stirred at room temperature. After 48 h, the reaction mixture was filtered and concentrated. The resulting residue was diluted with DCM (300 mL), washed with water (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated. trans-4-(Dibenzylamino)cyclohexan-1-ol (77 g, 261 mmol, 75% yield) was obtained as a pale pink solid. The crude product was carried forward without further purification. MS (ESI) m / z 116.3 [M+1] + ; 1H NMR400MHz DMSO-d6δ7.27-7.34(m,8H),7.19-7.21(m,2H),4.42(d,J=4.8Hz,1H),3.55(s,4H),2.33 -2.36(m,1H),1.74-1.84(m,4H),1.40(dd,J=12.4Hz,2.0Hz,2H),0.98(d,J=13.2Hz,2H).

[0179] trans-N,N-Dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine. To a mixture of trans-4-(dibenzylamino)cyclohexan-1-ol (60 g, 203 mmol, 1.0 equiv) and tetrabutylammonium hydrogen sulfate (13.8 g, 40.6 mmol, 0.2 equiv) in THF (400 mL) and water (200 mL) at 0 °C was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (84.9 g, 406 mmol, 61.5 mL, 2.0 equiv) and sodium hydroxide (200 g, 5.00 mol, 24.6 equiv). The reaction was heated to 65 °C. After 12 h, the reaction was poured into ice water (1.0 L) and the aqueous phase was extracted with ethyl acetate (2 × 300 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 column chromatography (SiO, 2–50% ethyl acetate in petroleum ether) to afford trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (60 g, 142 mmol, 70% yield) as a colorless oil. 1 H NMR 400MHz CDCl3δ 7.37-7.39(m,4H),.7.28-7.32(m,4H),7.22(m,2H),4.63-4.67(m,1H),3.57-3.89(m,9H),3.23-3.25(m,1H) ,2.55(m,1H),2.08-2.11(m,2H),1.92-1.95(m,5H),1.58-1.64(m,6H),1.54-1.56(m,2H),1.20-1.39(m,2H).

[0180] trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine. To a mixture of trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (65 g, 153 mmol, 1.0 equiv) in methanol (500 mL) under N was added 10% palladium on carbon (6.5 g). The suspension was degassed under vacuum and purged with hydrogen gas three times. The reaction was stirred at room temperature under an atmosphere of hydrogen gas (15 psi). After 1 h, the reaction was filtered and the filtrate was concentrated to give trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexane-1-amine (46 g) as an off-white oil. This crude material was carried forward without further purification. 1 H NMR400MHz CDCl3δ 7.34-7.36(m,1H),.4.63-4.65(m,1H),3.82-3.91(m,3H),3.52-3.66(m,5H),3.28(m,1H),2.70-2.71(m,1H),2. 01-2.04(m,2H),1.85-1.89(m,3H),1.58-1.59(m,1H),1.45-1.56(m,8H),1.29-1.32(m,2H),1.11-1.14(m,2H).

[0181] Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate. To a mixture of trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (25 g, 103 mmol, 1.0 equiv) in acetonitrile (175 mL) was added methyl 2-bromo-2-methylpropanoate (37.2 g, 205 mmol, 26.6 mL, 2.0 equiv), potassium carbonate (28.4 g, 205 mmol, 2.0 equiv), and potassium iodide (1.71 g, 10.3 mmol, 0.1 equiv). The reaction was heated to 110° C. After 16 h, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by column chromatography (SiO, 0-50% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54 mmol, 53% yield) as a yellow oil. MS (ESI) m / z 344.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 4.63(t,J=3.2Hz,1H),.3.82-3.87(m,2H),3.70(s,3H),3.61-3.63(m,4H),3.51-3.60(m,2H),3.22-3.24(m,1H) ),2.36(m,1H),1.99(m,2H),1.83-1.86(m,3H),1.62(m,1H),1.53-1.60(m,6H),1.30(m,6H),1.12-1.14(m,2H).

[0182] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54.2 mmol, 1.0 equiv.) in ethyl acetate (130 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (24.7 g, 108 mmol, 2.0 equiv.) and N,N-diisopropylethylamine (14.0 g, 108 mmol, 2.0 equiv.). The reaction was heated to 90° C. with stirring. After 12 hours, the reaction mixture was concentrated, and the resulting crude material was purified by silica gel column chromatography (0–50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (25 g, 46.3 mmol, 86% yield) as a yellow oil.

[0183] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (42.5 g, 78.8 mmol, 1.0 equiv) in dichloromethane (300 mL) was added 4 M hydrochloric acid in 1,4-dioxane (400 mL) dropwise. The reaction was stirred at room temperature. After 1 hour, the reaction mixture was concentrated and purified by silica gel column chromatography (1-20% THF in dichloromethane) to give 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (21 g, 46.1 mmol, 59% yield) as a yellow glassy oil. MS(ESI) m / z 456.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 7.95(d,J=8.0Hz,1H),7.85(m,1H),7.72(dd,J=10.0Hz,1.6Hz,1H),3.73-3.77(m,4H),3.60-3.62(m,2H),3.37-3 .39(m,1H),2.88-2.91(m,2H),2.21-2.24(m,2H),1.97(m,1H),1.83-1.88(m,3H),1.61(s,6H),1.33-1.41(m,2H).

[0184] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a mixture of 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.500 g, 7.72 mmol, 1.0 equiv) in dichloromethane (80 mL) was added N,N-dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol, 2.0 equiv) at 0° C. After 12 h, the reaction was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (9-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (4.200 g, 8.13 mmol, crude) as a yellow solid. MS (ESI) m / z 518.1 [M+1] + .

[0185] 1-Methyl-7-nitro-1H-indazol-3-amine. To a mixture of 2-fluoro-3-nitrobenzonitrile (19.50 g, 117.4 mmol, 1 equiv.) in N,N-dimethylacetamide (30 mL, 3.9 M) was added methylhydrazine (40.56 g, 352.2 mmol, 46.36 mL, 3 equiv.) and N,N-diisopropylethylamine (16.69 g, 129.13 mmol, 22.49 mL, 1.1 equiv.). The mixture was stirred at 20 °C for 30 minutes. The reaction mixture was diluted with 1000 mL of water and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-methyl-7-nitro-1H-indazol-3-amine (30.50 g, crude) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.18-8.16(m,1H),8.07(dd,J=0.8,7.6Hz,1H),7.08(t,J=8.0Hz,1H),5.93(s,2H),3.82(s,3H).

[0186] 3-((1-Methyl-7-nitro-1H-indazol-3-yl)amino)propanoic acid. To a mixture of 1-methyl-7-nitro-1H-indazol-3-amine (30.20 g, 157.2 mmol, 1 equiv.) in 1,4-dioxane (300 mL, 0.52 M), aluminum oxide (48.07 g, 471.5 mmol, 3 equiv.) and acrylic acid (33.97 g, 471.5 mmol, 32.36 mL, 3 equiv.) were added. The mixture was stirred at 110 °C for 12 h. The crude material was purified by silica gel column chromatography (20-100% ethyl acetate in petroleum ether) to give 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoic acid (17.10 g, 26.7 mmol, 17% yield) as a red solid. MS(ESI)m / z 265.1[M+1] +

[0187] Methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate. To a mixture of 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoic acid (17.10 g, 26.7 mmol, 1 equiv.) in methanol (5 mL, 2.7 M) and toluene (5 mL, 2.7 M) was added trimethylsilyldiazomethane (2 M, 42.37 mL, 3.17 equiv.). The reaction was stirred at 25 °C for 8 h. The reaction was concentrated, diluted with water (200 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by reverse-phase HPLC (35-65% acetonitrile in water with 0.225% formic acid). The product fractions were adjusted to pH = 7 with saturated sodium bicarbonate and then extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate (7.10 g, 25.5 mmol, 95% yield) as a red solid. MS (ESI) m / z 279.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.16(dd,J=0.8,7.6Hz,1H),8.10(dd,J=1.2,8.0Hz,1H),7.10(t,J=8.0Hz,1H),6.69 (t,J=6.0Hz,1H),3.85(s,3H),3.62(s,3H),3.56-3.50(m,2H),2.72(t,J=6.8Hz,2H).

[0188] Methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate. To a mixture of methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate (7.10 g, 25.5 mmol) in acetic acid (70 mL, 0.36 M) was added potassium cyanate (12.42 g, 153.1 mmol, 6 equiv). The reaction was stirred at 25° C. for 8 hours. The reaction was concentrated, diluted with water (200 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with 80 mL of brine, dried over anhydrous sodium sulfate, and concentrated to give a residue. The crude material was purified by silica gel column chromatography (20-100% ethyl acetate in petroleum ether) to give methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate (3.00 g, 9.34 mmol, 37% yield) as a yellow solid. MS (ESI) m / z 321.9 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.20(dd,J=0.8,7.6Hz,1H),7.99(dd,J=0.8,8.0Hz,1H),7.34(t,J=8.0Hz,1H),6. 16(s,2H),4.06(s,3H),3.93(t,J=6.8Hz,2H),3.46(s,3H),2.60(t,J=7.2Hz,2H).

[0189] 1-(1-Methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. To methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate (3.09 g, 0.38 mmol) was added 4 M hydrochloric acid in 1,4-dioxane (25 mL, 0.02 M). The mixture was stirred at 25 °C for 8 hours. The reaction mixture was filtered, and the filter cake was treated with saturated sodium bicarbonate solution to pH 7. The precipitate was filtered to give 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione as a yellow solid. MS (ESI) m / z 290.0 [M+1] + .

[0190] 1-(7-Amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. To a solution of 1-(1-methyl-7-nitro-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.70 g, 9.33 mmol) in methanol (30 mL, 0.15 M) and tetrahydrofuran (30 mL, 0.15 M) was added 10% palladium on activated carbon (12.5 g, 1.18 mmol, 1.3 equiv.) under 15 psi of hydrogen gas. The mixture was stirred at 25 °C for 8 hours. The reaction mixture was filtered to give 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.04 g, 7.19 mmol, 77% yield) as a yellow solid. MS (ESI) m / z 260.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.50(s,1H),6.90-6.75(m,2H),6.59(d,J=6.4Hz,1H),5.24(s,2H),4.22(s,3H),3.84(t,J=6.8Hz,2H),2.75(t,J=6.4Hz,2H).

[0191] (3R,5S)-tert-butyl 4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. A solution of tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5 g, 23.33 mmol, 1 equiv.), methyl bromoacetate (3.57 g, 23.33 mmol, 1 equiv.), and triethylamine (10.2 mL, 70 mmol, 3 equiv.) in THF (100 mL, 0.23 M) was stirred at 50 °C. After 18 h, the reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (6.2 g, 21.6 mmol, 92% yield) as a yellow oil. MS(ESI) m / z 287.2 [M+1] + .

[0192] 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid. To a solution of tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (2.27 g, 7.93 mmol, 1 equiv) in THF (20 mL) was added lithium hydroxide (208.8 mg, 8.7 mmol, 1.1 equiv) in water (5 mL), and the reaction was stirred at room temperature. After 18 h, the reaction was concentrated in vacuo and azeotroped three times with chloroform to remove residual water to provide crude 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (2.19 g, 7.8 mmol, 99% yield) as an off-white glassy solid. This material was carried forward without further purification. MS(ESI) m / z 273.2 [M+1] + .

[0193] tert-Butyl (3S,5R)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. To a 20 mL vial containing 2-((2R,6S)-4-(tert-butoxycarbonyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.20 g, 0.7 mmol, 1 equiv.) and N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (0.45 g, 1.6 mmol, 2.2 equiv.), acetonitrile (2 mL) was added, followed by 1-methylimidazole (0.18 mL, 2.2 mmol, 3 equiv.). The reaction was stirred at room temperature for 10 minutes. A solution of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.19 g, 0.73 mmol, 1.0 equiv) in acetonitrile (1 mL) was then added and the reaction was stirred at room temperature. After 16 h, the reaction was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was removed, washed with 100 mL 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (0.15 g, 0.29 mmol, 40% yield). MS (ESI) m / z 514.0 [M+1]+.

[0194] 2-((2S,6R)-2,6-Dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a 20 mL vial containing tert-butyl (3S,5R)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (0.15 g, 0.29 mmol, 1 equiv.), 2 mL of dichloromethane was added, followed by 4 M hydrochloric acid in dioxane (1.35 mL, 5.41 mmol, 20 equiv.), and the reaction was stirred at room temperature. After 2 h, the reaction was concentrated and dried under vacuum to provide 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.1 g, 0.24 mmol, 82.8% yield) as a yellow solid, which was carried on without further purification. MS (ESI) m / z 414.0 [M+1]+.

[0195] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 0.19 mmol), 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1 H-indazol-7-yl)acetamide hydrochloride (130 mg, 0.29 mmol, 1.5 equiv), sodium iodide (43 mg, 0.29 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.13 mL, 0.77 mmol, 4 equiv) were combined in acetonitrile (1 mL, 0.13 M) and N,N-dimethylformamide (0.5 mL, 0.13 M) and heated at 50° C. overnight. The reaction was filtered and purified by standard methods to give 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (8 mg, 0.009 mmol, 5% yield). MS(ESI) m / z 851.0 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ ppm 10.58(s,1H),8.35(d,J=8.31Hz,1H),8.20(d,J=1.83Hz,1H),7.98(dd,J=8.25,1.77Hz,1H),7.56(d,J=8.07Hz,1H),7.3 1(s,1H),7.16-7.24(m,2H),7.09-7.15(m,1H),7.05(s,1H),4.09(s,3H),3.78-3.95(m,7H),3.30-3.44(m,3H),3.24(br s,2H),2.81-3.05(m,4H),2.78(t,J=6.66Hz,2H),2.09-2.16(m,2H),1.74(br d,J=11.13Hz,2H),1.56(s,6H),1.33-1.45(m,2H),1.22(br d,J=1.83Hz,6H).

[0196] Example 2: 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] tert-Butyl (trans-4-formylcyclohexyl)carbamate. To a mixture of tert-butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate (240 g, 1.05 mol, 1 equiv.) in acetonitrile (1.60 L) at 15 °C was added IBX (352 g, 1.26 mol, 1.2 equiv.). The reaction was stirred at 65 °C for 1 h. Two batches were combined for workup and purification. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl (trans-4-formylcyclohexyl)carbamate (470 g, crude) as a white solid. This crude product was used directly in the next step without further purification. 1H NMR(400MHz CDCl3)δ 9.62(s,1H),4.43(s,1H),4.41(s,1H),2.10-2.14(m,3H),2.01-2.05(m,2H),1.45(s,9H),1.38-1.41(m,2H),1.14-1.18(m,2H).

[0197] Ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate. Ethyl 2-(diethoxyphosphoryl)acetate (255 g, 1.14 mol, 1.1 eq) was added dropwise to a mixture of sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2 eq) in THF (900 mL) at 0° C. The reaction was stirred at 0° C. for 1 hour. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (235 g, 1.03 mol, 1 eq) in THF (500 mL) was added dropwise at 0° C. The reaction was stirred at 25° C. for 2 hours. The reaction was poured into ice water (3.0 L) and stirred for 20 minutes. The aqueous phase was extracted with ethyl acetate (800 mL, 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (560 g, crude) as a pale yellow solid. This material was carried on without further purification. 1H NMR(400MHz CDCl3)δ 6.88(dd,J=15.6Hz,6.8Hz 1H),5.75-5.79(m,1H),4.40(s,1H),4.12-4.23(m,3H),3.39(s,1H),2.04-2.08(m,3H), 1.81-1.85(m,2H),1.44(s,9H),1.33-1.35(m,1H),1.26-1.30(m,6H),1.10-1.16(m,3H).

[0198] tert-Butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate. Reaction setup as two parallel reactions. To a solution of the compound (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)ethyl acrylate (280 g, 942 mmol, 1 equiv.) in dichloromethane (1.12 L) at −78° C. under an argon atmosphere was added diisobutylaluminum hydride (1 M, 1.88 L, 2 equiv.). The reaction was stirred at −78° C. for 1 hour. The reaction was quenched with MeOH (280 mL) at −60° C. The two reaction mixtures were combined and the resulting mixture was cooled to −10° C. with saturated citric acid (4.0 L). The crude material was poured into a solution of 1.0 kg citric acid in HO. The mixture was extracted with ethyl acetate (2.0 L, 1.5 L). The combined organic layers were washed with aqueous sodium bicarbonate (2.0 L), brine (2.0 L), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 50 / 1 → 0 / 1) to provide tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (420 g, 1.645 mol, 87% yield) as a pale yellow solid. 1 H NMR(400MHz CDCl3)δ 5.58-5.60(m,2H),4.39(s,1H),4.06-4.07(m,2H),3.35(s,1H),1.80-2.00(m,3H),1.74-1.78(m,2H),1.42(s,9H),1.08-1.20(m,4H).

[0199] tert-Butyl ((trans-4-(3-hydroxypropyl)cyclohexyl)carbamate. Four batches of this reaction were run in parallel. A mixture of tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (105 g, 411 mmol, 1 equiv.) and palladium on carbon (10.5 g, 10% purity) in MeOH (600 mL) was degassed and purged with H three times, then the mixture was heated under H (15 psi) at 25 °C for 12 h. The mixture was stirred. These four batches were combined for workup and purification. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 → 0 / 1). tert-Butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (82 g, 19% yield) and tert-butyl (trans-4-(3-oxopropyl)cyclohexyl)carbamate (200 g, 48% yield) were obtained as white solids. 1 H NMR(400MHz CDCl3)δ 4.38(s,1H),3.63(t,J=6.4Hz,2H),3.37(s,1H),1.98-2.01(m,2H),1.60-1.79 (m,2H),1.55-1.59(m,2H),1.44(s,9H),1.22-1.28(m,3H),0.95-1.05(m,4H).

[0200] 3-(trans-4-Aminocyclohexyl)propan-1-ol hydrochloride. Two reactions were carried out in parallel. To a solution of tert-butyl (trans-4-(3-hydroxypropyl)cyclohexyl)carbamate (115 g, 447 mmol, 1 equiv.) in methanol (200 mL) was added 4 M hydrochloric acid in methanol (500 mL). The reaction was stirred at 15 °C for 6 h. The two batches were combined for workup and purification. The reaction was filtered and concentrated to give 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (160 g, 92% yield) as a pale yellow solid. This material was carried forward without further purification. 1H NMR(400MHz DMSO-d6)δ 8.09(s,4H),4.62(s,2H),3.35(t,J=6.8Hz,2H),2.87(d,J=4.4Hz,1H),1.93(d,J=10.8Hz,2H),1. 73(d,J=12.8Hz,2H),1.38-1.42(m,2H),1.29-1.31(m,3H),1.13-1.17(m,3H),0.89-0.92(m,2H).

[0201] Methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate. To a mixture of 3-(trans-4-aminocyclohexyl)propan-1-ol hydrochloride (120 g, 619 mmol, 1 equiv.) in acetonitrile (750 mL) was added potassium carbonate (428 g, 3.10 mol, 5 equiv.) and methyl 2-bromo-2-methylpropanoate (449 g, 2.48 mol, 4 equiv.). The mixture was stirred at 110 °C for 12 h. The reaction was filtered and concentrated. The crude material was purified by silica gel column chromatography (5 to 100% ethyl acetate in petroleum ether) to give methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 34% yield) as a yellow oil. MS(ESI)m / z 258.2[M+1] + .

[0202] 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (62.2 g, 273 mmol, 1.3 equiv.) in ethyl acetate (350 mL) was added N,N-diisopropylethylamine (54.2 g, 420 mmol, 2 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO, petroleum ether / ethyl acetate = 15 / 1 → 0 / 1) to give 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (63 g, 139 mmol, 66% yield) as a yellow solid. 1H 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).

[0203] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.820 g, 1.81 mmol, 1 equiv.) in N,N-dimethylformamide (0.800 mL) and dichloromethane (8 mL) was added thionyl bromide (0.752 g, 3.620 mmol, 2 equiv.) slowly at 0° C. After stirring at 0°C for 2 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (15-25% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.650 g, 1.259 mmol, 70% yield) as a brown solid. MS(ESI) m / z 516.1 [M+1] + .

[0204] Methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate. To a solution of tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (1 g, 3.49 mmol, 1 equiv.) in dichloromethane (3 mL) was added 4 M HCl in 1,4-dioxane (8.7 mL, 34.9 mmol, 10 equiv.) and the reaction was stirred at room temperature. After 2 h, the reaction was concentrated, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate (5 × 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to provide methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (510 mg, 2.72 mmol, 78% yield) as a yellow oil. MS(ESI)m / z 187.5[M+1] + .

[0205] 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)methyl acetate. To a solution of 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (500 mg, 0.968 mmol, 1 equiv.) and methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (270 mg, 1.45 mmol, 1.5 equiv.) in N,N-dimethylformamide (4.8 mL, 0.2 M) was added N,N-diisopropylethylamine (0.46 mL, 4.84 mmol, 5 equiv.) and the reaction was stirred at 50° C. After 18 h, the reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1-10% methanol in dichloromethane) to give methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate (487 mg, 0.784 mmol, 81% yield) as a pale yellow oil. MS(ESI) m / z 622.3 [M+1] + .

[0206] 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid. To a solution of methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate (500 mg, 0.82 mmol, 1 equiv.) in 5:1 THF / water (4 mL, 0.2 M) was added lithium hydroxide (59 mg, 2.46 mmol, 3 equiv.). The reaction was stirred at room temperature. After 12 hours, the reaction was diluted with water (10 mL), adjusted to pH 5 by the addition of 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-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (364 mg, 0.599 mmol, 73% yield) as an off-white solid. MS (ESI) m / z 608.4 [M+1] + ; 1 H NMR(400MHz CDCl3)δ 8.33(d,J=8.0Hz,1H),8.19(s,1H),7.97(d,J=8.4Hz,1H),3.83(s,1H),3.37(s,2H),3.14(s,2H),2.89(s,2H),2.73(s,2H),2.40(s,2H),2 .00(s,2H),1.81(d,J=12.0Hz,2H),1.72(d,J=10.4Hz,2H),1.44-1.54(m,8H),1.15-1.19(m,3H),1.05-1.08(m,2H),1.01(d,J=6.4Hz,6H).

[0207] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. Acetonitrile (1.65 mL, 0.2 M) was added to a two-dram vial containing 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetic acid (0.1 g, 0.16 mmol) and 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.06 g, 0.25 mmol, 1.5 equiv). The reaction was stirred until all solids were dissolved. 1-Methylimidazole (0.07 mL, 0.84 mmol, 5 equiv) was added followed by N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (0.1 g, 0.36 mmol, 2.2 equiv) and the reaction was stirred at room temperature. After 1 hour, the reaction was diluted with dimethyl sulfoxide to a total volume of 3 mL, filtered, and purified by standard methods to give 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.03 g, 0.03 mmol, 18% yield).MS(ESI)m / z 849.4[M+1]+;1H NMR(DMSO-d6,400MHz)δ 10.5-10.7(m,1H),9.7-10.1(m,1H),8.1-8.3(m,1H),7.8-8.0(m,1H),7.4-7.7(m,1H),7.2-7.3(m,1H),6.7-7.1(m,1H),4.0-4.2(m,3H) ,3.8-4.0(m,3H),3.5-3.6(m,2H),3.1-3.3(m,3H),2.9-3.1(m,2H),2.6-2.9(m,6H),1.6-2.0(m,7H),1.4-1.6(m,6H),1.0-1.4(m,12H).

[0208] Example 3: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (2 g, 5.82 mmol, 1 equiv.) in ethyl acetate (1.3234 mL) was added 2-chloro-4-isothiocyanatobenzonitrile (2.27 g, 11.65 mmol, 2 equiv.) and N,N-diisopropylethylamine (2.03 mL, 11.65 mmol, 2 equiv.). The reaction was heated to 90° C. with stirring. After 18 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (2 g, 3.9521 mmol, 68% yield) as a white solid. MS(ESI) m / z 506.2 [M+1] + .

[0209] 2-Chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (4.0 g, 7.9 mmol, 1 equiv) in chloroform (5.7 mL) was added 4 M HCl in dioxane (39.52 mL, 158.08 mmol, 20 equiv) and the reaction was stirred at room temperature. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to give 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.5 g, 2.883 mmol, 36% yield) as an off-white solid. MS(ESI) m / z 422.2 [M+1] + .

[0210] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.51 g, 3.06 mmol) in dichloromethane (38 mL) and N,N-dimethylformamide (3.8 mL) was added thionyl bromide (0.59 mL, 7.64 mmol, 2.5 equiv.) and the reaction was stirred at room temperature. After 1 h, the reaction was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0–80% ethyl acetate in hexanes) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (1.171 g, 2.42 mmol, 79% yield) as a pale yellow solid. MS (ESI) m / z 484.0 [M+1]+.

[0211] 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)methyl acetate. To a solution of 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (400 mg, 0.825 mmol, 1 equiv) and methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate hydrochloride (239 mg, 1.073 mmol, 1.3 equiv) in N,N-dimethylformamide was added N,N-diisopropylethylamine (1.03 mL, 5.94 mmol, 7 equiv) and the reaction was stirred at 60° C. After 18 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (1-10% methanol in dichloromethane) to give methyl 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)acetate (311 mg, 0.528 mmol, 64% yield) as a yellow solid. MS(ESI) m / z 590.0 [M+1] + .

[0212] 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)acetic acid. To a solution of methyl 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)acetate (311 mg, 0.528 mmol, 1 equiv) in a 4:1 solution of 1,4-dioxane in water (1 mL) was added lithium hydroxide (38 mg, 1.58 mmol, 3 equiv) and the reaction was stirred at room temperature. After 7 h, the reaction was diluted with water (10 mL) and the pH was adjusted to approximately 7 by the addition of 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-thioxoimidazolidin-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 carried on without further purification. MS (ESI) m / z 576.0 [M+1]+.

[0213] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 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)acetic acid (100 mg, 0.160 mmol, 1 equiv) and 1-(7-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (102 mg, 0.390 mmol, 2.4 equiv) was added N,N-dimethylformamide (0.82 mL, 0.2 M) and 1-methylimidazole (0.07 mL, 0.830 mmol, 5 equiv). The reaction was stirred at room temperature until all solids had dissolved. After 5 minutes, N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (101 mg, 0.360 mmol, 2.2 equiv) was added and the reaction was stirred at room temperature. After 2 hours, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (8.7 mg, 0.0102 mmol, 6% yield) as a white solid. MS(ESI) m / z 817.0 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.57(s,1H),10.16(br s,1H),9.95(br s,1H),8.13(d,1H,J=8.3Hz),7.92(d,1H,J=1.8Hz),7.60(dd,1H,J=1.9,8.4Hz),7.55(d,1H,J=8.2Hz),7.19(d,1H,J=7.3Hz),7.10( t,1H,J=7.5Hz),4.07(s,3H),3.90(t,2H,J=6.7Hz),3.81(t,2H,J=4.7Hz),3.5-3.6(m,3H),3.2-3.3(m,5H),2.8-2.9(m,4H),2.77(br t,2H,J=6.7Hz),2.5-2.6(m,2H),2.10(br d,2H,J=10.8Hz),1.72(br d,2H,J=11.0Hz),1.53(s,6H),1.36(q,2H,J=10.6Hz),1.19(d,6H,J=5.5Hz).

[0214] Example 4: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 5-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (6.70 g, 19.51 mmol, 1 equiv.), 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.94 g, 39.0 mmol, 2 equiv.), and N,N-diisopropylethylamine (6.8 mL, 39.0 mmol, 2 equiv.) were combined in ethyl acetate (56 mL, 0.35 M) and heated to 90° C. in a sealed tube for 16 hours. The reaction was diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (10% to 100% ethyl acetate in hexanes) to afford 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.5 g, 6.4743 mmol, 33% yield) as a brown solid. MS (ESI) m / z 541.3 [M+1] + .

[0215] 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.50 g, 6.47 mmol, 1 equiv.) in dichloromethane (30 mL) was added 4 M hydrochloric acid (16.2 mL, 64.7 mmol, 10 equiv.) and the reaction was stirred at room temperature. After 3 hours, the reaction was concentrated to provide 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.4 mmol, 99% yield) as a reddish oil. This crude material was carried forward without further purification. MS(ESI) m / z 457.0 [M+1] + .

[0216] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. A solution of 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.49 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide (5 mL) was combined with thionyl bromide (1.26 mL, 16.2 mmol, 2.5 equiv) and the reaction was stirred at room temperature. After 2 hours, the reaction was concentrated and the crude material was purified by silica gel column chromatography (5% to 80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (2.00 g, 3.85 mmol, 59% yield) as a reddish-brown oil. MS(ESI) m / z 519.8 [M+1] + .

[0217] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.093 g, 0.18 mmol, 1 equivalent), 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidine) To a 1-dram vial containing (1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.097 g, 0.23 mmol, 1.3 equiv.) and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.), acetonitrile (2 mL) was added, followed by N,N-diisopropylethylamine (0.19 mL, 1.08 mmol, 6 equiv.). The reaction vial was heated to 60°C with stirring. After 16 hours, the reaction mixture was diluted to a total volume of 3 mL with dimethyl sulfoxide and purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.04 g, 0.05 mmol, 28% yield). MS(ESI) m / z 853.0 [M+1] + ; 1H NMR(DMSO-d6,500MHz)δ 10.5-10.6(m,1H),9.1-9.2(m,1H),8.7-8.8(m,1H),7.5-7.6(m,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),4.1-4.2(m,3H),4.0-4.1(m,1H) ,3.8-3.9(m,4H),3.7-3.8(m,4H),3.2-3.3(m,3H),2.7-2.9(m,4H),2.1-2.2(m,2H),1.6-1.8(m,4H),1.5-1.6(m,6H),1.2-1.4(m,10H).

[0218] Example 5: 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)propanamide [ka] tert-Butyl (3R,5S)-4-(3-ethoxy-3-oxopropyl)-3,5-dimethylpiperazine-1-carboxylate. tert-Butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5 g, 23.33 mmol, 1 equiv.) was combined with lithium perchlorate (10.02 g, 93.33 mmol, 4 equiv.) and ethyl acrylate (26.7 mL, 233.32 mmol, 10 equiv.), and the reaction was heated to 30 °C for 18 h. The solution was concentrated and purified by silica gel column chromatography (1-5% MeOH in dichloromethane) to provide tert-butyl (3R,5S)-4-(3-ethoxy-3-oxopropyl)-3,5-dimethylpiperazine-1-carboxylate (3.43 g, 11.43 mmol, 49% yield). MS(ESI)m / z 301.2[M+1] + .

[0219] Ethyl 3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propanoate. To a 30 mL vial containing tert-butyl (3R,5S)-4-(3-methoxy-3-oxopropyl)-3,5-dimethylpiperazine-1-carboxylate (680 mg, 2.16 mmol), dichloromethane (1 mL) was added, followed by 4 M hydrochloric acid in 1,4-dioxane (13.52 mL, 54.07 mmol, 25 equiv). The reaction was stirred at room temperature. After 15 minutes, the reaction was concentrated to give a yellow solid. This material was taken up in ethyl acetate and washed with sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with 3 x 25 mL ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to provide ethyl 3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propanoate (380 mg, 1.78 mmol, 82% yield) as a yellow oil. MS (ESI) m / z 215.2 [M+1] + .

[0220] Ethyl 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)propanoate. To a 20 mL vial containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (290 mg, 0.56 mmol) and ethyl 3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propanoate (120 mg, 0.56 mmol, 1 equiv.) was added N,N-dimethylformamide (1.1666 mL, 0.48 M) and N,N-diisopropylethylamine (0.59 mL, 3.36 mmol, 6 equiv.). The reaction was heated to 50° C. with stirring. After 14 hours, the reaction was diluted with 100 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate (100 mL) followed by brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated to give a yellow oil. The crude material was purified by column chromatography (1-8% MeOH in DCM containing 0.2% triethylamine) to give methyl 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)propanoate as a clear, colorless oil. MS(ESI) m / z=652.4[M+1] + . 1H NMR(400MHz,CDCl3)δ 7.94(d,J=8.2Hz,1H),7.83(s,1H),7.71(dd,J=2.1,8.3Hz,1H),4.12(q,J=7.1Hz,2H), 3.60(t,J=6.2Hz,2H),3.38-3.25(m,1H),3.20-3.11(m,2H),2.95-2.81(m,2H),2.78(br d,J=10.6Hz,2H),2.71-2.59(m,2H),2.52(t,J=6.2Hz,2H),2.44-2.35(m,2H),2.23-2.17(m,2H),1.92(t,J=1 0.7Hz,2H),1.86-1.76(m,2H),1.60-1.59(m,6H),1.41-1.29(m,2H),1.26(t,J=7.1Hz,3H),1.11-1.06(m,6H)

[0221] 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)propanoic acid. To a 2-dram vial containing methyl 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)propanoate (289 mg, 0.4400 mmol) was added 1,4-dioxane (1.478 mL), followed by a solution of lithium hydroxide (15.93 mg, 0.6700 mmol) in 0.2 mL water. The reaction was stirred at room temperature for 2 hours. The solution was concentrated to provide 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)propanoic acid (263 mg, 0.4217 mmol, 95% yield) as a glassy oil, which was carried on without further purification. MS(ESI) m / z 624.3 [M+1] +.

[0222] 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)propanamide. 33-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)propanoic acid (50.0 mg, 0.08 mmol, 1.0 equiv), 1-(7-amino-1-methyl N,N-Diisopropylethylamine (0.04 mL, 0.24 mmol, 3.0 equiv.), and HATU (67.1 mg, 0.18 mmol, 2.2 equiv.) were combined in N,N-dimethylformamide (0.5 mL) and stirred at room temperature. After 18 h, the reaction mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by standard methods to give 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)propanamide (5.1 mg, 0.01 mmol, 7% yield). MS(ESI) m / z 865.0 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ ppm 10.58(s,1H),10.07(br s,1H),8.35(d,J=8.31Hz,1H),8.20(s,1H),7.97(d,J=7.80Hz,1H),7.55(d ,J=7.95Hz,1H),7.07-7.19(m,2H),4.06(s,5H),3.73-3.94(m,7H),3.35(br s,5H),2.72-2.93(m,5H),2.67(br d,J=1.71Hz,2H),2.10(br d,J=10.15Hz,2H),1.74(br d,J=12.10Hz,2H),1.56(s,6H),1.37(br d,J=11.37Hz,3H),1.23(br s,6H).

[0223] Example 6: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 3-Chloro-5-isothiocyanato-pyridine-2-carbonitrile. To a solution of 5-amino-3-chloro-pyridine-2-carbonitrile (10.00 g, 65.12 mmol, 1 equiv.) in toluene (20 mL) was added thiophosgene (5.96 mL, 78.14 mmol, 1.2 equiv.). The mixture was stirred at 110 °C. After 16 h, the reaction was concentrated and purified by silica gel chromatography (20-50% ethyl acetate in petroleum ether) to give 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (8.000 g, 40.89 mmol, 63% yield) as a red solid.

[0224] 3-Chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile. A mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (4.000 g, 20.45 mmol, 1 equiv.) and methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (7.720 g, 22.49 mmol, 1.1 equiv.) in ethyl acetate (100 mL, 0.2 M) was combined with triethylamine (5.7 mL, 40.89 mmol, 2 equiv.) and the reaction was stirred at 90° C. After 6 hours, the reaction mixture 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-thioxoimidazolidin-1-yl)picolinonitrile (4.000 g, 7.89 mmol, 39% yield) as a yellow solid. MS(ESI) m / z = 507.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.92-8.72(m,1H),8.62-8.31(m,1H),4.68-4.50(m,1H),3.91-3.63(m,4H),3.62-3.52(m,3H),3.50- 3.39(m,3H),2.91-2.73(m,3H),2.10-2.03(m,2H),1.75-1.68(m,3H),1.55(s,6H),1.50-1.43(m,4H).

[0225] 3-Chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile. To a solution of 3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile (4.000 g, 7.89 mmol, 1 equiv.) in methanol (30 mL, 0.27 M) was added 2 M hydrochloric acid (3 mL, 15.78 mmol, 2 equiv.). The reaction 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 to 100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.400 g, 0.01 mmol, 69% yield) as a yellow solid. MS (ESI) m / z 423.3 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.59(s,1H),7.43-7.33(m,2H),7.15(br d,J=7.0Hz,1H),6.57(br s,1H),4.40(t,J=6.7Hz,2H),2.98(s,3H),2.70-2.55(m,2H),1.53(s,5H), 1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H).

[0226] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile. To a solution of 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.150 g, 5.08 mmol, 1 equiv.) in dichloromethane (5 mL, 1 M) and N,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.65 mL, 10.17 mmol, 2 equiv.) at 0° C. The mixture was stirred at 25° C. for 16 hours. The pH of the mixture was adjusted to 8 with saturated sodium carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (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-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (2.3 g, 4.73 mmol, 93% yield) as a red solid. MS (ESI) m / z 485.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.90-8.72(m,1H),8.60-8.44(m,1H),3.93-3.81(m,1H),3.79-3.72(m,2H),3.61-3.53(m,2H),3.34(br s,1H),2.90-2.74(m,2H),2.12-2.02(m,2H),1.76-1.67(m,2H),1.59-1.52(m,6H),1.44-1.28(m,2H).

[0227] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.122 g, 0.250 mmol, 1.1 equiv.) and 5-(3-(trans-4-(2 To a mixture of (-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (0.100 g, 0.206 mmol, 1 equiv.), N,N-diisopropylethylamine (0.14 mL, 0.820 mmol, 4 equiv.) and sodium iodide (0.030 g, 0.210 mmol, 1 equiv.) was added. The mixture was stirred at 50° C. After 12 h, the reaction mixture was poured into water (20 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (2×20 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (53.720 mg, 0.066 mmol, 32% yield) as a white solid. MS(ESI) m / z 818.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.58(s,1H),10.18-9.73(m,1H),8.82(d,J=2.0Hz,1H),8.52(d,J=2.0Hz,1H),7.56(d,J=8 .0Hz,1H),7.25-7.17(m,1H),7.15-7.07(m,1H),4.08(s,3H),3.90(t,J=6.8Hz,2H),3.83(br d,J=3.2Hz,3H),3.43-3.33(m,4H),3.31-3.20(m,3H),2.90-2.84(m,2H),2.78(t,J=6.8Hz,2H),2.53(br s,2H),2.16-2.07(m,2H),1.77-1.68(m,2H),1.56(s,6H),1.43-1.33(m,2H),1.23(br s,6H).

[0228] Example 7: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] trans-N,N-Dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine. To a solution of trans-4-(dibenzylamino)cyclohexanol (60.00 g, 203.1 mmol, 1 equiv) in xylene (450 mL, 0.45 M) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (113.28 g, 507.75 mmol, 2.5 equiv), tetra-N-butylammonium bromide (13.09 g, 40.62 mmol, 0.2 equiv), and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 equiv), and the reaction was stirred at room temperature. After 24 hours, the reaction was diluted with ethyl acetate (500 mL), washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (100% petroleum ether) to afford trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (40.0 g, 91.4 mmol, 45% yield) as a pale yellow oil. MS (ESI) m / z 438.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.38-7.32(m,4H),7.31-7.28(m,4H),7.24-7.22(m,2H),4.61-4.57( m,1H),3.88-3.84(m,2H),3.63(s,4H),3.55-3.52(m,4H),3.51-3.16( m,1H),2.54-2.09(m,1H),2.08-2.07(m,2H),1.92-1.90(m,2H),1.61 -1.60(m,2H),1.59-1.57(m,6H),1.55-1.53(m,2H),1.38-1.16(m,2H)

[0229] trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine. To a solution of trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (20.0 g, 45.7 mmol, 1 equiv) in methanol (100 mL) was added 10% palladium on carbon (10.0 g, 9.39 mmol). The reaction flask was evacuated and purged with hydrogen gas three times, then stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 h, the reaction was filtered, and the filtrate was concentrated to provide trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexane-1-amine (11.00 g, 42.74 mmol, 94% yield) as a pale yellow oil. This material was carried forward without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.52(m,1H),3.79-3.61(m,2H),3.50-3.30(m,4H),3.18-3.05(m,1H),1.94-1.83( m,2H),1.77-1.65(m,6H),1.64-1.55(m,1H),1.53-1.38(m,4H),1.20-0.91(m,4H).

[0230] Methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate. To a solution of trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (7.00 g, 27.2 mmol, 1 equiv) and methyl 2-bromo-2-methyl-propanoate (12.5 mL, 108.79 mmol, 4 equiv) in acetonitrile (10 mL) was added potassium iodide (0.451 g, 2.72 mmol, 0.1 equiv) and potassium carbonate (7.518 g, 54.4 mmol, 2 equiv). The reaction vessel was sealed and heated to 110° C. with stirring. After 12 h, the reaction was filtered and concentrated. The crude material was purified by silica gel column chromatography (10-80% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (8.00 g, 22.4 mmol, 82% yield) as a pale yellow oil. MS(ESI) m / z 358.4 [M+1] + .

[0231] 5-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.00 g, 14.0 mmol, 1 equiv.) and 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (6.41 g, 28.0 mmol, 2 equiv.) in ethyl acetate (50 mL, 0.28 M) was added N,N-diisopropylethylamine (4.62 mL, 28.0 mmol, 2 equiv.) and the reaction was stirred at 90 °C. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (10–50% ethyl acetate in petroleum ether) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 90% yield) as a brown oil. 1 H NMR(400MHz,CDCl3)δ 8.95(s,1H),8.23(s,1H),4.55-4.51(m,1H),3.81-3.78(m,2H),3.70-3.68(m,1H),3.57-3.54(m,2H),3.48-3.45(m, 2H),3.29-2.87(m,1H),2.85(d,J=10.8Hz,2H),1.85-1.80(m,8H),1.60(s,6H),1.56-1.52(m,4H),1.32-1.29(m,2H).

[0232] 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 1 equiv) in methanol (50 mL) was added 1 M hydrogen chloride (5.0 mL, 5 mmol) and the reaction was stirred at room temperature. After 2 h, the reaction 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 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 84% yield) as a brown oil. MS (ESI) m / z 471.2 [M+1] + .

[0233] 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (5.00 g, 10.6 mmol, 1 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 2 equiv.) at 0° C. After stirring for 12 h, the reaction was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. (ESI) m / z 535.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.98(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),3.76-3.65(m,1H),3.62(t,J=5.6Hz,2H),3.53(t,J=6.4Hz,2H),3.40-3. 29(m,1H),2.89(s,2H),2.30-2.18(m,2H),2.16-2.05(m,2H),1.83(d,J=12.4Hz,2H),1.63(s,6H),1.45-1.24(m,2H).

[0234] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.150 g, 0.28 mmol, 1 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.208 g, 0.42 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 mL, 0.28 M) was added N,N-diisopropylethylamine (0.49 mL, 2.81 mmol, 10 equiv.) and the mixture was stirred at 50° C. After 12 hours, the reaction was filtered and purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (120 mg, 0.13 mmol, 48% yield) as a yellow solid. MS(ESI) m / z 866.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.57(s,1H),10.42-10.19(m,1H),9.14(s,1H),8.74(s,1H),7.56(d,J=8.4Hz,1H),7.22(d ,J=7.2Hz,1H),7.11(t,J=7.6Hz,1H),4.09(s,3H),3.90(t,J=6.4Hz,3H),3.86-3.85(m,1H) ,3.29-3.20(m,2H),3.08(d,J=1.2Hz,3H),3.07-2.93(m,1H),2.91-2.70(m,6H),2.07(d,J= 10.4Hz,2H),1.97(d,J=2.8Hz,2H),1.72(d,J=10.4Hz,2H),1.57(s,6H),1.34-1.25(m,10H).

[0235] Example 8: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (5.0 g, 14.0 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (6.4 g, 28.0 mmol, 2 equiv.) in ethyl acetate (50 mL) was added N,N-diisopropylethylamine (4.6 mL, 28.0 mmol, 2 equiv.) and the reaction was stirred at 90° C. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (10-50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol, 84% yield) as a brown oil. MS(ESI) m / z 554.4 [M+1] + ; 1 H NMR (400 MHz, CDCl3) δ 7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),4.60-4.58(m ,1H),3.84-3.82(m,2H),3.71-3.61(m,1H),3.60-3.52(m,2H),3.50-3.49(m, 2H),3.47-3.32(m,1H),2.22-2.20(m,2H),2.19(d,J=12.0Hz,2H),1.88-1.87 (m,6H),1.85-1.84(m,2H),1.60(s,6H),1.56-1.55(m,2H),1.54-1.35(m,2H).

[0236] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol) in methanol (50 mL) was added 1 M aqueous hydrochloric acid (5.0 mL, 5 mmol), and the reaction was stirred at room temperature. After 2 h, the reaction was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 91% yield) as a brown oil. MS(ESI) m / z 470.2 [M+1] + .

[0237] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 10.7 mmol, 1 equiv.) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 4 equiv.) at 0° C., and the reaction was allowed to warm gradually to room temperature. After 12 h, the reaction was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.0 g, 9.4 mmol, 88% yield) as a pale yellow oil. MS (ESI) m / z 534.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),3.71-3.61(m,1H),3.60-3.53(m,2H),3.52(t,J=6.4 Hz,2H),3.35-3.32(m,1H),2.21(d,J=12.0Hz,2H),2.19-2.05(m,2H),1.83(d,J=12.0Hz,2H),1.65(s,2H),1.60(s,6H),1.35-1.32(m,2H).

[0238] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.150 g, 0.28 mmol, 1 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.208 g, 0.420 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 mL, 0.28 M) was added N,N-diisopropylethylamine (0.49 mL, 2.82 mmol, 10 equiv.). The reaction was heated to 50° C. with stirring. After 13 h, the reaction 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (106.24 mg, 0.12 mmol, 43% yield) as a yellow solid. MS(ESI) m / z: 865.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.58(s,1H),10.31-10.07(m,1H),8.34(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.98-7.96(m,1H),7 .56(d,J=8.0Hz,1H),7.21(d,J=7.2Hz,1H),7.13-7.09(m,1H),4.09(s,3H),3.90(t,J=6.8Hz,2H),3.8 8-3.79(m,2H),3.52-3.49(m,4H),3.32-3.22(m,2H),3.08(d,J=1.2Hz,2H),3.02-2.90(m,1H),2.88- 2.76(m,5H),2.07-2.02(m,2H),2.01-1.96(m,2H),1.73-1.70(m,2H),1.55(s,6H),1.33-1.27(m,8H).

[0239] Example 9: 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 2-Chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (10.0 g, 28.0 mmol, 1 equiv.) in ethyl acetate (100 mL, 0.28 M) was added 2-chloro-4-isothiocyanatobenzonitrile (10.9 g, 56.0 mmol, 2 equiv.) and triethylamine (7.8 mL, 56.0 mmol, 2 equiv.), and the reaction was stirred at 80° C. After 8 hours, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 × 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 afford 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (8.50 g, 16.3 mmol, 58% yield) as a red oil. MS (ESI) m / z 542.2 [M+23] + .

[0240] 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (6.80 g, 13.1 mmol) in methanol (50 mL) was added 1 M hydrochloric acid (5 mL, 13.07 mmol) and the reaction was stirred at 25 °C. After 2 h, the reaction was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (20–70% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.60 g, 12.8 mmol, 98% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.12(d,J=8.4Hz,1H),7.92(d,J=1.6Hz,1H),7.61(dd,J=2.0,8.4Hz,1H),3.89-3.76(m,1H),3.48-3.42(m,4H),3.24-3.16(m, 1H),2.79(d,J=11.2Hz,2H),2.04(d,J=10.8Hz,2H),1.70(d,J=10.8Hz,2H),1.65-1.59(m,2H),1.53(s,6H),1.34-1.25(m,2H).

[0241] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.8 g, 13.3 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (2.1 mL, 26.6 mmol, 2 equiv.) at 0° C. After 8 h, the reaction was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0–35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (4.8 g, 9.6 mmol, 72% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.14-8.11(m,1H),7.93(d,J=1.6Hz,1H),7.61(dd,J=1.6,8.0Hz,1H),3.84(s,1H),3.58-3.51(m,4H),3.27-3 .21(m,1H),2.81(d,J=11.6Hz,2H),2.06(m,2H),1.71(d,J=11.6Hz,2H),1.53(s,6H),1.33(d,J=13.2Hz,2H).

[0242] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (0.100 g, 0.200 mmol, 1 equiv.) in N,N-dimethylformamide (1 mL, 0.2 M) was added 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.149 g, 0.300 mmol, 1.5 equiv.) and N,N-diisopropylethylamine (0.17 mL, 1 mmol, 5 equiv.) and the mixture was stirred at 50° C. After 16 hours, the reaction 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.139 g, 0.166 mmol, 82% yield) as a white solid. MS (ESI) m / z 831.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),8.14(d,J=8.4Hz,1H),7.93(d,J=2.0Hz,1H),7.63-7.56(m,3H),7.20(d ,J=8.4Hz,2H),3.83(dd,J=5.2,11.6Hz,4H),3.65-3.57(m,4H),3.51(t,J=5.6Hz,2H) ,3.35-3.19(m,2H),3.10(s,2H),2.87-2.77(m,2H),2.73-2.62(m,2H),2.25-2.16(m, 1H),2.15-1.87(m,6H),1.72(d,J=12.0Hz,2H),1.54(s,6H),1.33(m,2H),1.24(s,6H).

[0243] Example 10: 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.47 g, 5.71 mmol, 1 equiv.) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.44 g, 6.28 mmol, 1.1 equiv.) in ethyl acetate (15 mL, 0.38 M) was added N,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 equiv.) and the reaction was stirred at 80 °C. After 16 h, the reaction was concentrated under reduced pressure and the crude material was purified by standard methods to give 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 69% yield) as a brown solid. MS(ESI) m / z 455.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.72(m,1H),3.65(t,J=6.4Hz,2H),2.72-2.70(m,2H),1 .97-1.94(m,2H),1.85-1.82(m,2H),1.63(s,6H),1.58-1.54(m,1H),1.42-1.29(m,4H),1.12-1.02(m,2H).

[0244] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 1 equiv.) in dichloromethane (18 mL, 0.22 M) and N,N-dimethylformamide (1.8 mL) was added thionyl bromide (1.650 g, 7.92 mmol, 2 equiv.) slowly at 0° C. The reaction was stirred at 0° C. After 12 hours, the reaction was diluted with water (30 mL) and extracted with dichloromethane (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (5–80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.75 g, 3.38 mmol, 85% yield) as a brown solid. MS (ESI) m / z 516.9 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.99(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.80-3.71(m,1H),3.42(t,J=6.8Hz,2H),2 .74-2.72(m,2H),1.96-1.79(m,6H),1.63(s,6H),1.40-1.33(m,3H),1.13-1.04(m,2H).

[0245] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.150 g, 0.28 mmol, 1 equiv.) and 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.214 g, 0.43 mmol, 1.5 equiv.) in N,N-dimethylformamide (1 mL, 0.28 M) was added N,N-diisopropylethylamine (0.5 mL, 2.90 mmol, 10 equiv.). The reaction was heated to 50° C. with stirring. After 12 hours, the reaction was filtered and concentrated. The crude material was 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-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (74.98 mg, 0.08 mmol, 30% yield) as a yellow solid. MS (ESI) m / z 850.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.58(s,1H),10.31-10.12(m,1H),9.14(s,1H),8.74(s,1H),7.55(d,J= 8.4Hz,1H),7.20(d,J=6.8Hz,1H),7.13-7.09(m,1H),4.08(s,3H),3.90(t ,J=6.4Hz,3H),3.86-3.82(m,1H),3.02-2.95(m,3H),2.95-2.86(m,1H),2 .77(t,J=6.4Hz,5H),1.86-1.71(m,7H),1.57(s,6H),1.25-1.08(m,12H).

[0246] Example 11: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 2-Chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile. To a solution of methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (1.31 g, 5.1 mmol, 1 equiv.) and 2-chloro-4-isothiocyanatobenzonitrile (1.08 g, 5.57 mmol, 1.1 equiv.) in ethyl acetate (25 mL) was added N,N-diisopropylethylamine (2.51 mL, 15.18 mmol, 3 equiv.) and the reaction mixture was stirred at 80 °C. After 18 h, the reaction was concentrated and purified by column chromatography (15-50% ethyl acetate in petroleum ether) to give 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.26 g, 3.01 mmol, 59% yield) as a brown oil. MS(ESI) m / z 420.1 [M+1] + .

[0247] 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.26 g, 3.01 mmol) in N,N-dimethylformamide (0.30 mL) and dichloromethane (3 mL) was added thionyl bromide (1.88 g, 9.03 mmol, 3 equiv) slowly at 0 °C. After 12 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (15–30% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (1.21 g, 2.50 mmol, 83% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 7.79(d,J=8.4Hz,1H),7.58(d,J=2.0Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),3.87(m,1H),3.43(t,J =6.8Hz,2H),2.70(s,2H),1.94-1.82(m,6H),1.59(s,6H),1.39-1.36(m,3H),1.12-1.03(m,2H).

[0248] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (0.100 g, 0.210 mmol) and 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.143 g, 0.290 mmol, 1.4 equiv) in N,N-dimethylformamide (2 mL, 0.1 M) was added N,N-diisopropylethylamine (0.134 g, 1.040 mmol, 5 equiv) and the reaction mixture was stirred at 50° C. for 12 h. The reaction was concentrated under reduced pressure and purified by standard methods to give 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.083 g, 0.097 mmol, 47% yield) as a yellow solid. MS(ESI) m / z 815.4 [M+1] +. 1 H NMR(400MHz,DMSO-d6)δ 11.36(s,1H),10.58(s,1H),8.14-8.12(d,J=8.4Hz,1H),7.93-7.92(d,J=2.0Hz, 1H),7.62-7.56(m,2H),7.24-7.22(d,J=7.2Hz,1H),7.14-7.10(m,1H),4.10(s,3 H),3.92-3.89(m,4H),3.84-3.80(m,2H),3.62-3.58(m,2H),3.02(s,4H),2.79-2 .67(m,5H),1.85-1.71(m,6H),1.53(s,6H),1.32-1.22(m,9H),1.13-1.04(m,2H).

[0249] Example 12: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 3-Chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile. A mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (1.600 g, 8.18 mmol, 1 equiv.) and methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (2.320 g, 9 mmol, 1.1 equiv.) in ethyl acetate (100 mL) was combined with triethylamine (2.28 mL, 16.36 mmol, 2 equiv.). The reaction was stirred at 90° C. After 6 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (10-100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 58% yield) as a yellow solid. MS(ESI) m / z 421.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.67-8.50(m,1H),7.98-7.83(m,1H),3.80-3.48(m,4H),2.75-2.52(m,2H), 1.93-1.60(m,6H),1.51-1.28(m,3H),1.27-1.15(m,5H),1.06-0.89(m,3H).

[0250] 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile. To a solution of 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 1 equiv.) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.61 mL, 9.5 mmol, 2 equiv.) at 0° C. The reaction was stirred at 25° C. After 16 h, the pH of the reaction was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (50-100% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (1.600 g, 3.31 mmol, 70% yield) as a red solid. MS (ESI) m / z 483.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.73-8.50(m,1H),7.98-7.82(m,1H),3.78-3.65(m,1H),3.37-3.29(m ,2H),2.77-2.49(m,2H),1.93-1.80(m,4H),1.57-1.52(m,6H),1.30(br t,J=5.6Hz,3H),1.08-0.97(m,2H).

[0251] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (120 mg, 0.25 mmol, 1 equiv.), 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (184 mg, 0.37 mmol, 1.5 equiv.) and N,N-dimethylformamide (4 mL, 0.06 M) was added N,N-diisopropylethylamine (96 mg, 0.74 mmol, 3 equiv.). The mixture was stirred at 60° C. After 16 h, the reaction was filtered and purified by standard methods to provide 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (56 mg, 0.09 mmol, 27% yield) as a yellow solid. MS (ESI) m / z 816.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 10.68-10.49(m,1H),8.98-8.72(m,1H),8.59-8.35(m,1H),7.69-7.50(m,1H),7.35-6.97(m,2H),4.15-4.07(m,3H),3.94-3.87(m,3H) ,3.86-3.78(m,3H),3.65-3.53(m,3H),3.08-2.98(m,2H),2.86-2.67(m,5H),1.91-1.67(m,7H),1.61-1.52(m,6H),1.41-1.05(m,12H).

[0252] Example 13: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] (2S,6R)-1-Benzyl-2,6-dimethylpiperidin-4-one. To a solution of 3-oxopentanedioic acid (100.0 g, 684.5 mmol, 1 equiv.) in water (200 mL) at 20 °C was added acetaldehyde (150.8 g, 1368.9 mmol, 2 equiv.). The reaction was stirred at 20 °C for 20 minutes, then cooled to 0 °C, and phenylmethanamine (74.61 mL, 684.5 mmol, 1 equiv.) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 48 hours. The reaction 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 layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography to give (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (27.70 g, 127.5 mmol, 19% yield) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 7.42(d,J=7.2Hz,2H),7.37-7.29(m,2H),7.27-7.20(m,1H),3.86(s,2H),3 .17-3.09(qd,J=6.4,13.2Hz,2H),2.42-2.28(m,4H),1.16(d,J=6.4Hz,6H).

[0253] Ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate. To a solution of sodium hydride (8.283 g, 207.1 mmol, 1.5 equiv) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (40.23 g, 179.5 mmol, 1.3 equiv) in THF (100 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 minutes. To the above solution was added dropwise (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (30.00 g, 138.1 mmol, 1 equiv) in THF (200 mL), and the reaction was allowed to warm to room temperature. After 12 hours, the reaction was neutralized by the addition of saturated ammonium chloride solution and poured into ice water (200 mL). The aqueous phase was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel chromatography (2.0% ethyl acetate in petroleum ether) (petroleum ether:ethyl acetate = 3:1, Rf: 0.65) and then purified again by semi-preparative reverse-phase HPLC (55–85% acetonitrile in water + 0.05% ammonium hydroxide, 20 min). The collected fractions were concentrated, and the aqueous phase was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate (11.7 g, 40.7 mmol, 30% yield) as a yellow oil. MS (ESI) m / z 288.2 [M+1] + ; 1H NMR(400MHz,CDCl3)δ 7.45-7.35(m,2H),7.30(t,J=7.6Hz,2H),7.26-7.16(m,1H),5.63(s,1H),4.15(q,J=7.2Hz,2H),3.82(s,2H),3.5 7(dd,J=2.8,14.0Hz,1H),2.84-2.62(m,2H),2.29-2.08(m,3H),1.33-1.23(m,3H),1.14(dd,J=6.4,16.4Hz,6H).

[0254] tert-Butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of ethyl 2-((2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene)acetate (5.300 g, 18.44 mmol, 1 equiv.) and di-tert-butyl dicarbonate (6.037 g, 27.66 mmol, 1.5 equiv.) in THF (80 mL, 0.23 M) was added 10% palladium on carbon (1.500 g, 1.84 mmol, 10 mol%) under nitrogen. The reaction mixture was stirred at room temperature under hydrogen (50 psi) for 12 hours. The reaction mixture was filtered and concentrated to give a residue which was purified by flash silica gel chromatography (1% ethyl acetate in petroleum ether, petroleum ether:ethyl acetate=5:1) to give tert-butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.784 mmol, 48% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.26(s,1H),4.21(m,1H),4.17-4.10(m,2H),2.26-2.18(m,2H),2.13-2.05(m,1H),1.99-1.84(m,1H),1. 66-1.55(m,1H),1.47(s,9H),1.36-1.29(m,1H),1.29-1.25(m,3H),1.24-1.19(m,6H),1.15-1.02(m,2H).

[0255] (2S,6R)-tert-butyl 4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of lithium aluminum hydride (0.500 g, 13.18 mmol, 1.5 equiv.) in THF (10 mL) was added a solution of tert-butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.630 g, 8.780 mmol, 1 equiv.) in THF (40 mL) at 0 °C. The reaction was allowed to warm slowly to room temperature over 1 h. The reaction 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 in vacuo. The crude material was diluted with 100 mL of water and extracted with three 100 mL portions of ethyl acetate. The combined organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give tert-butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 96% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 4.40-4.25(m,1H),4.24-4.07(m,1H),3.77-3.65(m,2H),2.12-2.03(m,1H),1.68-1.56(m,2 H),1.55-1.49(m,2H),1.49-1.42(m,9H),1.33-1.26(m,1H),1.25-1.17(m,6H),1.05(m,1H).

[0256] (2S,6R)-tert-butyl 4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate. Tert-butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 1 equiv.) and triphenylphosphine (3.332 g, 12.71 mmol, 1.5 equiv.) were dissolved in dichloromethane (40 mL, 0.21 M). To this reaction mixture was added carbon tetrabromide (4.214 g, 12.71 mmol, 1.5 equiv.) at 0 °C. The reaction mixture was allowed to warm slowly to room temperature. After 2 h, the reaction mixture was poured into saturated sodium bicarbonate solution (100 mL) and the aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to give tert-butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 6.744 mmol, 80% yield) as a clear, colorless oil. 1 H NMR(400MHz,CDCl3)δ 4.45-4.27(m,1H),4.26-4.06(m,1H),3.51-3.29(m,2H),2.18-1.96(m,2H),1.89-1.75(m,2H), 1.73-1.53(m,2H),1.48-1.39(m,9H),1.33-1.25(m,1H),1.24-1.19(m,6H),1.13-0.97(m,1H).

[0257] (2R,6S)-tert-butyl 4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of trans-4-(dibenzylamino)cyclohexanol (12.18 g, 41.22 mmol, 2 equiv.) and tert-butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (6.600 g, 20.61 mmol, 1 equiv.) in xylene (120 mL, 0.17 M) was added potassium hydroxide (5.318 g, 94.80 mmol, 4.6 equiv.) and tetrabutylammonium bromide (1.328 g, 4.120 mmol, 0.2 equiv.). The reaction was stirred at 30 °C. After 24 h, the reaction was diluted with water (200 mL) and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography (2.5–3% ethyl acetate in petroleum ether) to provide tert-butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.236 mmol, 25% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.42-7.33(m,4H),7.33-7.27(m,4H),7.24-7.17(m,2H),4.36-4.23(m,2H),4.22-4.15(m,1H),3 .62(s,4H),3.48(t,J=6.4Hz,1H),3.45-3.37(m,1H),3.19-3.06(m,1H),2.53(m,1H),2.09-2.04( m,3H),2.01-1.86(m,3H),1.63-1.59(m,1H),1.57-1.51(m,2H),1.47-1.46(m,9H),1.43-1.33(m, 2H),1.28-1.24(m,2H),1.21(s,2H),1.17(d,J=7.0Hz,6H),1.14-1.08(m,1H),1.07-0.92(m,1H).

[0258] (2R,6S)-tert-butyl 4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.240 mmol, 1 equiv) in methanol (60 mL) was added palladium on carbon (2.000 g) under nitrogen. The reaction was stirred under hydrogen (15 psi) at room temperature for 12 hours. The reaction mixture was filtered and concentrated to give tert-butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 98% yield) yellow oil, which was carried on without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.23-4.08(m,2H),4.08-3.93(m,1H),3.50-3.40(m,2H),3.40-3.33(m,1H),3.18-3.04(m,1H),2.55-2.51(m,2H),2.49(br s,1H),2.05-1.83(m,4H),1.82-1.68(m,2H),1.67-1.47(m,2H),1.46- 1.32(m,16H),1.29-1.15(m,2H),1.15-1.07(m,9H),1.07-0.87(m,3H).

[0259] (2S,6R)-tert-butyl 4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 1 equiv) in acetonitrile (10 mL, 0.5 M) was added potassium iodide (0.086 g, 0.520 mmol, 10 mol%), potassium carbonate (2.148 g, 15.54 mmol, 3 equiv), and methyl 2-bromo-2-methylpropanoate (3.75 mL, 25.91 mmol, 5 equiv). The reaction was stirred at 110° C. After 48 h, the reaction was filtered and concentrated to give tert-butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 5.279 mmol, crude) as a yellow oil, which was carried on without further purification. MS(ESI) m / z 455.5 [M+1] + .

[0260] (2R,4s,6S)-tert-butyl 4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate and tert-butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.160 g, 4.750 mmol, 1 equiv) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.084 g, 4.750 mmol, 1 equiv) in ethyl acetate (10 mL, 0.47 M) was added N,N-diisopropylethylamine (1.660 mL, 9.500 mmol, 2 equiv). The reaction was stirred at 90° C. After 12 h, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.The crude material was purified by flash silica gel column chromatography to give a mixture of diastereomers, which was separated by SFC (DAICEL CHIRAL PAK IG: 250 mm × 30 mm, 10 μm, 20% methanol + 0.1% NH₃.H₂O) to give tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. (1.060 g, 1.629 mmol, 34% yield) and (2R,4r,6S)-tert-butyl 4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.553 mmol, 12% yield). (2R,4s,6S)-tert-butyl 4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1H NMR(400MHz,CDCl3)δ 7.95(d,J=8.0Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0Hz,1H),4.38-4.22(m,2H ),3.72-3.59(m,1H),3.54(t,J=6.4Hz,2H),3.37-3.24(m,1H),3.03-2.75(m,2H),2.21(br d, J = 12.4 Hz, 2H), 2.03-1.90 (m, 1H), 1.89-1.77 (m, 2H), 1.61 (s, 6H), 1.58 (m, 2H), 1.54-1.48 (m, 2H), 1.47 (s, 9H), 1.40-1.26 (m, 4H), 1.19 (d, J = 7.2 Hz, 6H). (2R,4r,6S)-tert-butyl 4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=8.4Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),4.28-4.10(m ,2H),3.76-3.58(m,1H),3.49(t,J=6.0Hz,2H),3.30(m,1H),3.03-2.76(m,2H),2.19(br d,J=12.0Hz,2H),2.12-1.98(m,2H),1.89-1.76(m,2H),1.61(s,6H),1.52(br t,J=6.4Hz,2H),1.47(s,9H),1.40-1.25(m,3H),1.22(d,J=6.8Hz,6H),1.03(m,2H).

[0261] 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.060 g, 1.630 mmol, 1 equiv) in dichloromethane (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (20 mL, 80.00 mmol) and the reaction was stirred at room temperature. After 2 hours, the reaction was concentrated. The resulting yellow solid was taken up in saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to provide 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.920 g, 1.67 mmol, 99% yield) as a yellow solid, which was carried on without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=8.0Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0Hz,1H),3 .74-3.59(m,1H),3.51(t,J=6.8Hz,2H),3.31(m,1H),2.92(m,4H),2.20(br d,J=12.0Hz,2H),2.02-1.92(m,1H),1.82(br d,J=12.0Hz,2H),1.70(q,J=6.8Hz,2H),1.64-1.56(s,6H),1.51(br d,J=12.8Hz,2H),1.40-1.27(m,4H),1.09(br d,J=6.0Hz,6H).

[0262] 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)benzyl acetate. To a mixture of 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.080 g, 0.150 mmol, 1 equiv.) and benzyl 2-bromoacetate (0.040 g, 0.170 mmol, 1.2 equiv.) in acetonitrile (0.5 mL, 0.3 M) was added N,N-diisopropylethylamine (0.08 mL, 0.440 mmol, 3 equiv.) and the reaction was stirred at room temperature. After 12 hours, the reaction was filtered, concentrated, and the crude material was purified by preparative TLC (dichloromethane:methanol=10:1, Rf=0.7) to give 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.092 g, 0.132 mmol, 91% yield) as a yellow solid. MS(ESI) m / z 699.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.33(d,J=8.0Hz,1H),8.19(s,1H),7.96(d,J=8.0Hz,1H),7.36-7.34(m ,5H),5.10(s,2H),3.53(s,2H),3.43-3.40(m,2H),3.17-3.16(m,4H),2 .92(s,2H),2.85-2.75(m,2H),2.05-2.02(m,2H),1.72-1.69(m,3H),1. 56(s,6H),1.45-1.35(m,2H),1.30-1.25(m,4H),0.95(d,J=6.0Hz,6H).

[0263] 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)acetic acid. To a mixture of 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)benzyl acetate (0.082 g, 0.1200 mmol, 1 equiv.) in THF (1 mL) was added lithium hydroxide (0.011 g, 0.4700 mmol, 4 equiv.). The reaction was stirred at 25 °C for 3 h. Hydrochloric acid (1 M) was added to the reaction to adjust the pH to 5-6. The mixture was concentrated in vacuo and purified by semi-preparative reverse-phase HPLC (30% to 60% acetonitrile in water with 0.225% formic acid, 10 min) to give 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid (0.042 g, 0.069 mmol, 59% yield) as a yellow liquid. MS (ESI) m / z 609.4 [M+1] + .

[0264] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.019 g, 0.070 mmol, 1.2 equiv.) and 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)acetic acid (0.037 g, 0.060 mmol, 1 equiv.) in pyridine (1 mL, 0.06 M) was added EDCI (0.023 g, 0.120 mmol, 2 equiv.). The reaction was stirred at 50° C. After 12 hours, the reaction was diluted with DMSO and purified by standard methods to give 2-((2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.026 g, 0.003 mmol, 50% yield) as a yellow solid. MS (ESI) m / z 850.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.73-10.68(m,1H),10.67-10.60(m,1H),9.12-9.10(m,1H),8.34(d,J=7.6Hz,1H),8.19(s,1H),7.97(d,J=8.0 Hz,1H),7.62-7.59(m,1H),7.24-7.22(m,1H),7.16-7.14(m,1H),4.38(s,1H),4.26-4.18(m,1H),4.12-4.05(m,3 H),3.94-3.86(m,3H),3.85-3.64(m,3H)3.53-3.44(m,2H),3.26-3.20(m,1H),2.92-2.74(m,4H),2.48-2.44(m, 1H),2.10-1.88(m,4H),1.86-1.70(m,7H),1.56(s,6H),1.37-1.32(m,3H),1.30-1.15(m,2H),1.14-1.08(m,3H).

[0265] Example 14: 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.550 mmol, 1 equiv) in dichloromethane (3 mL, 0.12 M) was added 4 M hydrochloric acid in 1,4-dioxane (12 mL, 48 mmol), and the reaction was stirred at 15 °C. After 14 h, the reaction was concentrated. The resulting solid was diluted with saturated bicarbonate solution (20 mL) to pH 8-9, and the aqueous solution was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.330 g, 0.56 mmol) as a yellow solid, which was carried on without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),3.73-3.59 (m,1H),3.52(t,J=6.4Hz,2H),3.30(m,1H),3.03-2.80(m,2H),2.74(m,2H),2.20(br d,J=12.4Hz,2H),1.82(br d,J=11.6Hz,2H),1.68(br d,J=13.2Hz,2H),1.61(s,6H),1.54-1.48(m,2H),1.41-1.27(m,3H),1.14(br d,J=6.4Hz,6H),0.92-0.76(m,2H).

[0266] 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate. To a mixture of 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.060 g, 0.110 mmol, 1 equiv.) and benzyl 2-bromoacetate (0.030 g, 0.130 mmol, 1.2 equiv.) in acetonitrile (0.5 mL, 0.2 M) was added N,N-diisopropylethylamine (0.06 mL, 0.330 mmol, 3 equiv.) and the reaction was stirred at room temperature. After 12 hours, the reaction was filtered, concentrated, and the crude material was purified by preparative TLC (dichloromethane:methanol=10:1, Rf=0.7) to give 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.063 g, 0.090 mmol, 83% yield) as a yellow solid. MS(ESI) m / z 699.4 [M+1] + .

[0267] 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid. To a mixture of 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.063 g, 0.090 mmol, 1 equiv.) in THF (1 mL) was added lithium hydroxide (0.009 g, 0.360 mmol, 4 equiv.). The reaction was stirred at 25 °C for 3 h. Hydrochloric acid (1 M) was added to the reaction to adjust the pH to 5-6. The mixture was concentrated in vacuo and purified by semi-preparative reverse-phase HPLC (30% to 60% acetonitrile in water with 0.225% formic acid, 10 min) to give 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid (0.028 g, 0.046 mmol, 51% yield) as a yellow liquid. MS(ESI) m / z 609.1 [M+1] + .

[0268] 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (14.31 mg, 0.0600 mmol, 1.2 equiv.) and 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid (0.028 g, 0.050 mmol, 1 equiv.) in pyridine (1 mL, 0.05 M) was added EDCI (0.018 g, 0.090 mmol, 1.8 equiv.). The reaction was stirred at 50° C. After 12 hours, the reaction was diluted with DMSO and purified by standard methods to give 2-((2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.012 g, 0.0014 mmol, 31.2% yield) as a yellow solid. MS(ESI) m / z 850.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.85-10.78(m,H),10.60-10.60(m,1H),9.14(s,1H),8.34(d,J=7.6Hz,1H),8.19(s,1H),7.97(d,J=8 .0Hz,1H),7.62-7.59(m,1H),7.24-7.22(m,1H),7.16-7.14(m,1H),4.40(s,1H),4.31-4.20(m,1H),4.1 2-4.05(m,3H),3.93-3.75(m,3H),3.62-3.56(m,1H),3.55-3.35(m,3H),3.20-3.14(m,1H),2.90-2.70 (m,4H),2.12-2.00(m,2H),1.92-1.75(m,3H),1.60-1.50(m,6H),1.51-1.43(m,2H),1.30-1.10(m,9H).

[0269] Example 15: 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] Benzyl (3S,5R)-4-(2-chloroacetyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of (3S,5R)-benzyl 3,5-dimethylpiperazine-1-carboxylate (5.000 g, 20.14 mmol, 1 equiv) in dichloromethane (50 mL) at 0° C. was added triethylamine (4.2 mL, 30.20 mmol, 1.5 equiv) dropwise, followed by 2-chloroacetyl chloride (1.76 mL, 22.15 mmol, 1.1 equiv), and the reaction mixture was stirred at 0° C. After 2 h, the reaction mixture was concentrated and purified by silica gel column chromatography (20–50% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(2-chloroacetyl)-3,5-dimethylpiperazine-1-carboxylate (3.300 g, 10.16 mmol, 51% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.41-7.34(m,5H),5.19(s,2H),4.60(m,1H),4.16-4.07(m,5H),3.07(br,s,2H),1.32(m,6H).

[0270] Benzyl (3S,5R)-4-(2-((3-amino-1-methyl-1H-indazol-7-yl)oxy)acetyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of 3-amino-1-methyl-1H-indazol-7-ol (1.600 g, 9.810 mmol, 1 equiv.) and benzyl (3S,5R)-4-(2-chloroacetyl)-3,5-dimethylpiperazine-1-carboxylate (3.180 g, 9.810 mmol, 1 equiv.) in N,N-dimethylformamide (20 mL) was added potassium carbonate (4.070 g, 29.42 mmol, 3 equiv.), and the reaction was stirred at 70° C. After 12 h, the reaction was diluted with water (80 mL) and extracted with ethyl acetate (80 mL×3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude material was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(2-((3-amino-1-methyl-1H-indazol-7-yl)oxy)acetyl)-3,5-dimethylpiperazine-1-carboxylate (3.800 g, 8.416 mmol, 86% yield) as a brown solid. MS (ESI) m / z 452.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.36-7.31(m,5H),7.14-7.12(d,J=8.0Hz,1H),6.89-6.85(t,J=8.0Hz,1H),6.68-6.67(d,J=7.6Hz,1H ),5.19(s,2H),4.81(s,2H),4.68(br,s,1H),4.13(s,3H),4.00(m,3H),3.06-3.05(m,2H),1.31(m,6H).

[0271] Benzyl (3S,5R)-4-(2-((3-amino-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of benzyl (3S,5R)-4-(2-((3-amino-1-methyl-1H-indazol-7-yl)oxy)acetyl)-3,5-dimethylpiperazine-1-carboxylate (7.500 g, 16.61 mmol, 1 equiv.) in THF (80 mL) was added borane-dimethyl sulfide complex (5.81 mL, 58.14 mmol, 3.5 equiv.), and the reaction was diluted with 1 M hydrochloric acid (20 mL) and water (120 mL) and stirred for 10 min. The solution was adjusted to pH 6-7 by adding saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (20-40% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(2-((3-amino-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (4.300 g, 9.828 mmol, 59.2% yield) as a brown solid. MS (ESI) m / z 438.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.52-7.50(d,J=8.0Hz,1H),7.39-7.22(m,5H),7.10-7.08(d,J=8.0Hz,1H),7.05-7.01(t,J=8.0Hz,1H),6.64(m,2H),5.09(s, 2H),4.16-4.13(t,J=6.4Hz,2H),3.87(s,3H),3.82-3.80(m,2H),3.12-3.08(t,J=6.4Hz,2H),2.61(m,4H),1.07-1.06(m,6H).

[0272] (3S,5R)-4-(2-((3-((3-ethoxy-3-oxopropyl)amino)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of benzyl (3S,5R)-4-(2-((3-amino-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (4.100 g, 9.370 mmol, 1 equiv) in ethyl acrylate (18.76 g, 187.42 mmol, 20 equiv) was added aluminum oxide (2.390 g, 23.43 mmol, 2.5 equiv) and the reaction mixture was stirred at 115° C. After 24 h, the reaction was diluted with ethyl acetate (150 mL), filtered, and concentrated. The resulting material was purified by semi-preparative reverse-phase HPLC (20% to 60% heptane in ethanol + 0.1% ammonium hydroxide, 10 min) to give benzyl (3S,5R)-4-(2-((3-((3-ethoxy-3-oxopropyl)amino)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.700 g, 5.022 mmol, 54% yield) as a brown oil. MS(ESI) m / z 538.4 [M+1] + .

[0273] (3S,5R)-benzyl 4-(2-((3-(1-(3-ethoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of benzyl (3S,5R)-4-(2-((3-((3-ethoxy-3-oxopropyl)amino)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (2.700 g, 5.020 mmol, 1 equiv) in acetic acid (30 mL) was added potassium cyanate (1.220 g, 15.07 mmol, 3 equiv) and the reaction was stirred at room temperature. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (5-10% methanol in dichloromethane) to give benzyl (3S,5R)-4-(2-((3-(1-(3-ethoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.300 g, 2.239 mmol, 45% yield) as a brown oil. MS(ESI) m / z 581.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.40-7.30(m,5H),7.19-7.17(d,J=8.0Hz,1H),7.07-7.03(t,J=8.0Hz,1H),6.74-6.72(d,J=8.0Hz,1H),5.14(s,2H),4.96( s,2H),4.25(s,3H),4.14-4.11(m,4H),4.06-3.95(m,4H),3.19-3.15(t,J=6.8Hz,2H),2.72-2.68(m,6H),1.20-1.16(m,9H).

[0274] 1-(7-(2-((2S,6R)-2,6-dimethylpiperazin-1-yl)ethoxy)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. A mixture of benzyl (3S,5R)-4-(2-((3-(1-(3-ethoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.300 g, 2.240 mmol, 1 equiv) in concentrated aqueous hydrochloric acid (12 mL) was stirred at 10° C. After 12 h, the reaction was concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (0% to 20% acetonitrile in water with 0.05% hydrochloric acid, 20 min) to afford 1-(7-(2-((2S,6R)-2,6-dimethylpiperazin-1-yl)ethoxy)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (620.65 mg, 1.542 mmol, 69% yield) as an off-white solid. MS (ESI) m / z 401.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 12.49(s,1H),10.55(s,1H),10.14(s,2H),7.24-7.22(d,J=8.8Hz,1H),7.05-7.02(m,2H),4.55(s,2H),4.20(s,3H),3. 99-3.95(m,2H),3.89-3.86(t,J=6.8Hz,4H),3.58-3.55(m,2H),3.32(m,2H),2.77-2.74(t,J=6.8Hz,2H),1.48(s,6H).

[0275] 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. A flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol, 1 equiv.) was charged with 1-(7-(2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethoxy)-1-methyl- (1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione dihydrochloride (164 mg, 0.35 mmol, 1.2 equiv), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 equiv), sodium iodide (52 mg, 0.35 mmol, 1.2 equiv), and N,N-dimethylformamide (2.0 mL, 0.15 M) were added and the reaction was stirred at 50° C. After 15 h, the reaction was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (96 mg, 0.11 mmol, 38% yield) as an off-white solid. MS(ESI) m / z 838.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.55(s,1H),8.34(d,J=8.19Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.65,8.25Hz,1H),7.22(br d,J=7.70Hz,1H),7.02(q,J=7.30Hz,2H),4.20(s,3H),3.92-4.03(m,4H),3.74 -3.91(m,9H),3.21-3.44(m,4H),2.80-2.91(m,2H),2.73-2.79(m,2H),2.10(br d,J=11.13Hz,2H),1.72(br d,J=10.64Hz,2H),1.55(s,7H),1.23-1.51(m,8H).

[0276] Example 16: 4-(3-(trans-4-(2-((3S,5R)-4-(3-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] (3R,5S)-benzyl 4-(3-bromopropyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of (3R,5S)-benzyl 3,5-dimethylpiperazine-1-carboxylate (5.000 g, 20.140 mmol, 1 equiv.) and 1,3-dibromopropane (40.65 g, 201.35 mmol, 10 equiv.) in acetonitrile (50 mL) was added potassium carbonate (8.350 g, 60.410 mmol, 3 equiv.), and the reaction mixture was stirred at 100° C. After 12 h, the reaction was diluted with ethyl acetate (100 mL), filtered, and concentrated. The crude material was purified by silica gel column chromatography (25-50% ethyl acetate in petroleum ether) to give benzyl (3R,5S)-4-(3-bromopropyl)-3,5-dimethylpiperazine-1-carboxylate (2.000 g, 5.630 mmol, 28% yield) as a colorless oil. MS(ESI) m / z 371.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.39-7.30(m,5H),5.13(s,2H),3.96-3.91(m,2H),3.39-3.36(t,J=6.4Hz,2H),2. 91-2.87(m,2H),2.62-2.54(m,4H),1.97-1.90(m,2H),1.10-1.09(d,J=5.2Hz,6H).

[0277] 7-Methoxy-1-methyl-1H-indazol-3-amine. To a solution of 2-fluoro-3-methoxybenzonitrile (20.00 g, 132.33 mmol, 1 equiv) in N,N-dimethylacetamide (200 mL) was added methylhydrazine (76.20 g, 661.64 mmol, 5 equiv) and N,N-diisopropylethylamine (20.52 g, 158.79 mmol, 1.2 equiv), and the reaction was stirred at 130° C. After 3 h, the reaction was diluted with ice water (500 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude material was purified by silica gel column chromatography (30–50% ethyl acetate in petroleum ether) to give 7-methoxy-1-methyl-1H-indazol-3-amine (18.20 g, 102.71 mmol, 78% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 7.25-7.23(d,J=8.0Hz,1H),6.83-6.79(m,1H),6.73-6.71(m,1H),5.33(s,2H),3.90(s,3H),3.87(s,3H).

[0278] 3-Amino-1-methyl-1H-indazol-7-ol. To a solution of 7-methoxy-1-methyl-1H-indazol-3-amine (18.00 g, 101.58 mmol, 1 equiv.) in dichloromethane (200 mL) was added aluminum trichloride (54.18 g, 406.32 mmol, 4 equiv.), and the reaction mixture was stirred at 45 °C. After 12 h, the reaction mixture was slowly poured into water (500 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were concentrated and purified by silica gel column chromatography (50–75% ethyl acetate in petroleum ether) to give 3-amino-1-methyl-1H-indazol-7-ol (6.500 g, 39.833 mmol, 39% yield) as a brown solid. MS (ESI) m / z 164.1 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 9.81(s,1H),7.10-7.08(d,J=8.0Hz,1H),6.70-6.66(m,1H),6.60-6.58(d,J=7.2Hz,1H),5.25(s,2H),3.91(s,3H).

[0279] (3S,5R)-4-(3-((3-amino-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of 3-amino-1-methyl-1H-indazol-7-ol (1.170 g, 7.150 mmol, 1.1 equiv) and (3R,5S)-benzyl 4-(3-bromopropyl)-3,5-dimethylpiperazine-1-carboxylate (2.400 g, 6.500 mmol, 1 equiv) in acetonitrile (20 mL) was added potassium carbonate (2.690 g, 19.50 mmol, 3 equiv) and the reaction mixture was stirred at 60° C. After 12 h, the reaction was diluted with water (80 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (50-75% ethyl acetate in petroleum ether) to give benzyl (3S,5R)-4-(3-((3-amino-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.300 g, 2.879 mmol, 44% yield) as a brown solid. MS (ESI) m / z 452.4 [M+1] + .

[0280] Benzyl (3S,5R)-4-(3-((3-((3-ethoxy-3-oxopropyl)amino)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a suspension of (3S,5R)-benzyl 4-(3-((3-amino-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (2.500 g, 5.540 mmol, 1 equiv.) and ethyl acrylate (4.430 g, 44.290 mmol, 8 equiv.) was added aluminum oxide (1.410 g, 13.840 mmol, 2.5 equiv.), and the reaction suspension was stirred at 110° C. After 70 h, the reaction was diluted with ethyl acetate (50 mL), filtered, and concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (30%-60% acetonitrile in water with 0.1% TFA, 20 min). The pH value of the collected fractions was adjusted to 7-8 with saturated sodium bicarbonate. It was then concentrated to remove organic volatiles, and the aqueous solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (3S,5R)-4-(3-((3-((3-ethoxy-3-oxopropyl)amino)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (0.800 g, 1.450 mmol, 26% yield) as a brown solid. MS (ESI) m / z 552.2 [M+1] + ;1H NMR(400MHz,CDCl3)δ 7.40-7.31(m,5H),7.07-7.05(d,J=8.0Hz,1H),6.87-6.83(t,J=8.0Hz,1H),6.65- 6.64(d,J=7.6Hz,1H),5.15(s,2H),4.38(br,s,1H),4.19-4.14(q,J=7.2Hz,2H),4 .08-4.06(m,5H),4.01-3.91(m,2H),3.72-3.69(t,J=6.0Hz,2H),3.04-3.00(m,2H) ),2.75-2.62(m,6H),2.00-1.93(m,.2H),1.29-1.25(t,J=7.2Hz,3H),1.12(s,6H).

[0281] Benzyl (3S,5R)-4-(3-((3-(1-(3-ethoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of benzyl (3S,5R)-4-(3-((3-((3-ethoxy-3-oxopropyl)amino)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.300 g, 2.360 mmol, 1 equiv.) in acetic acid (12 mL) was added potassium isocyanate (0.478 g, 5.890 mmol, 2 equiv.) and the reaction mixture was stirred at room temperature. After 12 h, the reaction was concentrated and purified by semi-preparative reverse-phase HPLC (15%-45% acetonitrile in water with 0.05% hydrochloride, 22 min). The pH of the collected fractions was adjusted to 7-8 with saturated sodium bicarbonate and concentrated to remove organic volatiles, and the aqueous solution was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give benzyl (3S,5R)-4-(3-((3-(1-(3-ethoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.100 g, 1.850 mmol, 79% yield) as a brown solid. MS (ESI) m / z 595.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.31(m,5H),7.07-6.99(m,2H),6.85-6.83(d,J=7.2Hz,1H),5.88(s,2H),5.08(s,2H),4.17(s,3H),4.15-4.12(t,J=5 .6Hz,2H),3.92-3.79(m,6H),2.92-2.88(m,2H),2.62-2.58(m,2H),2.48-2.47(m,4H),1.91-1.87(m,2H),1.08-1.03(m,9H).

[0282] 1-(7-(3-((2S,6R)-2,6-dimethylpiperazin-1-yl)propoxy)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. A mixture of benzyl (3S,5R)-4-(3-((3-(1-(3-ethoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.700 g, 2.690 mmol, 1 equivalent) in hydrogen chloride (17 mL, 541.70 mmol) was stirred at room temperature. After 12 h, the reaction was concentrated and purified by semi-preparative reverse-phase HPLC (1% to 30% acetonitrile in water with 0.05% hydrogen chloride, 20 min) to give 1-(7-(3-((2S,6R)-2,6-dimethylpiperazin-1-yl)propoxy)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.533 g, 1.287 mmol, 48% yield) as a white solid. MS(ESI) m / z 415.4 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 12.06(s,1H),10.55(s,1H),9.93(br,s,1H),7.20-7.18(d,J=8.0Hz,1H),7.04-7.00(t,J=8.0Hz,1H),6.88-6.86(d,J=7.6Hz, 1H),4.29(m,2H),4.21(s,3H),3.90-3.68(m,4H),3.52-3.44(m,6H),2.78-2.75(t,J=6.8Hz,2H),2.23(m,2H),1.41(br,s,6H).

[0283] 4-(3-(trans-4-(2-((3S,5R)-4-(3-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. A flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol, 1 equiv.) was charged with 1-(7-(3-((2R,6S)-2,6-dimethylpiperazin-1-yl)propoxy)-1-methyl (1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione dihydrochloride (169 mg, 0.35 mmol, 1.2 equiv), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 equiv), sodium iodide (52 mg, 0.35 mmol, 1.2 equiv), and N,N-dimethylformamide (2.0 mL, 0.15 M) were added and the reaction was stirred at 50° C. After 14 h, the reaction was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3S,5R)-4-(3-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (61 mg, 0.069 mmol, 24% yield) as an off-white solid. MS(ESI) m / z 852.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),8.34(d,J=8.31Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J= 1.71,8.19Hz,1H),7.18(d,J=8.19Hz,1H),7.01(t,J=7.89Hz,1H),6.87(br d,J=7.58Hz,1H),4.29(br s,2H),4.20(s,3H),3.65-3.91(m,14H),3.45-3.53(m,2H),2.71-2.95(m,5H),2.24(br s,1H),2.12(br d,J=9.90Hz,2H),1.73(br d,J=10.88Hz,2H),1.55(s,6H),1.28-1.49(m,8H).

[0284] Example 17: 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] tert-Butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate. To a solution of 2-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid (2.000 g, 7.770 mmol, 1 equiv.) and N,O-dimethylhydroxylamine hydrochloride (0.830 g, 8.550 mmol, 1.1 equiv.) in N,N-dimethylformamide (20 mL, 0.38 M) was added N,N-diisopropylethylamine (6.94 mL, 38.86 mmol) and HATU (4.430 g, 11.66 mmol, 5 equiv.), and the reaction was stirred at room temperature. After 12 h, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0–30% ethyl acetate in petroleum ether) to afford tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.200 g, 7.323 mmol, 94% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.41(s,1H),3.66(s,3H),3.37(s,1H),3.17(s,3H),2.31-2.29(d,J=6.4Hz ,2H),2.04-1.97(m,2H),1.85-1.79(m,3H),1.43(s,9H),1.18-1.02(m,4H).

[0285] tert-Butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate. To a solution of tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.2 g, 7.320 mmol, 1 equiv.) in dichloromethane (10 mL) was added a solution of 70% bis(2-methoxyethoxy)aluminum hydride (4.08 mL, 14.65 mmol, 2 equiv.) in sodium toluene at 0° C. After stirring for 2 hours, the reaction was diluted with water (20 mL) and saturated aqueous ammonium chloride (10 mL). The solution was extracted with dichloromethane (3×30 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was purified by silica gel column chromatography (0–25% ethyl acetate in petroleum ether) to afford tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.008 mmol, 82% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 9.65-9.64(t,J=2.0Hz,1H),6.69-6.64(m,1H),3.19-3.13(m,1H),2.55-2.52(m,1H),2 .29-2.27(m,2H),1.75-1.64(m,5H),1.36(s,9H),1.17-1.08(m,2H),1.06-0.83(m,2H).

[0286] Ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate. To a solution of tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.010 mmol, 1 equiv.) in toluene (10 mL, 0.6 M) was added ethyl 2-(triphenylphosphoranylidene)acetate (2.300 g, 6.610 mmol, 1.1 equiv.), and the reaction mixture was stirred at 80 °C. After 12 h, the reaction mixture was concentrated, and the resulting crude material was purified by silica gel column chromatography (0–20% ethyl acetate in hexanes) to give ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.858 mmol, 48% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 6.95-6.88(m,1H),5.82-5.78(m,1H),4.36(s,1H),4.24-4.14(m,2H),3.37(s,1H),2.12-2.08(m,2H),2 .05-1.99(m,2H),1.79-1.76(m,2H),1.46-1.36(m,10H),1.31-1.27(t,J=7.2Hz,3H),1.13-0.99(m,4H).

[0287] tert-Butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate. To a solution of sodium borohydride (0.811 g, 21.43 mmol, 7.5 equiv.) in ethanol (16 mL) and THF (16 mL) at 0 °C was added anhydrous lithium chloride (0.900 g, 21.43 mmol, 7.5 equiv.), and the solution was stirred for 10 minutes. To this reaction was added a solution of ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.860 mmol, 1 equiv.) in THF (8 mL), and the reaction was stirred at 15 °C. After 12 h, the reaction was quenched by the slow addition of 1 M aqueous hydrochloric acid (10 mL), and the solution was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0-25% ethyl acetate in hexanes) to give tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.763 mmol, 96% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 4.37(s,1H),3.66-3.62(t,J=6.8Hz,2H),3.36(s,1H),2.00-1.98(m,2H),1.78-1.75(m,2H ),1.58-1.51(m,2H),1.44(s,9H),1.40-1.32(m,2H),1.28-1.14(m,4H),1.08-0.94(m,4H).

[0288] 4-(trans-4-aminocyclohexyl)butan-1-ol. To a solution of tert-butyl (trans-4-(4-hydroxybutyl)cyclohexyl)carbamate (0.750 g, 2.760 mmol, 1 equiv.) in dichloromethane (2 mL) was added 4 M hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol, 5.8 equiv.), and the reaction was stirred at room temperature. After 12 h, the reaction was concentrated to remove the organic solvent, then diluted with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.394 mmol, 87% yield) as a white solid, which was carried on without further purification. 1 H NMR(400MHz,CDCl3)δ 3.62-3.59(t,J=6.4Hz,2H),2.61-2.54(m,1H),1.85-1.81(m,2H),1.75-1.72(m,2H),1.56 -1.49(m,4H),1.39-1.31(m,2H),1.25-1.12(m,3H),1.10-1.00(m,2H),0.97-0.87(m,2H).

[0289] Methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate. To a solution of methyl 2-bromo-2-methylpropanoate (1.733 g, 9.570 mmol, 4 equiv.) and 4-(trans-4-aminocyclohexyl)butan-1-ol (0.410 g, 2.390 mmol, 1 equiv.) in acetonitrile (3 mL), potassium carbonate (0.993 g, 7.180 mmol, 3 equiv.) and sodium iodide (0.072 g, 0.480 mmol, 0.2 equiv.) were added and the reaction was stirred at 80 °C. After 12 h, the reaction was diluted with ethyl acetate, filtered, and concentrated to provide crude methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, crude) as a brown oil. MS(ESI)m / z 272.3[M+1] + .

[0290] 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-((trans-4-(4-hydroxybutyl)cyclohexyl)amino)-2-methylpropanoate (1.000 g, 2.320 mmol, 1 equiv.) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.556 g, 2.440 mmol, 1.1 equiv.) in ethyl acetate (12 mL) was added N,N-diisopropylethylamine (1.15 mL, 6.960 mmol, 3 equiv.) and the reaction mixture was stirred at 80° C. After 3 h, the reaction was diluted with ethyl acetate (20 mL) and concentrated. The crude oil was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.736 mmol, 32% yield) as a brown solid. MS(ESI) m / z 468.1 [M+1] + .

[0291] 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.770 mmol, 1 equiv) in dichloromethane (3 mL) was added N,N-dimethylformamide (0.30 mL) and thionyl bromide (0.400 g, 1.920 mmol, 2.5 equiv), and the reaction was stirred at 15 °C. After 12 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.280 g, 0.517 mmol, 67% yield) as a brown solid. MS(ESI) m / z 530.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.96-7.94(d,J=8.4Hz,1H),7.86-7.85(d,J=1.6Hz,1H),7.75-7.72(d,J=8.4,1.6Hz,1H),3.85(s,1H),3.45-3.41(t,J=6.8Hz,2H),2.6 9(s,2H),1.95-1.92(m,2H),1.88-1.83(m,4H),1.61(s,6H),1.50-1.44(m,2H),1.36-1.34(m,1H),1.27-1.25(m,2H),1.11-1.01(m,2H).

[0292] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrobromide (0.081 g, 0.200 mmol, 1.3 equiv.) and 44-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.079 g, 0.150 mmol, 1 equiv.) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.065 g, 0.500 mmol, 3.3 equiv.) and the reaction was stirred at 50° C. After 12 hours, the reaction was diluted with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to give 2-((2R,6S)-4-(4-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.050 g, 0.056 mmol, 38% yield). MS (ESI) m / z 863.3 [M+1] + .

[0293] Example 18: 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] 1-Methyl-7-nitro-1H-indazol-3-amine. To a solution of 2-fluoro-3-nitrobenzonitrile (20.000 g, 120.400 mmol, 1 equiv.) in N,N-dimethylacetamide (200 mL) was added methylhydrazine (48 mL, 361.210 mmol, 3 equiv.) and N,N-diisopropylethylamine (23 mL, 132.050 mmol, 1.1 equiv.), and the reaction was stirred at room temperature. After 30 minutes, the reaction was diluted with water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated to give 1-methyl-7-nitro-1H-indazol-3-amine (13.20 g, 68.689 mmol, 57% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.16(dd,J=7.6,1.2Hz,1H),8.08(dd,J=7.6,1.2Hz,1H),7.09(t,J=7.6Hz,1H),5.91(s,2H),3.81(s,3H).

[0294] 3-((1-Methyl-7-nitro-1H-indazol-3-yl)amino)propanoic acid. To a mixture of 1-methyl-7-nitro-1H-indazol-3-amine (12.70 g, 66.090 mmol, 1 equiv.) in 1,4-dioxane (50 mL), aluminum oxide (20.214 g, 198.260 mmol, 3 equiv.), tris(trifluoromethylsulfonyloxy)ytterbium (2.050 g, 3.304 mmol, 5 mol%), and acrylic acid (14.29 g, 198.260 mmol, 3 equiv.) were added and the reaction was stirred at 110° C. After 24 h, the reaction was filtered and concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (20%-50% acetonitrile in water with 0.225% formic acid, 26 min) to give 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoic acid (12.000 g, 45.413 mmol, 69% yield) as a black solid. MS (ESI) m / z 265.1 [M+1] + .

[0295] Methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate. To a mixture of 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoic acid (12.00 g, 45.410 mmol, 1 equiv.) in toluene (80 mL) and methanol (80 mL) was added diazomethyl(trimethyl)silane (72 mL, 45.410 mmol, 1 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The mixture was warmed to 25° C. and stirred for 12 hours. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (35% to 65% acetonitrile in water with 0.225% formic acid, 25 min) to give methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate (8.600 g, 30.906 mmol, 68% yield) as a black solid. MS (ESI) m / z 279.1 [M+1] + ; 1H NMR(400MHz,CDCl3)δ 8.09(dd,J=7.6,0.8Hz,1H),7.78(dd,J=7.6,0.8Hz,1H),7.03(t,J=8.0Hz,1H),4.66(s,1H),3.71-3.75(m,5H),2.78(t,J=6.00Hz,2H).

[0296] Methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate. To a mixture of methyl 3-((1-methyl-7-nitro-1H-indazol-3-yl)amino)propanoate (8.600 g, 30.910 mmol, 1 equiv.) in acetic acid (80 mL) was added potassium isocyanate (7.521 g, 92.720 mmol, 3 equiv.) and the reaction was stirred at room temperature. After 12 h, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×20 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 semi-preparative reverse-phase HPLC (16% to 46% acetonitrile in water with 0.225% formic acid, 23 min) to give methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate (6.400 g, 19.920 mmol, 64% yield) as a pale orange solid. MS (ESI) m / z 322.1 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 8.17(dd,J=7.6,1.2Hz,1H),7.99(dd,J=8.0,0.8Hz,1H),7.27-7.31(m,1H),4.9 2(s,2H),4.20(s,3H),4.17(t,J=6.8Hz,2H),3.61(s,3H),2.75(t,J=6.8Hz,2H).

[0297] Methyl 3-(1-(7-amino-1-methyl-1H-indazol-3-yl)ureido)propanoate. To a solution of methyl 3-(1-(1-methyl-7-nitro-1H-indazol-3-yl)ureido)propanoate (7.100 g, 22.100 mmol, 1 equiv) in THF (100 mL) and methanol (100 mL) under a nitrogen atmosphere was added palladium hydroxide (1.000 g, 28.530 mmol). The suspension was degassed under vacuum, purged with hydrogen gas three times, and stirred at room temperature under a hydrogen atmosphere (15 psi). After 5 h, the reaction was filtered and concentrated to give methyl 3-(1-(7-amino-1-methyl-1H-indazol-3-yl)ureido)propanoate (6.100 g, 20.940 mmol, 95% yield) as a pale yellow oil. MS(ESI)m / z292.1[M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.08(dd,J=8.0,0.8Hz,1H),6.93-7.01(m,1H),6.65(d,J=7.2Hz,1H),4.77(s,2 H),4.34(s,3H),4.07-4.17(m,2H),3.91(s,2H),3.59(s,3H),2.65-2.78(m,2H).

[0298] (3S,5R)-4-(2-((3-(1-(3-methoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of benzyl (3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (0.200 g, 0.680 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.36 mL, 2.050 mmol, 3 equiv.) in acetonitrile (4 mL) was added a solution of trifluoromethanesulfonic anhydride (0.14 mL, 0.820 mmol, 1.2 equiv.) in acetonitrile (1 mL) at 0° C. After stirring at 0°C for 2 hours, methyl 3-(1-(7-amino-1-methyl-1H-indazol-3-yl)ureido)propanoate (0.199 g, 0.680 mmol, 1 equiv) in acetonitrile (10 mL) was added and the reaction was allowed to warm slowly to room temperature. After 12 hours, the reaction was concentrated, resuspended in 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 silica gel column chromatography (1.5% methanol in dichloromethane) to afford benzyl (3S,5R)-4-(2-((3-(1-(3-methoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.500 g, 2.652 mmol, 39% yield) as a yellow solid. MS (ESI) m / z 566.3 [M+1] + ; 1 H NMR(400MHz,CDCl3-d)δ 7.46-7.29(m,5H),7.12-6.90(m,2H),6.50(d,J=7.2Hz,1H),5.15(br s,2H),4.90-4.69(m,2H),4.69-4.50(m,1H),4.35(s,3H),4.13-4.07(m,2H),3.99-3.7 7(m,2H),3.59(s,3H),3.29-3.13(m,2H),3.06-2.95(m,2H),2.87-2.56(m,6H),1.15(br d,J=5.6Hz,6H).

[0299] Benzyl (3S,5R)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazine-1-carboxylate. To a solution of benzyl (3S,5R)-4-(2-((3-(1-(3-methoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.500 g, 2.650 mmol, 1 equiv.) in THF (30 mL) was added potassium tert-butoxide (0.298 g, 2.650 mmol, 1 equiv.) at 0° C. After stirring for 2 hours, the reaction was acidified with 1 M aqueous hydrochloric acid (10 mL), and the solution was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford benzyl (3S,5R)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.290 g, 2.364 mmol, 89% yield) as a yellow solid. MS (ESI) m / z 534.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.49(s,1H),7.39-7.30(m,5H),6.92-6.86(m,2H),6.48(dd,J=1.2,6.4Hz,1H),5.35(t,J=5.4Hz,1H),5.08(s,2H),4.2 3(s,3H),3.90-3.66(m,4H),3.13(q,J=6.4Hz,2H),3.01-2.85(m,2H),2.74(t,J=6.4Hz,2H),2.70-2.53(m,4H),1.09(br d,J=3.6Hz,6H).

[0300] 1-(7-((2-((2S,6R)-2,6-dimethylpiperazin-1-yl)ethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. To a solution of benzyl (3S,5R)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazine-1-carboxylate (1.290 g, 2.380 mmol, 1 equiv) in THF (10 mL) and methanol (10 mL) was added 10% palladium on carbon (500 mg, 0.4700 mmol). The reaction vessel was degassed, purged with hydrogen, and stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 h, the reaction was filtered and concentrated to provide 1-(7-((2-((2S,6R)-2,6-dimethylpiperazin-1-yl)ethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.935 g, 2.289 mmol, 96% yield) as a yellow solid. MS (ESI) m / z 400.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.89-10.00(m,1H),6.98-6.78(m,2H),6.46(d,J=6.4Hz,1H),5.36(t,J=5.6Hz,1H),4.24(s,3H),3.83(t,J=6.4Hz, 2H),3.16-3.11(m,2H),2.93-2.84(m,2H),2.79-2.68(m,4H),2.49-2.42(m,2H),2.25(m,2H),1.01(d,J=6.0Hz,6H).

[0301] 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. A flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol, 1 equiv.) was charged with 1-(7-((2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (138 mg, 0.35 mmol, 1.2 equiv.), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 equiv.), sodium iodide (52 mg, 0.35 mmol, 1.2 equiv.), and N,N-dimethylformamide (2.0 mL) was added. 0.15 M) was added. The reaction was stirred at 50° C. After 18 h, the reaction was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (159 mg, 0.182 mmol, 63% yield) as an off-white solid. MS (ESI) m / z 837.4 [M+1]; 1H NMR(400MHz,DMSO-d6)δ 10.51(s,1H),8.34(d,J=8.31Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.65,8.25Hz,1H),6.91-7.01(m,2H),6.57(br s,1H),4.30(s,3H),3.90-4.06(m,4H),3.77-3.88(m,7H),3.54-3.67(m,4H),3.19-3.42(m,4H),2.79-2. 93(m,2H),2.75(t,J=6.66Hz,2H),2.05-2.16(m,2H),1.66-1.78(m,2H),1.55(s,6H),1.24-1.49(m,8H).

[0302] Example 19: 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride [ka] Benzyl (3S,5R)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate. To a mixture of benzyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (4.000 g, 16.110 mmol, 1 equiv.) and 3-bromopropan-1-ol (3.360 g, 24.160 mmol, 2.18 mL, 1.5 equiv.) in N,N-dimethylformamide (50 mL) was added sodium iodide (2.410 g, 16.110 mmol, 1 equiv.) and N,N-diisopropylethylamine (6.250 g, 48.320 mmol, 8.42 mL, 3 equiv.) all at once at 25 °C. The mixture was heated to 70 °C and stirred for 12 h. The aqueous phase was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (25% to 45% acetonitrile in water with 0.05% ammonium hydroxide, 15 min) to afford benzyl (3S,5R)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate (3.400 g, 11.100 mmol, 69% yield) as a pale yellow oil. MS (ESI) m / z 307.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.29-7.41(m,5H),5.13(s,2H),3.81-4.03(m,2H),3.76(t,J=5.4Hz,2H),3.60-3.74(m,1H),2.85(t, J=6.8Hz,2H),2.60-2.78(m,2H),2.40-2.55(m,2H),1.70(quin,J=6.0Hz,2H),1.17(d,J=6.0Hz,6H).

[0303] Benzyl (3S,5R)-3,5-dimethyl-4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylate. To a mixture of benzyl (3R,5S)-4-(3-hydroxypropyl)-3,5-dimethylpiperazine-1-carboxylate (3.400 g, 11.10 mmol, 1 equiv) in dichloromethane (50 mL) was added triethylamine (2.250 g, 22.190 mmol, 3.09 mL, 2 equiv) all at once at 0 °C. To this reaction mixture was added methanesulfonyl chloride (1.910 g, 16.640 mmol, 1.29 mL, 1.5 equiv) slowly, and the reaction mixture was stirred at 0 °C. After 2 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0–2% methanol in dichloromethane) to afford benzyl (3S,5R)-3,5-dimethyl-4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylate (3.250 g, 8.450 mmol, 76% yield) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.29-7.42(m,5H),5.14(s,2H),4.24(t,J=6.4Hz,2H),3.80-4.07(m,2H),3.02(s,3 H),2.80-2.92(m,2H),2.45-2.69(m,4H),1.77-1.91(m,2H),1.09(d,J=5.2Hz,6H).

[0304] (3S,5R)-4-(3-((3-(1-(3-methoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)amino)propyl)-3,5-dimethylpiperazine-1-carboxylate benzyl. To a mixture of methyl 3-(1-(7-amino-1-methyl-1H-indazol-3-yl)ureido)propanoate (2.500 g, 8.580 mmol, 1 equiv.) in acetonitrile (50 mL) was added N,N-diisopropylethylamine (2.218 g, 17.160 mmol, 2 equiv.), benzyl (3S,5R)-3,5-dimethyl-4-(3-((methylsulfonyl)oxy)propyl)piperazine-1-carboxylate (4.289 g, 11.160 mmol, 1.3 equiv.), and sodium iodide (1.286 g, 8.580 mmol, 1 equiv.) and the reaction was stirred at 90° C. After 12 h, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by semi-preparative reverse-phase HPLC (30%-60% acetonitrile in water with 0.05% ammonium hydroxide, 20 min) to afford benzyl (3S,5R)-4-(3-((3-(1-(3-methoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)amino)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.300 g, 4.463 mmol, 52% yield) as a pale pink solid. MS (ESI) m / z 580.3 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.30-7.41(m,5H),6.99-7.07(m,2H),6.52(dd,J=7.0,1.2Hz,1H),5.14(s,2H),4.74(s,2H),4.33(s,3H),4.09-4.15(m,2H),3.85-4 .00(m,2H),3.59(s,3H),3.14-3.23(m,2H),2.87-2.94(m,2H),2.69-2.76(m,2H),2.52-2.69(m,4H),1.82-1.90(m,2H),1.12(s,6H).

[0305] 1-(7-((3-((2S,6R)-2,6-dimethylpiperazin-1-yl)propyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. 12 M aqueous hydrochloric acid solution (15 mL) was added to benzyl (3S,5R)-4-(3-((3-(1-(3-methoxy-3-oxopropyl)ureido)-1-methyl-1H-indazol-7-yl)amino)propyl)-3,5-dimethylpiperazine-1-carboxylate (1.620 g, 2.790 mmol, 1 equivalent), and the reaction mixture was stirred at room temperature. After 12 h, the reaction was concentrated and purified by semi-preparative reverse-phase HPLC (15% to 45% acetonitrile in water with 10 mM ammonium carbonate) to give 1-(7-((3-((2S,6R)-2,6-dimethylpiperazin-1-yl)propyl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.310 g, 0.750 mmol, 27% yield) as a yellow solid. MS (ESI) m / z 414.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 10.49(s,1H),6.82-6.94(m,2H),6.45(dd,J=5.6,1.6Hz,1H),5.43(s,1H),4.24(s,3H),3.83(t,J=6.8Hz,2H),3.05(q,J=6. 28Hz,2H),2.72-2.85(m,4H),2.62-2.72(m,2H),2.35-2.45(m,2H),2.16-2.32(m,2H),1.67-1.82(m,2H),0.87-1.08(m,6H).

[0306] 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. A flask containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (150 mg, 0.29 mmol, 1 equiv.) was charged with 1-(7-((2-((2R,6S)-2,6-dimethylpiperazin-1-yl)ethyl)amino)-1- Methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (138 mg, 0.35 mmol, 1.2 equiv), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 equiv), sodium iodide (52 mg, 0.35 mmol, 1.2 equiv), and N,N-dimethylformamide (2.0 mL, 0.15 M) were added and the reaction was stirred at 50° C. After 18 h, the reaction was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (159 mg, 0.182 mmol, 63% yield) as an off-white solid. MS(ESI) m / z 837.4 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.51(s,1H),8.34(d,J=8.31Hz,1H),8.19(d,J=1.59Hz,1H),7.97(dd,J=1.65,8.25Hz,1H),6.91-7.01(m,2H),6.57(br s,1H),4.30(s,3H),3.90-4.06(m,4H),3.77-3.88(m,7H),3.54-3.67(m,4H),3.19-3.42(m,4H),2.79-2. 93(m,2H),2.75(t,J=6.66Hz,2H),2.05-2.16(m,2H),1.66-1.78(m,2H),1.55(s,6H),1.24-1.49(m,8H).

[0307] Example 20: 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] (R)-tert-Butyl 4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a 40 mL vial was added (R)-tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol), N,N-diisopropylethylamine (0.69 mL, 3.93 mmol, 2 equiv.), methyl bromoacetate (1.09 mL, 11.8 mmol, 6 equiv.), and THF (20 mL, 0.1 M). The reaction was stirred at room temperature. After 18 hours, the solution was diluted with 100 mL ethyl acetate and 100 mL water. The organic layer was removed, and the aqueous layer was extracted with 2 x 50 mL ethyl acetate. The combined organic layers were then dried over magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1-50% ethyl acetate in hexanes) to provide (R)-tert-butyl 4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.557 g, 1.71 mmol, 88% yield) as a yellow oil. MS(ESI) m / z 227 [M-99] + .

[0308] (R)-2-(2-(trifluoromethyl)piperazin-1-yl)methyl acetate. (R)-tert-Butyl 3-(trifluoromethyl)piperazine-1-carboxylate (250 mg, 0.7 mmol) and trifluoroacetic acid (0.58 mL, 7.6 mmol, 10 equiv.) were combined in dichloromethane (7.6 mL, 1 M) and stirred at room temperature in a screw-cap scintillation vial. After 1 h, the solution was concentrated to give (R)-2-(2-(trifluoromethyl)piperazin-1-yl)methyl acetate (255 mg, 0.75 mmol, 98% yield) as a yellow oil, which was carried forward without further purification. MS (ESI) m / z 227 [M+1] + .

[0309] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)methyl acetate. To a 1-dram vial containing 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.5 g, 0.96 mmol, 1 equiv.), (R)-2-(2-(trifluoromethyl)piperazin-1-yl)methyl acetate (0.33 g, 0.96 mmol, 1 equiv.), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.) was added acetonitrile (5 mL), followed by N,N-diisopropylethylamine (0.8 mL, 4.82 mmol, 5 equiv.). The reaction vial was heated to 60° C. with stirring. After 16 h, the reaction was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0–100% ethyl acetate in hexanes) to give methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (0.6 g, 0.89 mmol, 91% yield). MS (ESI) m / z 664.2 [M+1]+.

[0310] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid. To a cooled solution of methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate (0.6 g, 0.9 mmol, 1 equiv.) in a mixture of tetrahydrofuran / methanol / water (3:1:1, 5 mL) was added lithium hydroxide monohydrate (0.58 g, 1.3 mmol, 1.5 equiv.) all at once at 0 °C. The resulting solution was stirred at room temperature. After 3 h, the reaction was diluted with water (20 mL) and extracted with 10% methanol in dichloromethane (4 × 50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.33 g, 0.46 mmol, 51% yield), which was carried on without further purification. MS (ESI) m / z 650.2 [M+1]+.

[0311] 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a two-dram vial containing 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.12 g, 0.19 mmol, 1 equiv.) and 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.06 g, 0.22 mmol, 1.2 equiv.) was added acetonitrile (1.5 mL) and dimethylformamide (1.5 mL), and the solution was stirred until all solids were dissolved. 1-Methylimidazole (0.07 mL, 0.84 mmol, 5 equiv) was added followed by N-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (0.12 g, 0.41 mmol, 2.2 equiv) and the reaction was stirred at room temperature. After 1 h, the reaction was diluted to a total volume of 3 mL with dimethyl sulfoxide, filtered, and purified by standard methods to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.09 g, 0.09 mmol, 50.4% yield). MS (ESI) m / z 891.2 [M+1]+.1H NMR(DMSO-d6,400MHz)δ 10.4-10.6(m,1H),9.9-10.1(m,1H),8.2-8.3(m,1H),8.1-8.2(m,1H),7.8-8.0 (m,1H),7.4-7.6(m,1H),7.1-7.2(m,1H),7.0-7.1(m,1H),4.2-4.4(m,1H),4.00 (s,3H),3.8-3.9(m,6H),3.6-3.7(m,4H),3.4-3.5(m,2H),3.1-3.2(m,3H),2.6- 2.9(m,4H),2.0-2.1(m,2H),1.6-1.7(m,2H),1.4-1.5(m,6H),1.2-1.3(m,2H).

[0312] Example 21: 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6 -sulfanyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride [ka] 4-Bromo-3-(pentafluoro-λ 6 -sulfanyl)aniline. 3-(pentafluoro-λ)aniline in dimethylformamide (15 mL) under nitrogen atmosphere. 6 To a solution of N-bromosuccinimide (1.9 g, 10.95 mmol, 1.2 equiv.) in 100 ml of N-sulfanylaniline (2.0 g, 9.12 mmol, 1 equiv.) was added N-bromosuccinimide (1.9 g, 10.95 mmol, 1.2 equiv.) in one portion at 0° C. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–20% ethyl acetate in hexanes) to give 4-bromo-3-(pentafluoro-λ)-2-( ... 6 -sulfanyl)aniline (1.7 g, 5.7 mmol, 59% yield).1 H NMR(CDCl3,400MHz)δ 7.4-7.5(m,1H),7.1-7.2(m,1H),6.6-6.7(m,1H),3.8-4.0(m,2H).

[0313] 4-amino-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. 4-Bromo-3-(pentafluoro-λ)benzonitrile in N-methylpyrrolidinone (30 mL) 6 A 100 mL round-bottom flask containing 4-amino-2-(pentafluoro-λ6-sulfanyl)aniline (1.7 g, 5.7 mmol, 1 equiv.) and copper(I) cyanide (0.61 g, 6.84 mmol, 1.2 equiv.) was heated to 180 °C with stirring. After 4 h, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography (50 g column, 0–20% ethyl acetate in hexanes) to give 4-amino-2-(pentafluoro-λ6-sulfanyl)benzonitrile (1.0 g, 4.09 mmol, 72% yield) as a white solid. MS (ESI) m / z 244.8 [M+1]+.

[0314] 4-Isothiocyanato-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. To a 100 mL round-bottom flask was added thiophosgene (0.94 mL, 12.29 mmol, 1.2 equiv.) in water (10 mL) to obtain an orange solution. 4-Amino-2-(pentafluoro-λ)benzonitrile in dichloromethane (10 mL) 6 -sulfanyl)benzonitrile (2.5 g, 10.24 mmol, 1 equiv.) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to give 4-isothiocyanato-2-(pentafluoro-λ)-benzonitrile. 6-sulfanyl)benzonitrile (1.3 g, 4.54 mmol, 44% yield) was obtained as a white solid which was carried forward without further purification. MS (ESI) m / z 286.9 [M+1]+.

[0315] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (1.0 g, 2.91 mmol, 1 equiv.) in ethyl acetate (10 mL) was added 4-isothiocyanato-2-(pentafluoro-λ 6 N,N-diisopropylethylamine (1.02 mL, 5.82 mmol, 3 equiv.) was added to the reaction mixture. The reaction mixture was stirred at 80°C. After 18 hours, the reaction mixture was concentrated and purified by column chromatography (0-50% ethyl acetate / hexanes) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile, a white solid, was obtained. This intermediate solid was suspended in dichloromethane (1.5 mL), followed by the addition of 4 M hydrochloric acid in dioxane (4 mL, 16 mmol, 3 equiv.) and allowed to stir at 25° C. for 12 hours. The reaction was concentrated, and the solid was dissolved in dichloromethane and purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to give 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ)benzonitrile. 6(-sulfanyl)benzonitrile was obtained as an off-white solid (0.80 g, 1.33 mmol, 46% yield). MS (ESI) m / z 513.8 [M+1]+.

[0316] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ) in dichloromethane (30 mL) 6 To a solution of 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ)-benzonitrile (1.0 g, 1.95 mmol, 1 equiv.) was added dimethylformamide (5 mL) and thionyl bromide (1.0 g, 4.87 mmol, 2.5 equiv.) sequentially. The reaction was stirred at room temperature overnight. After 16 h, the reaction was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ)-benzonitrile. 6 (-sulfanyl)benzonitrile (0.59 g, 1.02 mmol, 53% yield) was obtained as a light brown solid. MS (ESI) m / z 578.8 [M+1]+.

[0317] 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6-sulfanyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride; 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 To a 1-dram vial containing 2-((2S,6R)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.11 g, 0.26 mmol, 1.3 equiv.), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv.) was added acetonitrile (2 mL), followed by N,N-diisopropylethylamine (0.2 mL, 1.2 mmol, 6 equiv.). The reaction vial was heated to 60° C. with stirring. After 16 hours, the reaction mixture was diluted to a total volume of 3 ml with dimethyl sulfoxide and purified by standard methods to give 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6 -sulfanyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.07 g, 0.07 mmol, 34% yield) was obtained as a yellow solid. MS (ESI) m / z 910.3 [M+1] + ; 1H NMR(DMSO-d6,400MHz)δ 10.5-10.5(m,1H),9.8-9.9(m,1H),9.5-9.7(m,1H),8.3-8.4(m,1H),8.2-8.3(m,1H),7. 8-7.9(m,1H),7.4-7.5(m,1H),7.1-7.2(m,1H),7.0-7.1(m,1H),4.0-4.0(m,3H),3.8-3. 9(m,2H),3.7-3.7(m,2H),3.4-3.5(m,2H),3.2-3.4(m,3H),3.1-3.2(m,4H),2.7-2.9(m, 5H),2.0-2.1(m,2H),1.6-1.7(m,2H),1.4-1.5(m,6H),1.2-1.4(m,3H),1.1-1.1(m,6H).

[0318] Example 22: 2-((R)-4-(3-(trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride [ka] (R)-tert-butyl 4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a solution of (R)-2-(4-(tert-butoxycarbonyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.460 g, 1.470 mmol) in pyridine (4 mL) was added EDCI (0.565 g, 2.950 mmol) followed by 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.401 g, 1.550 mmol) and the reaction mixture was stirred at 60° C. After 12 h, the reaction was concentrated and purified by standard methods to provide (R)-tert-butyl 4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.500 g, 0.903 mmol, 61% yield) as a brown solid. MS (ESI) m / z 498.1 [M-55] + .

[0319] (R)—N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide. To a solution of (R)-tert-butyl 4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.500 g, 0.900 mmol) in dichloromethane (6 mL) was added 30% hydrogen bromide in acetic acid (2.0 mL), and the reaction mixture was stirred at 15° C. After 12 h, the reaction was concentrated to provide crude (R)—N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.550 g, 1.029 mmol) as a brown solid, which was carried on without further purification. MS (ESI) m / z 454.2 [M+1] + .

[0320] 2-((R)-4-(3-(trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 5-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.080 g, 0.150 mmol) in DMF (1 mL) was added R)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (0.107 g, 0.200 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.060 g, 0.460 mmol) and the reaction was stirred at 50° C. After 12 h, the reaction was concentrated, taken up in DMSO, 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-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.050 g, 0.054 mmol, 35% yield) as a white solid. MS (ESI) m / z 890.1 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),10.57(s,1H),10.06-9.97(m,1H),9.15-9.14(d,J=2.0Hz,1H),8.75-8. 74(d,J=2.0Hz,1H),7.55-7.53(d,J=8.0Hz,1H),7.19-7.15(m,1H),7.12-7.08(m,1H), 4.34(m,1H),4.05(s,3H),3.91-3.78(m,4H),3.72-3.65(m,2H),3.55-3.43(m,2H),3. 23-3.10(m,5H),2.79-2.75(m,4H),1.85-1.71(m,6H),1.57(s,6H),1.26-1.05(m,5H).

[0321] Example 23: 2-((R)-4-(3-(trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide. [ka] 2-((R)-4-(3-(trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 4-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.069 g, 0.130 mmol) and (R)—N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide (0.086 g, 0.160 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.220 mmol) and the reaction was stirred at 50° C. After 8 h, the reaction was diluted with DMSO, filtered, 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-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.073 g, 0.082 mmol, 61% yield) as a yellow solid. MS(ESI) m / z 889.5 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.58(s,1H),10.54-10.38(m,1H),10.08-9.89(m,1H),8.34(d,J=8.4Hz,1H),8.20(s, 1H),8.01(d,J=10.0Hz,1H),7.54(m,1H),7.21-7.08(m,2H),4.38-4.26(m,1H),4.06(s ,3H),3.90(t,J=6.8Hz,2H),3.87-3.63(m,4H),3.59-3.44(m,2H),3.20-3.03(m,4H),2 .81-2.71(m,4H),1.88-1.81(m,2H),1.79-1.66(m,4H),1.55(s,6H),1.34-0.99(m,6H).

[0322] Example 24: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 2-((R)-4-(3-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 5-(3-((trans)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.850 g, 1.594 mmol) and (R)—N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide hydrobromide (1.235 g, 2.310 mmol) in DMF (15 mL), N,N-dimethylformamide (1.39 mL, 7.970 mmol) was added all at once under nitrogen and the reaction was stirred at 50° C. After 12 hours, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (4 × 40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (1.024 g, 1.127 mmol, 71% yield) as a yellow solid. MS(ESI)m / z906.2[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ11.13(br s,1H),10.57(s,1H),10.09(s,1H),9.14(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),7.54(br d,J=8.0Hz,1H),7.20-7.14(m,1H),7.12-7.07(m,1H),4.06(s,3H),3.90(br t,J=6.8Hz,3H),3.79(br d,J=18.4Hz,1H),3.69(br d,J=18.0Hz,2H),3.57-3.43(m,4H),3.30-3.10(m,1H),3.31-3.07(m,6H),2.87-2.74(m,4H),2.07(br d,J=10.4Hz,2H),1.98(br s,2H),1.71(br d,J=10.4Hz,2H),1.56(s,6H),1.37-1.28(m,2H).

[0323] Example 25: 2-((2R,4s,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-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 2-((2R,4s,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-dimethylpiperidin-1-yl)benzyl acetate. To a solution of 5-(3-((trans)-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.300 g, 0.540 mmol) and benzyl 2-bromoacetate (0.187 g, 0.820 mmol) in acetonitrile (8 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.28 mL, 1.63 mmol). The reaction mixture was stirred at 25° C. After 12 hours, the reaction was concentrated and purified by flash silica gel column chromatography (0-3% methanol in dichloromethane) to give 2-((2R,4s,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-dimethylpiperidin-1-yl)benzyl acetate (350 mg, 0.5001 mmol, 92% yield) as a clear, colorless oil. MS(ESI) m / z: 700.5 [M+1] + .

[0324] 2-((2R,4s,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-dimethylpiperidin-1-yl)acetic acid. To a solution of 2-((2R,4s,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-dimethylpiperidin-1-yl)benzyl acetate (0.365 g, 0.520 mmol) in methanol (10 mL) was added 10% palladium on activated carbon (0.100 g, 0.940 mmol). The mixture was stirred under an atmosphere of hydrogen gas at 25° C. After 6 hours, the reaction slurry was filtered and concentrated to provide 2-((2R,4s,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-dimethylpiperidin-1-yl)acetic acid (0.290 g, 0.477 mmol, 91% yield) as a yellow oil. MS (ESI) m / z: 610.5 [M+1] + .

[0325] 2-((2R,4s,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-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a mixture of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.083 g, 0.320 mmol) and 2-((2R,4s,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-dimethylpiperidin-1-yl)acetic acid (0.130 g, 0.210 mmol) in pyridine (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (81.75 mg, 0.4300 mmol) and the reaction was stirred at 50° C. After 12 hours, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.090 g, 0.102 mmol, 48.0% yield) as a yellow solid. MS(ESI)m / z:851.6[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.32-10.96(m,1H),10.60(d,J=2.0Hz,1H),9.15-9.13(m,1H),8.74(t,J=2.1Hz,1H),7.59(dd,J=2.9,7.8Hz,1H),7. 25(t,J=7.8Hz,1H),7.13(dt,J=3.3,7.8Hz,1H),4.43-4.32(m,2H),4.12(s,3H),3.90(dt,J=1.7,6.6Hz,2H),3.84(br s,2H),3.48-3.45(m,1H),3.27-3.18(m,1H),2.87-2.72(m,4H),2.10-1 .94(m,4H),1.86-1.58(m,8H),1.56(d,J=4.8Hz,6H),1.46-1.19(m,9H).

[0326] Example 26: 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide. To a solution of (R)—N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide (0.080 g, 0.150 mmol) and 4-(3-((trans)-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.082 g, 0.150 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.072 g, 0.150 mmol) and the reaction was stirred at 50° C. After 12 hours, the reaction was diluted with DMSO and purified by standard methods to give 2-((R)-4-(3-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.054 g, 0.053 mmol, 35% yield) as a yellow solid. MS (ESI) m / z: 905.1 [M+1] + ; 1HNMR(400MHz,DMSO-d6)δ10.58(s,1H),10.15-9.87(m,1H),8.34(d,J=8.4Hz,1H),8.19(d,J=1.2Hz ,1H),7.97(dd,J=8.19,1.6Hz,1H),7.60-7.51(m,1H),7.25-7.04(m,2H),4.40-4.23(m,1H),4.09-4 .03(m,3H),3.90(t,J=6.4Hz,2H),3.86-3.63(m,4H),3.62-3.50(m,3H),3.31-3.05(m,6H),2.92-2. 71(m,4H),2.20-2.02(m,2H),2.01-1.84(m,2H),1.81-1.63(m,2H),1.55(s,6H),1.42-1.20(m,2H).

[0327] Example 27: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 2-((R)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 5-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.097 g, 0.19 mmol) and (R)—N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)-2-(2-(trifluoromethyl)piperazin-1-yl)acetamide (0.100 g, 0.19 mmol) in DMF (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.22 mL, 1.29 mmol) and the reaction was stirred at 50° C. After 12 h, the reaction was diluted with DMSO 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (66.4 mg, 0.0745 mmol, 40% yield) as an off-white solid. MS(ESI) m / z 892.0 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.95-10.91(m,1H),10.57(s,1H),10.16-9.95(m,1H),9.14(d,J=1.6Hz,1H),8.74(d,J=2.0Hz,1H), 7.54(d,J=8.0Hz,1H),7.17(d,J=6.8Hz,1H),7.13-7.07(m,1H),4.48-4.26(m,1H),4.06(s,3H),3.96 -3.80(m,6H),3.79-3.69(m,2H),3.59-3.43(m,3H),3.28-3.14(m,3H),2.93-2.82(m,2H),2.77(t,J= 6.8Hz,2H),2.58-2.53(m,2H),2.15-2.06(m,2H),1.78-1.68(m,2H),1.57(s,6H),1.45-1.28(m,2H).

[0328] Example 28: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate. To a solution of 5-(3-((trans)-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.300 g, 0.540 mmol) and 2-bromobenzyl acetate (0.187 g, 0.820 mmol) in acetonitrile (10 mL) was added diisopropylethylamine (0.28 mL, 1.63 mmol) and the reaction was stirred at room temperature. After 12 h, the reaction was concentrated and purified by standard methods to provide 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate (370 mg, 0.5287 mmol, 97% yield) as a yellow oil. MS(ESI) m / z 722.4 [M+23] + .

[0329] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.370 g, 0.530 mmol) in methanol (10 mL) was added 10% palladium on activated carbon (0.112 g, 1.05 mmol) and the reaction was stirred at room temperature under an atmosphere of hydrogen gas. After 6 hours, the reaction slurry was filtered and 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid (290 mg, 0.4756 mmol, 90% yield) as a brown oil. MS (ESI) m / z 610.4 [M+1] + .

[0330] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide. To a mixture of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.128 g, 0.490 mmol) and 22-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)acetic acid (0.200 g, 0.330 mmol) in pyridine (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.126 g, 0.660 mmol) and the reaction was stirred at 50° C. After 12 hours, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by 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-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.078 g, 0.091 mmol, 28% yield) as a yellow solid. MS(ESI)m / z 851.5[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.60(d,J=1.6Hz,1H),9.14(s,1H),8.74(s,1H),7.59(dd,J=3.4,8.0Hz,1H),7.27 -7.21(m,1H),7.13(dt,J=3.7,7.7Hz,1H),4.40(s,1H),4.33-4.26(m,1H),4.11(s,3 H),3.90(t,J=6.6Hz,2H),3.67(d,J=8.4Hz,2H),3.42-3.18(m,2H),2.89-2.75(m,4 H),2.12-2.03(m,2H),2.00-1.59(m,6H),1.56(d,J=4.5Hz,6H),1.53-1.19(m,13H).

[0331] Example 29: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2S,4r,6R)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (3.000 g, 13.08 mmol) and (trans)-N,N-dibenzyl-4-(3-bromopropyl)cyclohexanamine (6.290 g, 15.70 mmol) in xylene (45 mL) was added tetrabutylammonium bromide (0.840 g, 2.620 mmol) and potassium hydroxide (3.5 mL, 65.41 mmol), and the reaction was stirred at 30 °C. After 12 h, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The 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 (5.300 g, 9.657 mmol, 74% yield) as a white solid. 1 H 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).

[0332] 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S) ... The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give crude (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (3.000 g, 8.140 mmol, 84% yield), which was carried on without further purification. 1 H NMR(400MHz,DMSO-d6)δ 4.17-4.03(m,2H),3.56(q,J=4.0Hz,1H),3.35(s,2H),2.47-2.39(m,1H),1.77-1 .60(m,8H),1.52-1.44(m,2H),1.39(s,9H),1.27-1.12(m,9H),1.01-0.79(m,4H).

[0333] 4-(3-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S))-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.500 g, 4.070 mmol) and methyl 2-bromo-2-methylpropanoate (3.680 g, 20.35 mmol) in acetonitrile (5 mL) were added sodium iodide (0.060 g, 0.410 mmol) and potassium carbonate (1.690 g, 12.21 mmol). The mixture was stirred at 110 °C. After 12 hours, the reaction was filtered and concentrated to provide crude 4-(3-((1r,4R)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate 2R,4r,6S)-tert-butyl ester (1.900 g, 4.054 mmol, 99.6% yield), which was carried on without further purification. MS(ESI) m / z 469.4 [M+1] + .

[0334] (2R,4r,6S)-tert-Butyl 4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.050 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.930 g, 4.050 mmol) in ethyl acetate (10 mL) was added N,N-diisopropylethylamine (2.11 mL, 12.16 mmol) and the reaction was stirred at 90° C. After 12 h, the reaction was filtered, 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-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 3.610 mmol, 89% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),4.14-4.06(m,2H),3.90-3.74(m,1H),3.59-3.54(m,1H),3.40-3.3 7(m,2H),2.80-2.63(m,2H),1.80(d,J=12.0Hz,2H),1.75-1.70(m,6H) ,1.56-1.47(m,8H),1.39(s,9H),1.27-1.23(m,9H),1.18-1.16(m,2H).

[0335] 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrobromide. To a solution of 4-(3-((transn)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl ester (2.400 g, 3.610 mmol) in dichloromethane (20 mL) was added 33% hydrogen bromide in acetic acid (20 mL, 3.610 mmol) and the reaction was stirred at room temperature. After 12 hours, the reaction 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-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrobromide (2.000 g, 3.542 mmol, 98% yield), which was carried on without further purification. MS(ESI) m / z 565.3 [M+1] + .

[0336] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate. To a solution of 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile and benzyl 2-bromoacetate (1.220 g, 5.310 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (3.080 mL, 17.71 mmol) and the reaction was stirred at room temperature. After 12 h, the reaction was concentrated 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-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.800 g, 1.122 mmol, 32% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 8.33(d,J=8.4Hz,1H),8.20(d,J=2.0Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),7.38-7.32(m,5H),5.09(s,2H),3.83(s,1H),3.53(s,2H),3.23-3.1 5(m,1H),2.79-2.66(m,4H),1.88-1.77(m,4H),1.71(d,J=10.4Hz,2H), 1.54(s,6H),1.50-1.42(m,3H),1.23-1.15(m,4H),1.06-0.95(m,10H).

[0337] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (0.800 g, 1.120 mmol) in THF (3 mL), methanol (3 mL), water (3 mL) was added lithium hydroxide (0.135 g, 5.610 mmol) and the mixture was stirred at room temperature. After 12 hours, the reaction 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-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (1.000 g, 1.606 mmol) as a yellow oil, which was carried on without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),3.83(s,1H),3.36(s,3H),3.18(s,4H),2.67(d,J=2.0Hz,2H),1 .88(d,J=12.4Hz,2H),1.81-1.78(m,2H),1.70(d,J=11.6Hz,2H),1.54(s,6H),1.48(d,J=7.2Hz,2H),1.18(s,3H),1.09(d,J=6.4Hz,10H).

[0338] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride. To a solution of 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.241 mmol) and 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.075 g, 0.290 mmol) in pyridine (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.092 g, 0.480 mmol) and the mixture was stirred at 50° C. After 12 hours, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was 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-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (51.8 mg, 0.059 mmol, 25% yield) as a white solid. MS(ESI)m / z864.3[M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 10.95-10.76(m,1H),10.59(d,J=2.0Hz,1H),9.97-9.12(m,1H),8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.9 7(dd,J=1.6,8.4Hz,1H),7.63-7.56(m,1H),7.27-7.21(m,1H),7.17-7.10(m,1H),4.44-4.27(m,2H),4.10(s,3H), 3.93-3.77(m,3H),3.72-3.50(m,3H),3.46-3.39(m,2H),2.82-2.68(m,4H),2.21-2.08(m,2H),1.82(d,J=11.2Hz, 2H),1.76-1.63(m,3H),1.55(d,J=2.0Hz,7H),1.46-1.32(m,4H),1.27(d,J=6.4Hz,4H),1.22(s,3H),1.08(s,2H).

[0339] Example 30: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 2-((2R,4r,6S)-4-(3-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide. To a solution of 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)acetic acid (0.120 g, 0.192 mmol) and 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.050 g, 0.192 mmol) in pyridine (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.074 g, 0.385 mmol) and the reaction was stirred at 50° C. After 12 hours, the reaction was diluted with water (20 mL) and washed with ethyl acetate (3 × 10 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 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (63.07 mg, 0.070 mmol, 36% yield) as a yellow solid. MS (ESI) m / z 865.3 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.26-10.80(m,1H),10.59(s,1H),10.48-8.99(m,2H),8.75(s,1H),7.59(dd,J=4.0,8.0Hz, 1H),7.28-7.20(m,1H),7.18-7.09(m,1H),4.38(s,2H),4.12(d,J=2.0Hz,3H),3.94-3.78(m, 3H),3.74-3.51(m,3H),3.45-3.40(m,2H),2.81-2.68(m,4H),2.21-2.07(m,2H),1.82(d,J=9 .6Hz,2H),1.72(s,3H),1.58-1.50(m,7H),1.46-1.34(m,4H),1.32-1.16(m,7H),1.10(s,2H).

[0340] Example 31: 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] (2R,4r,6S)-tert-Butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 2.640 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.200 g, 5.280 mmol) in ethyl acetate (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.38 mL, 7.920 mmol) and the reaction mixture was stirred at 80° C. After 12 h, the reaction was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.150 g, 1.767 mmol, 67% yield) as a brown oil. MS (ESI) m / z 551.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ 7.97-7.95(d,J=8.0Hz,1H),7.87(d,J=1.6Hz,1H),7.76-7.73(dd,J=8.0,1.6Hz,1 H),4.29-4.25(m,2H),3.87(s,1H),3.61-3.56(m,1H),3.49-3.46(t,J=6.0Hz,2H) ,2.69(s,2H),1.98-1.91(m,4H),1.88-1.85(m,2H),1.75-1.69(m,2H),1.63(s,6H ),1.54-1.51(m,3H),1.49(s.9H),1.35-1.34(d,J=6.8Hz,6H),1.18-1.07(m,2H).

[0341] 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.150 g, 1.770 mmol) in dichloromethane (15 mL) was added 2,2,2-trifluoroacetic acid (5 mL, 65.34 mmol), and the reaction mixture was stirred at room temperature. After 2 hours, the reaction was concentrated, and the resulting material was taken up in saturated aqueous sodium bicarbonate and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to provide 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.870 g, 1.580 mmol, 90% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.96-7.95(d,J=8.0Hz,1H),7.86(d,J=1.6Hz,1H),7.75-7.72(dd,J=8.0,1.6Hz,1H),3.86(s,1H),3.52-3.49(m,2H),3.35-3.27(m,1H), 2.75-2.59(m,4H),2.02-1.92(m,4H),1.86-1.83(m,2H),1.61(s,6H),1.52-1.49(m,3H),1.16-1.14(d,J=6.4Hz,6H),1.10-0.96(m,4H).

[0342] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate. To a solution of 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.870 g, 1.580 mmol) in acetonitrile (9 mL) was added benzyl 2-bromoacetate (0.723 g, 3.160 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.83 mL, 4.740 mmol) and the reaction was stirred at room temperature. After 12 h, the reaction was concentrated and purified by standard methods to provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (1.100 g, 1.574 mmol) as a brown solid. MS(ESI) m / z 699.3 [M+1] + .

[0343] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)benzyl acetate (1.100 g, 1.570 mmol) in THF (12 mL) and water (1.5 mL) was added lithium hydroxide (0.189 g, 7.870 mmol) and the reaction was stirred at 50° C. After 12 h, the reaction was concentrated and extracted with 10:1 DCM / methanol (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.900 g, 1.478 mmol, 93% yield) as a brown solid, which was carried on without further purification. MS (ESI) m / z 609.3 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.34-8.32(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.98-7.96(dd,J=8.0,1.6Hz,1H),3.79(s,2H),3.16(s,2H),2.72-2.67(m,2H) ),2.03-2.00(m,2H),1.81-1.70(m,4H),1.54(s,6H),1.45-1.38(m,5H),1.27-1.19(m,7H),1.15-1.01(m,3H),0.87-0.80(m,2H).

[0344] 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide. To a solution of 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.100 g, 0.160 mmol) in pyridine (1 mL) was added 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.051 g, 0.170 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.063 g, 0.330 mmol) and the reaction mixture was stirred at 50° C. After 12 h, the reaction was concentrated and the resulting 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-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide (0.079 g, 0.089 mmol, 54% yield) as a white solid. MS (ESI) m / z 850.5 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.11-10.92(m,1H),10.60(s,1H),9.20-9.15(m,2H),8.75(d,J=1.6Hz,1H),7.61-7.58(m, 1H),7.26-7.23(m,1H),7.16-7.11(m,1H),4.40-4.37(m,2H),4.11(s,3H),3.92-3.85(m,3H) ,3.71(m,1H),3.63-3.47(m,4H),2.79-2.67(m,4H),2.20-2.07(m,2H),1.84-1.82(m,2H),1. 75-1.66(m,3H),1.56-1.55(m,6H),1.44-1.39(m,6H),1.29-1.28(m,4H),1.13-1.12(m,2H).

[0345] Example 32: 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (trans)-N,N-dibenzyl-4-(2-bromoethyl)cyclohexanamine (5.660 g, 14.65 mmol) and 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (2S,4r,6R)-tert-butyl carboxylate (2.800 g, 12.21 mmol) in o-xylene (60 mL) was added potassium hydroxide (3.080 g, 54.95 mmol) and tetra-n-butylammonium bromide (0.790 g, 2.440 mmol), and the reaction mixture was stirred at 15 °C. After 12 h, the reaction 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 (3.500 g, 6.545 mmol, 53.6% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.43-7.36(m,5H),7.30-7.26(m,4H),7.22-7.18(m,1H),4.28-4.20(m,2 H),3.63(s,3H),3.56-3.52(m,1H),3.42-3.39(m,2H),2.50-2.44(m,1H), 1.97-1.87(m,4H),1.80-1.77(m,2H),1.72-1.66(m,2H),1.62-1.55(m,2 H),1.47(s,9H),1.44-1.38(m,4H),1.32-1.30(m,6H),0.90-0.82(m,2H).

[0346] 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S))-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.540 mmol) in methanol (40 mL) was added ammonium hydroxide (0.23 g, 6.54 mmol) and palladium on activated carbon (0.350 g, 0.330 mmol), and the reaction mixture was stirred under a molecular hydrogen atmosphere (15 Psi) at 20° C. for 12 h. The reaction mixture was poured into methanol (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.000 g, 5.640 mmol, 86% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 4.12-4.08(m,2H),3.57-3.55(m,1H),3.41-3.38(m,5H),2.45-2.39(m,1H),1. 73-1.65(m,8H),1.39-1.35(m,11H),1.25(d,J=6.8Hz,6H),0.98-0.84(m,4H).

[0347]

[0047] To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 5.360 mmol) and methyl 2-bromo-2-methylpropanoate (3.880 g, 21.44 mmol) in acetonitrile (6 mL) was added potassium carbonate (2.220 g, 16.08 mmol) and sodium iodide (0.080 g, 0.540 mmol), and the reaction was stirred at 110 °C. After 15 hours, the reaction 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-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (4.8 g), which was carried forward without further purification.

[0348] (2R,4r,6S)-tert-Butyl 4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 2.64 mmol, 50%) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (0.730 g, 3.170 mmol) in ethyl acetate (15 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.38 mL, 7.920 mmol) and the reaction mixture was stirred at 80° C. After 3 h, the reaction 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-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-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)δ 8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),4.29-4.21(m,2H),3.82(m, 1H),3.59-3.54(m,1H),3.48-3.45(t,J=6.4Hz,2H),2.68-2.59(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).

[0349] 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.200 g, 1.840 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL), and the reaction mixture was stirred at 15° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Water (30 mL) was added, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and 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-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.010 g, 1.831 mmol, 99% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.98(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).

[0350] 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)acetate tert-butyl. To a solution of 5-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.650 g, 1.180 mmol) in acetonitrile (12 mL) was added tert-butyl 2-bromoacetate (0.253 g, 1.300 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.62 mL, 3.530 mmol) and the reaction mixture was stirred at room temperature. After 12 h, the reaction was concentrated and purified by standard methods 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-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.600 g, 0.901 mmol, 77% yield) as a brown oil. MS(ESI) m / z 666.3 [M+1] + .

[0351] 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)acetic acid. To a solution of tert-butyl 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.600 g, 0.900 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.0 mL) and the reaction mixture was stirred at room temperature. After 12 h, the reaction was concentrated and purified by standard methods to provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.820 mmol) as a brown solid. MS (ESI) m / z 610.3 [M+1] + .

[0352] 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-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide. To a solution of 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.100 g, 0.160 mmol) in pyridine (1 mL) was added 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (0.053 g, 0.180 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.063 g, 0.330 mmol) and the reaction was stirred at 50° C. After 12 h, the reaction was concentrated, taken up in DMSO, and 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-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide hydrochloride (0.051 g, 0.058 mmol, 35% yield) as a white solid. MS (ESI) m / z 851.5 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δ 11.08-10.91(m,1H),10.62(s,1H),10.13-9.21(m,1H),8.36-8.34(d,J=8.4Hz,1H),8.21-8.20(d,J=1.6 Hz,1H),7.99-7.97(m,1H),7.62-7.59(m,1H),7.26-7.23(m,1H),7.16-7.11(m,1H),4.41-4.36(m,2H),4 .11(s,3H),3.92-3.85(m,3H),3.71(m,1H),3.63-3.47(m,4H),2.79-2.67(m,4H),2.20-2.07(m,2H),1.8 4-1.82(m,2H),1.72-1.66(m,3H),1.57(m,6H),1.44-1.36(m,6H),1.29-1.24(m,4H),1.14-1.12(m,2H).

[0353] Example 33: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide [ka] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (1.400 g, 6.110 mmol) and (trans)-N,N-dibenzyl-4-(2-bromoethoxy)cyclohexanamine (3.680 g, 9.157 mmol) in xylene (30 mL) was added tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol), and the reaction was stirred at room temperature. After 12 h, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The r...

Claims

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

2. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein is methyl.

3. a is 1 and R ２ and R ３ and R are both H, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

4. Each R ４ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein is substituted or unsubstituted methyl.

5. 5. The compound of any one of claims 1 to 4, wherein m is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

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

7. L is -O(CH ２ ) (CH ２ ) -, -O(CH ２ ) (CH ２ ) O—, or —(CH ２ ) (CH ２ ) (CH ２ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein:

8. R Ｃ But CF ３ , Cl, or SF ５ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein:

9. R ５ and R ６ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein is methyl.

10. Formula II 【Transformation 3】 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, having the formula:

11. A compound selected from compounds 1 to 36 set forth in Table 1 below, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18

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

13. 12. A therapeutic agent for an androgen receptor-mediated disease, comprising the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

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

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

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