Cereblon binding compounds, compositions thereof, and methods of use thereof

Abstract

Provided herein are piperidinedione compounds having the following structure: (I), wherein R 1 、R 2 、R 3 、R 4 , L, V, X, A, A', a and m are as defined herein; compositions comprising an effective amount of a piperidinedione compound; and methods for treating or preventing androgen receptor-mediated diseases. #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 043,650, filed June 24, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] Provided herein are compounds, compositions comprising an effective amount 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 these compounds and compositions for use in these methods. Background Art

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

[0005] The androgen receptor is usually located in the cytoplasm and binds to molecular chaperones such as HSP90 (Brinkmann AO et al., J Steroid Biochem Mol Biol [Journal of Steroid Biochemistry and Molecular Biology], 1999, 69: 307-13). After binding to dihydrotestosterone (DHT), the androgen receptor changes its conformation and translocates to the nucleus, where it binds to the androgen response element (ARE) and drives the transcription of typical targets such as KLK3 (also known as prostate-specific androgen (PSA)), TMPRSS2, and KLK2 (Tran C et al., Science [Science], 2009, 324: 787-90; Murtha P et al., Biochemistry [Biochemistry] (Mosc.), 1993, 32: 6459-64).

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

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

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

[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. Summary of the Invention

[0010] Provided herein are compounds having the following Formula I:

[0011]

[0012] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein R 1 、R 2 、R 3 、R 4 , L, V, X, a and m are as defined herein.

[0013] The compound of Formula I or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof can be used to treat or prevent androgen receptor-mediated diseases in a subject.

[0014] In one aspect, provided herein are compounds as described in the disclosure (eg, such as in Table 1).

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

[0016] In one aspect, provided herein are methods for treating or preventing androgen receptor-mediated diseases in a subject, 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 are methods for treating or preventing androgen receptor-mediated diseases in a subject, 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 are compounds for use in methods of treating androgen receptor-mediated diseases. In another aspect, provided herein are compounds for use in methods of treating androgen receptor-mediated diseases.

[0017] In another aspect, provided herein are methods for preparing the compounds as described herein. In another aspect, provided herein are methods for preparing the compounds as described herein.

[0018] Embodiments of the present invention may be more fully understood by referring to the detailed description and examples, which are intended to illustrate non-limiting embodiments. DETAILED DESCRIPTION

[0019] definition

[0020] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the stated features or components mentioned, but not excluding the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include instances encompassed by the term "consisting of." Therefore, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

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

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

[0023] "Alkyl" groups are saturated, partially saturated or unsaturated straight or branched non-cyclic hydrocarbons 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 certain 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; and saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. In certain 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 containing one or more carbon-carbon double bonds. An alkynyl group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3), etc. Alkyl groups can be substituted or unsubstituted. When alkyl groups described herein are referred to as "substituted," they may be substituted with any one or more substituents such as those found in the exemplary compounds and examples 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, cycloalkylalkyloxy, alkyloxyalkyloxy; alkylamino, alkylamino, heterocyclylalkylamino, heteroarylalkylamino, heterocyclylalkylalkylamino; imino; imino; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; arylalkyloxyamino; hydrazine; hydrazide; hydrazono; azido; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxyl; ester; carbamate; acylamino; cyano; isocyanato; isothiocyanato; cyanato; thiocyano; or -B(OH)2.In certain embodiments, when alkyl groups described herein are referred to as "substituted," they 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 (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2, or O(alkyl)aminocarbonyl.

[0024] " cycloalkyl " group is the saturation or partially saturated cyclic alkyl group of 3 to 10 carbon atoms, and it has single ring or multiple condensed rings or bridged rings that can be optionally substituted.In certain embodiments, cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number range of ring carbon atoms is 3 to 5,3 to 6 or 3 to 7.In certain embodiments, cycloalkyl group is a saturated cycloalkyl group.This type of saturated cycloalkyl group includes for example monocyclic structure such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl etc., or polycyclic structure or bridged ring structure such as 1-bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, adamantyl etc. In other embodiments, cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, etc. The cycloalkyl group may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol, etc.

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

[0026] A "heteroaryl" group is an aromatic ring system having one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remainder of the ring atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms in the ring portion of the group, and in other embodiments, contains 6 to 9 or even 6 to 10 atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, benzothienyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-one or isoindolin-1-one), azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazole The heteroaryl groups may be substituted or unsubstituted.

[0027] "Heterocyclyl" is an aromatic cycloalkyl (also referred to as heteroaryl) or non-aromatic cycloalkyl, wherein one to four of the ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In certain embodiments, the heterocyclyl group includes 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. The heterocyclyl group can also be combined with other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocycloalkyl group can be substituted or unsubstituted. The heterocyclyl group encompasses unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-diketo) groups. The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidine.Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, dioxolyl, furanyl, thienyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, linyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodisulfinyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, indolyl (e.g., indolyl-2-one or isoindolyl-1-one), dihydroindolyl, isoindolyl, isoindolyl, azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, indolizinyl, benzotriazolyl ( For example, 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazolyl-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzooxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), imidazopyridinyl (e.g., azabenzimidazolyl or 1H

[00145] Examples of the present invention include 1,2-dihydro-2,4-dihydro-1,4-dihydro-2,4-dihydro-1,4-dihydro-2,4-dihydro-3 ... Representative non-aromatic heterocyclyl groups do not include fused ring species containing a fused aromatic group.Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-one), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono- or polysubstituted, such as, but not limited to, pyridyl groups or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with a variety of substituents, such as those listed below.

[0028] As used herein and unless otherwise indicated, a "cycloalkylalkyl" group is a group having the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted at both the alkyl, cycloalkyl, or 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, etc.

[0029] As used herein and unless otherwise indicated, an "aralkyl" group is a group having the formula: -alkyl-aryl, wherein the alkyl and aryl groups are defined above. A substituted aralkyl group may 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 an aryl group is fused to a cycloalkyl group, such as indan-4-ylethyl.

[0030] As used herein and unless otherwise indicated, a "heterocyclylalkyl" group is a group having the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. A "heteroarylalkyl" group is a group having the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above. A "heterocyclylalkylalkyl" group is a group having the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. A substituted heterocyclylalkyl group can be substituted at both the alkyl, heterocyclyl, or alkyl and heterocyclyl moieties 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.

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

[0032] A "hydroxyalkyl" group is an alkyl group as described above substituted with one or more hydroxy groups.

[0033] An "alkoxy" group is an -O-(alkyl) group, wherein alkyl is as defined above.

[0034] An "alkoxyalkyl" group is a -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0035] An "amino" group is a group having the formula: -NH2, -NH(R # ), or -N(R # )2, where each R # is independently an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) group as defined above, each of which is independently substituted or unsubstituted.

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

[0037] A "carboxy" group is a group having the formula: -C(O)OH.

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

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

[0040] In one embodiment, the "amido" group is an "aminocarbonyl" group, which is a group having the formula: -C(O)-NH2, -C(O)-NH(R # )、-C(O)-N(R # )2, where each R # are independently defined above.

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

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

[0043] A "urea" group is a group having 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)NH2, wherein each alkyl group and R # are independently as defined above.

[0044] When groups described herein (other than alkyl groups) are referred to as "substituted," they may be substituted with any one or more suitable substituents. Illustrative examples of substituents are those found in the exemplary compounds and examples disclosed herein, as well as halogen (chlorine, iodine, bromine, or fluorine); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; mercapto; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be Examples of the present invention include monocyclic or fused or non-fused polycyclic rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or heterocyclic rings, which may be monocyclic or fused or non-fused polycyclic rings (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl, or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0045] As used herein, the term "pharmaceutically acceptable salt(s)" 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, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts prepared from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acid includes but is not limited to inorganic acid and organic acid such as acetic acid, alginic acid, anthranilic acid, benzylsulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid and p-methyl benzenesulfonic acid. Special non-toxic acid comprises hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid and methanesulfonic acid. Therefore the example of special salt comprises hydrochloride, formate and mesylate. Others are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton PA (1995).

[0046] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of a compound as provided herein that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound with one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound with two chiral centers will be substantially free of other diastereomers of the compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. These compounds may have chiral centers and may exist as racemates, single enantiomers or diastereomers, and mixtures thereof. The embodiments disclosed herein include all such isomeric forms, including mixtures thereof.

[0047] The embodiments disclosed herein encompass the use of stereoisomerically pure forms of such compounds as well as the use of mixtures of these forms. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.See, e.g., Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation of Enantiomers: Synthetic Chemistry, 1996; and Eliel, EL, Stereochemistry of Carbon Compounds. Methods [Enantiomer Separation: Synthetic Methods] (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods [Enantiomer Separation: Fundamentals and Practical Methods] (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach [Chiral Separation Techniques: A Practical Approach] (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products [Chiral Separation Methods for Pharmaceutical and Biotechnological Products] (John Wiley & Sons, 2011).

[0048] It should also be noted that these compounds can include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, these compounds are separated into E or Z isomers. In other embodiments, these compounds are mixtures of E and Z isomers.

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

[0050]

[0051] As readily understood by those skilled in the art, various functional groups and other structures may exhibit tautomerism and all tautomers of compounds having Formula I are within the scope of the present invention.

[0052] It should also be noted that the compounds provided herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be treated with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 C) can be radiolabeled, or deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15( 15 N) isotopically enriched. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of the atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents such as cancer therapeutics, research reagents such as binding assay reagents, and diagnostic agents such as in vivo imaging agents. All isotopic variants of the compounds described herein, whether or not radioactive, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds are provided, for example, isotopologues are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, "deuterated" means a compound in which at least one hydrogen (H) is replaced by deuterium (by D or 2 H indicated), i.e., the compound is enriched in deuterium in at least one position.

[0053] It is understood that, independently of stereoisomer or isotopic composition, each compound mentioned herein can be provided in the form of any pharmaceutically acceptable salt discussed herein. Equally, it is understood that the isotopic composition can vary independently of the stereoisomer composition of each compound mentioned herein. Further, the isotopic composition, while limited to the elements present in each compound or its salt, can also vary independently of the choice of pharmaceutically acceptable salt of each compound.

[0054] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure shall prevail.

[0055] As used herein, "treating" refers to the complete or partial alleviation of a disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition, or the slowing down or cessation of further development or worsening of these symptoms, or the alleviation or elimination of one or more causes of the disorder, disease or condition itself. In one embodiment, the disorder is an androgen receptor-mediated disease as described herein, or a symptom of the disease.

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

[0057] The term "effective amount" with respect to a compound means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0058] As used herein, the terms "subject" and "patient" include animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment, mammals, and in another embodiment, humans. In one embodiment, the subject is a human suffering from an androgen receptor-mediated disease or its symptoms or a human at risk of suffering from an androgen receptor-mediated disease or its symptoms.

[0059] As used herein, the term "androgen receptor" or "AR" or "NR3C4" refers to a nuclear hormone receptor activated by binding to androgens (including testosterone or dihydrotestosterone). The term "androgen receptor" can refer to the nucleotide sequence or protein sequence of a human androgen receptor (e.g., Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeqNP_000035).

[0060] As used herein, the term "AR-full-length" (AR-FL) refers to an AR protein that contains all four functional domains, including the N-terminal transcriptional activation domain (NTD, exon 1), the DNA binding domain (DBD, exons 2-3), the hinge domain (exon 4), and the C-terminal ligand binding domain (LBD, exons 4-8).

[0061] The term "castration-resistant prostate cancer" (CRPC) refers to advanced prostate cancer that worsens or progresses while the patient is maintained on androgen deprivation therapy or other therapies for reducing testosterone, or is considered hormone-refractory, hormone-naive, non-androgen-dependent, or resistant to chemical or surgical castration. Castration-resistant prostate cancer (CRPC) is advanced prostate cancer that has progressed despite ongoing ADT and / or surgical castration. Castration-resistant prostate cancer is defined as prostate cancer that has progressed despite prior surgical castration, continued treatment with gonadotropin-releasing hormone (e.g., leuprorelin) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethimide), chemotherapeutics (e.g., docetaxel, paclitaxel, cabazitaxel, doxorubicin, mitoxantrone, estradiol mustard, cyclophosphamide), kinase inhibitors (imatinib), and / or chemotherapeutics. or gefitinib Cabozantinib ( Also known as XL184)) or other prostate cancer therapies (e.g., vaccines (sipuleucel-T GVAX, etc.), herbal inhibitors (PC-SPES), and lytic enzyme inhibitors (abiraterone)), which still continue to progress or worsen or adversely affect the patient's health, as evidenced by elevated or higher serum prostate-specific antigen (PSA) levels, metastasis, bone metastasis, pain, lymph node involvement, increase in volume or serum markers representing tumor growth, worsening of prognostic diagnostic markers, or worsening of the patient's condition.

[0062] Compound

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

[0064]

[0065] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

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

[0067] A is CH2 or C=O;

[0068] A' is NH or O;

[0069] a is 1 or 2;

[0070] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 and the carbon to which they are attached to form substituted or unsubstituted C 3-6 Cycloalkyl;

[0071] m is 0-8;

[0072] 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, form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4-7 membered heterocyclic group;

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

[0074] X is N or CR X ;

[0075] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl);

[0076] V is

[0077]

[0078] in

[0079] B is N, CH or CR B ;

[0080] Each R B independently selected from halogen, and substituted or unsubstituted C 1-6 alkyl;

[0081] R C is halogen, CF3 or SF5;

[0082] R 5 and R 6 It is C1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which they are attached, they form a substituted or unsubstituted C 3-6 cycloalkyl, or 3-6 membered heterocyclic group; and

[0083] b is 0-2.

[0084] In certain embodiments, provided herein are compounds having Formula I

[0085]

[0086] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0087] R 1 It is C 1-3 alkyl;

[0088] A is CH2 or C=O;

[0089] A' is NH or O;

[0090] a is 1 or 2;

[0091] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 and the carbon to which they are attached to form substituted or unsubstituted C 3-6 Cycloalkyl;

[0092] m is 0-8;

[0093] 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, form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4-7 membered heterocyclic group;

[0094] L is substituted or unsubstituted -O(C 1-6 Alkyl)-, -(C 1-6 alkyl)O- or -(C 1-9 alkyl)-;

[0095] X is N or CR X ;

[0096] R X is hydrogen, halogen, -O(C1-6 alkyl) or -(C 1-9 alkyl);

[0097] V is

[0098]

[0099] in

[0100] B is N, CH or CR B ;

[0101] Each R B independently selected from halogen, and substituted or unsubstituted C 1-6 alkyl;

[0102] R C is halogen, CF3 or SF5;

[0103] R 5 and R 6 It is C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which they are attached, they form a substituted or unsubstituted C 3-6 cycloalkyl, or 3-6 membered heterocyclic group; and

[0104] b is 0-2.

[0105] In some embodiments of compounds of Formula I, R 1 In some embodiments of compounds of Formula I, a is 1, and R 2 and R 3 Both are H. In some embodiments of compounds of Formula I, a is 2, and R 2 and R 3 Both are H. In some embodiments of compounds of Formula I, each R 4 is substituted or unsubstituted methyl. In some embodiments of compounds of Formula I, each R 4 Independently selected from methyl and CF3.

[0106] In some embodiments of compounds having formula I, A is C═O. In some embodiments of compounds having formula I, A is CH 2 .

[0107] In some embodiments of the compound of formula I, A' is NH. In some embodiments of the compound of formula I, A' or O.

[0108] In some embodiments of compounds of formula I, m is 0, 1, 2, 3, or 4. In some embodiments of compounds of formula I, m is 1 or 2.

[0109] In some embodiments of compounds of formula I, X is N. In some embodiments of compounds 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 compounds of Formula I, X is CH.

[0110] In some embodiments of compounds of Formula I, L is substituted or unsubstituted -O(CH2) p -、-(C 1-6 Alkyl)O-, -O(C 1-6 alkyl)O- or -(CH2) p -, and p is 1-4.

[0111] In some embodiments of compounds of Formula I, L is substituted or unsubstituted -O(CH2) p -, and p is 2 or 3.

[0112] In some embodiments of compounds of Formula I, L is substituted or unsubstituted -O(CH2) p O-, and p is 2 or 3.

[0113] In some embodiments of the compound of Formula I, L is substituted or unsubstituted -(CH2) p -, and p is 3 or 4.

[0114] In some embodiments of compounds having Formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -O(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0115] In some embodiments of compounds of Formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, or -(CH2)(CH2)(CH2)(CH2)-. In some embodiments of compounds of Formula I, L is -O(CH2)(CH2)-, -O(CH2)(CH2)O-, or -(CH2)(CH2)(CH2)-. In some embodiments of compounds of Formula I, L is -O(CH2)(CH2)- or -(CH2)(CH2)(CH2)-.

[0116] In some embodiments of compounds of formula I, B is CH. In some embodiments of compounds of formula I, B is N.

[0117] In some embodiments of compounds of Formula I, b is 0. In some embodiments of compounds of Formula I, R C is CF3, Cl or SF5. In some embodiments of the compound of Formula I, R C is CF3. In some embodiments of compounds of Formula I, R 5 and R 6 It's methyl.

[0118] In some embodiments of compounds of Formula I, the compound is

[0119]

[0120] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0121] In some embodiments of compounds of Formula I, the compound is

[0122]

[0123] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0124] R 1 It is a methyl group;

[0125] A is CH2 or C=O;

[0126] Each R 4m are independently hydrogen or substituted or unsubstituted methyl, wherein these substituents, when present, are selected from 1 to 5 halo;

[0127] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0128] V is

[0129]

[0130] B is N or CH;

[0131] R C is halogen, CF3 or SF5; and

[0132] R 5 and R 6 It is C 1-3alkyl.

[0133] In some embodiments of compounds of Formula I, the compound is

[0134]

[0135] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0136] R 1 It is a methyl group;

[0137] A is CH2 or C=O;

[0138] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0139] V is

[0140]

[0141] B is N or CH;

[0142] R C is halogen, CF3 or SF5; and

[0143] R 5 and R 6 It is C 1-3 alkyl.

[0144] In some embodiments of compounds of Formula I, the compound is

[0145]

[0146] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0147] R 1 It is a methyl group;

[0148] A is CH2 or C=O;

[0149] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0150] V is

[0151]

[0152] B is N or CH;

[0153] R C is halogen, CF3 or SF5; and

[0154] R 5 and R 6 It is C 1-3 alkyl.

[0155] In some embodiments of compounds of Formula I, the compound is

[0156]

[0157] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0158] R 1 It is a methyl group;

[0159] A' is NH or O;

[0160] a is 1 or 2;

[0161] Each R 4m are independently hydrogen or substituted or unsubstituted methyl, wherein these substituents, when present, are selected from 1 to 5 halo;

[0162] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0163] V is

[0164]

[0165] B is N or CH;

[0166] R C is halogen, CF3 or SF5; and

[0167] R 5 and R 6 It is C 1-3 alkyl.

[0168] In some embodiments of compounds of Formula I, the compound is

[0169]

[0170] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0171] R 1 It is a methyl group;

[0172] A' is NH or O;

[0173] a is 1 or 2;

[0174] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0175] V is

[0176]

[0177] B is N or CH;

[0178] R C is halogen, CF3 or SF5; and

[0179] R 5 and R 6 It is C 1-3 alkyl.

[0180] In some embodiments of compounds of Formula I, the compound is

[0181]

[0182] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0183] R 1 It is a methyl group;

[0184] A is CH2 or C=O;

[0185] a is 1 or 2;

[0186] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0187] V is

[0188]

[0189] B is N or CH;

[0190] R C is halogen, CF3 or SF5; and

[0191] R 5 and R 6 It is C 1-3 alkyl.

[0192] 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 CH 2 .

[0193] In certain embodiments of compounds having formula VI, VII, and VIII, A' is O. In certain embodiments of compounds having formula VI, VII, and VIII, A' is NH.

[0194] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, and VIII, R 1 is methyl; X is N or CR X , R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl); L is substituted or unsubstituted -O(CH2) p -、-O(CH2) p O- or -(CH2) p -, p is 1-4; 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 It's methyl.

[0195] In some embodiments of compounds of Formula I, II, III, IV, V, VI, VII, and VIII, R 1 is methyl; X is N or CR X , R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl); L is substituted or unsubstituted -O(CH2) p -or-(CH2) p -, p is 1-4; B is CH or N; b is 0; R C is CF3, Cl or SF5; R C is CF3; and R 5 and R 6 It's methyl.

[0196] 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)-.

[0197] 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)-, or -(CH2)(CH2)(CH2)(CH2)-.

[0198] Additional embodiments provided herein include any combination of one or more of the specific embodiments described above.

[0199] In some embodiments of the compound having Formula I, the compound is a compound from Table 1.

[0200] The compounds described in Table 1 were tested in the AR-mediated assays described herein and found to be active. In one embodiment, a compound described herein at a concentration of 1 μM resulted in degradation of AR protein by at least about 50% or more.

[0201] Preparation method of piperidinedione compound

[0202] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or the methods provided herein. For example, but not limited to, compounds 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 and can be prepared as outlined in the schemes shown below and in the examples described herein. It should be noted that those skilled in the art will know how to modify the procedures described in the illustrative schemes and examples to obtain the desired products.

[0203]

[0204] As shown in Scheme 1, a compound of formula (I) wherein X is N or CR X , 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 by reacting a piperidine derivative a with an ester intermediate b (wherein LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperature (e.g., between about 40°C and about 100°C) to provide intermediate c. In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to facilitate this transformation. Removal of the ester protecting group from intermediate c (e.g., when alk = Me, Et, or other alkyl, by treatment with a hydroxide base in a solvent such as LiOH in THF and water, or when alk = tert-butyl, by treatment with an acid in a solvent such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane) provides intermediate d. Intermediate d is coupled with piperidinedione intermediate e in the presence of a coupling agent such as HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt, and a base such as 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 70° C. to provide compounds of formula (I) wherein X is N or CR X , L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 alkyl)-, A is CO, and A' is NH). Alternatively, intermediate c (wherein X is N and L is -O(C 1-3 alkyl)- or -(C 1-4 (alkyl)-) can be prepared starting from the reaction of a derivative VL-LG (LG is a suitable leaving group such as Cl, Br, I, triflate or alkylsulfonate) with a suitably derivatized piperidinyl ester derivative f (e.g., wherein alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperature (e.g., between about 40°C and about 80°C) to provide an intermediate c. This intermediate can be further reacted to provide a compound of formula (I) wherein X is N and L is -O(C 1-3 alkyl)- or -(C 1-4 alkyl)-, A is CO, and A' is NH).

[0205]

[0206] Compounds of formula (I) wherein X is N and L is -O(C 1-3alkyl)- or -(C 1-4 Alkyl)-) can also be prepared by reacting the derivative VL-LG (LG is a suitable leaving group such as Cl, Br, I, triflate or alkylsulfonate) with a suitably derivatized intermediate g in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperature (e.g., between about 40°C and about 100°C) according to the alternative sequence shown in Scheme 2. In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to facilitate this transformation. Alternatively, compounds of formula (I) wherein X is N or CR X and L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 alkyl)-, A is CO, and A' is NH) can be prepared starting from reacting compound e with an appropriately functionalized carbonyl intermediate h (wherein LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base in a solvent such as N,N-diisopropylethylamine in DCM, or triethylamine in pyridine at a temperature of 0°C to about 60°C to provide intermediate i. Reacting i (wherein LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) with an amine intermediate a in the presence of a base in a solvent such as N,N-diisopropylethylamine in DMF, or K2CO3 in acetonitrile at an elevated temperature (e.g., between about 40°C and about 80°C) provides compounds of formula (I) (wherein X is N or CR X and L is -O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 alkyl)-, A is CO, and A' is NH).

[0207]

[0208] Intermediates such as amine g (wherein 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. It begins by reacting an appropriately functionalized piperazine j with an ester intermediate b (wherein LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate, and alk is an alkyl group such as Me, Et, Bn, or tert-Bu) in the presence of a base in a solvent such as N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile at elevated temperatures (e.g., between about 40°C and about 100°C) to provide intermediate k. In some cases, an iodide salt such as sodium iodide or potassium iodide is used to facilitate this transformation. Removal of the ester protecting group from intermediate k (e.g., when alk = Me, Et, or other alkyl, by treatment with a hydroxide base in a solvent such as LiOH in THF and water, or when alk = tert-butyl, by treatment with an acid in a solvent such as trifluoroacetic acid in dichloromethane or hydrochloric acid in 1,4-dioxane) provides intermediate 1. Intermediate 1 is coupled with piperidinedione intermediate e in the presence of a coupling agent such as HATU, HBTU, or EDC or TCFH, optionally in combination with HOBt, and a base such as N,N-diisopropylethylamine, triethylamine, or N-methylimidazole in a solvent such as DCM, DMF, NMP, or mixtures thereof at temperatures between 0° C. and 70° C. to provide amine intermediate g, which can be further reacted to provide compounds of formula (I) wherein L is —O(C 1-3 Alkyl)-, -(C 1-3 alkyl)O-, or -(C 1-4 alkyl)-, A is CO, and A' is NH). Intermediates such as amine f can be prepared by removing the N-protecting group P from intermediate k. N (For example, when P N When Boc is obtained, the reaction is carried out by treating with an acid in a solvent (eg, HCl in dioxane or EtOAc) at room temperature, or with TFA in DCM at room temperature, or when P is obtained by treating with an acid in a solvent (eg, HCl in dioxane or EtOAc) at room temperature, or with TFA in DCM at room temperature. N When it is Bn or Cbz, it is prepared by hydrogenation using a metal catalyst in a solvent (eg palladium on carbon in methanol).

[0209]

[0210] Intermediates such as a (wherein X is N and L is -O(C 1-3 alkyl)- or -(C 1-4 Alkyl)-) can be prepared according to Scheme 4. VL-LG (wherein L is -O(C 1-3 alkyl)- or -(C 1-4alkyl)- and LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate) is treated with an amine n in the presence of a base in a solvent (e.g., N,N-diisopropylethylamine in DMF or K2CO3 in acetonitrile) at elevated temperature (e.g., between about 40°C and about 100°C) to provide intermediate o. In some cases, an iodide salt (e.g., sodium iodide or potassium iodide) is used to promote this transformation. Removal of the N-protecting group P from intermediate o N (For example, when P N When Boc is obtained, the reaction is carried out by treating with an acid in a solvent (eg, HCl in dioxane or EtOAc) at room temperature, or with TFA in DCM at room temperature, or when P is obtained by treating with an acid in a solvent (eg, HCl in dioxane or EtOAc) at room temperature, or with TFA in DCM at room temperature. N When X is Bn or Cbz, hydrogenation with a metal catalyst in a solvent (e.g., palladium on carbon in methanol) provides intermediate a (wherein X is N and L is -O(C 1-3 alkyl)- or -(C 1-4 alkyl)-).

[0211]

[0212] Intermediates such as VLR Z (e.g. intermediate r) (where R Z is an alcohol, a protected alcohol, a leaving group or a heterocycle (e.g., a substituted piperidine or piperazine) can be prepared according to Scheme 5. Ester intermediate p (wherein alk is an alkyl group such as Me, Et, Bn, or tert-Bu) is treated with an appropriately derivatized 4-cyanophenylisothiocyanate or 5-isothiocyanatopicolinonitrile q in the presence of a base such as triethylamine in a solvent such as EtOAc at elevated temperature (e.g., between about 70° C. and about 90° C.) to provide intermediate r. Intermediates such as u (wherein LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate) and L is —O(C 1-3 alkyl)- or -(C 1-4 Alkyl)-) can be prepared from intermediate s (wherein P O is an alcohol protecting group such as THP, TBS, acetate or benzyl). O (For example, when P O When LG is THP, treatment with a catalytic acid in a solvent (e.g., HCl in dioxane) provides the alcohol intermediate t. Activation of the alcohol functionality in t as a leaving group (e.g., when LG is Br, by treatment of t with thionyl bromide in dichloromethane) provides the intermediate u (wherein LG is a leaving group (e.g., Cl, Br, I, triflate, or alkylsulfonate), and L is -O(C 1-3 alkyl)- or -(C 1-4alkyl)-), which can be further reacted to provide compounds of formula (I).

[0213]

[0214] Intermediate p (wherein L is -O(C 1-3 alkyl)- and R Z It is a protected alcohol OP O (e.g. THP ether or TBS ether)) For example aa can be prepared according to Scheme 6. From alcohol intermediate v (wherein P N is an amine protecting group such as Bn or Boc), and reacts it with an electrophile w (where LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate, and P O The reaction of the intermediate x with an oxygen protecting group such as THP or TBS in the presence of a base and, optionally, a catalyst, in a solvent such as KOH and tetrabutylammonium bromide in xylene at elevated temperature (e.g., between 70° C. and 130° C.) provides the intermediate x. N (For example, when P N When Bn is present, by hydrogenation with palladium on carbon in methanol, or when P N is Boc, by treatment with HCl in dioxane) provides the amine intermediate y. Reaction of the amine y with an ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base and, possibly, an iodide salt, in a solvent (such as potassium carbonate and potassium iodide in acetonitrile) at elevated temperature (e.g., between about 70° C. and 130° C.) provides intermediate aa, which can be further reacted to provide compounds of formula (I) (where L=-O(C 1-3 alkyl)-).

[0215]

[0216]

[0217] Intermediate p (wherein L is -(C 1-3 alkyl)- and R Z is an alcohol or protected alcohol (eg, THP ether or TBS ether) such as hh can be prepared according to Scheme 6. From the aldehyde intermediate bb (wherein P NStarting with an amine protecting group such as Bn or Boc), reaction with an olefinating agent in the presence of a base in a solvent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) at a temperature between 0°C and 60°C provides the olefin intermediate cc. Reduction of cc by hydrogenation in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at high pressure (e.g., between 10 and 100 psi) provides the intermediate dd. Reduction of the ester functionality is accomplished by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature between -78°C and 25°C, which provides the intermediate ee (where R Y is H). Alternatively, intermediate ee can be prepared by treating intermediate cc with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature between -78°C and 25°C to provide intermediate ff. Hydrogenating ff in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at high pressure (e.g., between 10 and 100 psi) provides intermediate ee. Removal of the protecting group P in ee is performed. N (For example, when P N When Bn is present, by hydrogenation with palladium on carbon in methanol, or when P N is Boc, by treatment with HCl in dioxane) provides the amine intermediate gg. Reaction of the amine gg with an ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base and, optionally, an iodide salt, in a solvent (such as potassium carbonate and potassium iodide in acetonitrile) at elevated temperature (e.g., between about 70° C. and 130° C.) provides the intermediate hh (where R Y is H or an alcohol protecting group (such as THP, TBS or Tr), which can be further reacted to provide a compound of formula (I) (wherein L-(C 1-3 alkyl)-).

[0218]

[0219] Intermediate p (wherein L is -(C 1-3 alkyl)O- and R Z is a heterocyclic or cycloalkyl group) such as mm can be prepared according to Scheme 8. From intermediate ii (P N’ is an amine protecting group such as Bn or Boc, and LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate) and reacts it with an alcohol jj (where P Nis an amine protecting group such as Bn or Boc), in the presence of a base and, optionally, a catalyst, in a solvent (such as KOH and tetrabutylammonium bromide in xylene) at elevated temperature (such as between 70° C. and 130° C.) to provide the ether intermediate kk. Removal of the protecting group P in kk N’ (For example, when P N’ When Bn is present, by hydrogenation with palladium on carbon in methanol, or when P N When Boc is used, treatment with HCl in dioxane provides the amine intermediate 11.

[0220] Reaction of amine ll with ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base and, optionally, an iodide salt, in a solvent such as potassium carbonate and potassium iodide in acetonitrile at elevated temperature (e.g., between about 70° C. and 130° C.) provides intermediate mm, which can be further reacted to provide compounds of formula (I) (where L is -(C 1-3 alkyl)O-).

[0221]

[0222] For certain intermediates p(where L is -O(C 1-3 alkyl)- and R Z is a protected heterocycle or cycloalkyl group) such as qq, an altered sequence as shown in Scheme 9 may be used. From alcohol v (wherein P N is an amine protecting group such as Bn or Boc), and reacts it with an electrophilic intermediate nn (wherein LG is a leaving group such as Cl, Br, I, triflate or alkylsulfonate, and P N’ is an amine protecting group such as Bn or Boc) in the presence of a base and, optionally, a catalyst, in a solvent (such as KOH and tetrabutylammonium bromide in xylene) at elevated temperature (such as between 70° C. and 130° C.) to provide the ether intermediate oo. Removal of the protecting group P in oo N (For example, when P N’ When Bn is present, by hydrogenation with palladium on carbon in methanol, or when P Nis Boc, by treatment with HCl in dioxane) provides the amine intermediate pp. Reaction of the amine pp with an ester z (where alk is an alkyl group such as Me, Et, Bn, or tert-Bu, and LG is a leaving group such as Cl, Br, I, triflate, or alkylsulfonate) in the presence of a base and, optionally, an iodide salt, in a solvent (such as potassium carbonate and potassium iodide in acetonitrile) at elevated temperature (e.g., between about 70° C. and 130° C.) provides intermediate qq, which can be further reacted to provide compounds of formula (I) (where L is —O(C 1-3 alkyl)-).

[0223]

[0224] Intermediate nn (where X is CR Z Some examples of ) (e.g., vv) were prepared according to Scheme 10. The ketone intermediate rr (wherein P N Olefination of an amine protecting group (e.g., Bn, Boc, or Cbz) with an olefination agent and a base in a solvent (e.g., ethyl 2-(diethoxyphosphoryl)acetate and sodium hydride in THF) at a temperature between 0°C and 60°C provides the olefin intermediate ss. Hydrogenation of ss in the presence of a catalyst in a solvent (e.g., palladium on carbon in methanol under a hydrogen atmosphere) at high pressure (e.g., between 10 and 100 psi) provides the intermediate tt. Reduction of the ester functionality in tt is accomplished by treatment with a reducing agent in a solvent (e.g., diisobutylaluminum hydride in DCM) at a temperature between -78°C and 25°C, providing the intermediate uu. Activation of the alcohol uu to a leaving group LG (e.g., by treatment with thionyl bromide in dichloromethane and DMF if LG is Br, or by treatment with trifluoromethanesulfonic anhydride in dichloromethane if LG is a triflate) provides intermediate vv, which can be further reacted to provide compounds of formula (I) (wherein L is -O(C 1-3 alkyl)- and X is CR X ).

[0225]

[0226] Piperidinyl dihydrouracil e can be prepared from indazole derivatives ww by treating them with acrylic acid in the presence of a Lewis acid catalyst in a solvent (e.g., alumina in dioxane) at elevated temperatures (e.g., between 60° C. and 150° C.) to provide intermediate xx. Methylation of the carboxylic acid in xx (e.g., by treatment with diazomethane in toluene and methanol, or catalytic sulfuric acid in methanol) provides the methyl ester yy, which, when reacted with an isocyanate (e.g., potassium or sodium isocyanate) in a solvent (e.g., acetic acid), gives 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 such as H2 in the presence of a catalyst such as Pd / C in a solvent such as EtOH or MeOH, or Fe and NHCl in a solvent such as EtOH and H2O) provides intermediate e, which can be further reacted to provide compounds of formula (I) (wherein A is CO and A' is NH).

[0227]

[0228] Amine intermediates g (wherein A is CH2 and A' is NH) can be prepared according to Scheme 12. Reduction of the nitro group in intermediate zz 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 Fe and NH4Cl in a solvent such as EtOH and H2O) provides intermediate bbb. bbb is reacted with an appropriately derivatized piperazine intermediate ccc (wherein P N is an amine protecting group (eg, Bn or Cbz), A is CH2 and R Y The coupling of the intermediate ddd to the intermediate eee can be accomplished by treatment with a strong acid (e.g., concentrated aqueous hydrochloric acid) followed by removal of P. N Protecting groups (e.g., when P N When Cbz is Cbz, hydrogenation in the presence of a catalyst in a solvent (eg, palladium on carbon in ethyl acetate) provides intermediate g, which can be further reacted to provide compounds of formula (I) wherein A is CH2 and A' is NH.

[0229]

[0230] Intermediate ccc (where P N is an amine protecting group (eg, Bn or Cbz), A is CH2 and R Yis a leaving group (such as Cl, Br, I, OTf or OMs), an alcohol, or a protected alcohol (such as OTBS, OPiv or OTHP)) can be prepared according to Scheme 13. Piperazine intermediate j (wherein P N is an amine protecting group (eg, Bn or Cbz)) and an intermediate fff (wherein LG is a leaving group (eg, Cl, Br, I, OTf, or OMs), 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)) in the presence of a base and, optionally, an iodide salt, in a solvent (e.g., N,N-diisopropylethylamine and sodium iodide in DMF) at elevated temperature (e.g., between 40° C. and about 100° C.) to provide the intermediate ccc (wherein P N is an amine protecting group (eg, Bn or Cbz), A is CH2 and R Y is a leaving group (such as Cl, Br, I, OTf or OMs), an alcohol, or a protected alcohol (such as OTBS, OPiv or OTHP). Intermediate ccc (wherein R Y is an alcohol or a protected alcohol) can be converted to the intermediate ccc (where R Y is a leaving group (e.g., Cl, Br, I, OTf, or OMs)) (e.g., ccc (where R Y is Br) can be achieved by treatment under brominating conditions (e.g., thionyl bromide in dichloromethane and DMF); or when R Y In the case of OTf, this is accomplished by treatment under triflation conditions (eg, by treatment with trifluoromethanesulfonic anhydride in dichloromethane).

[0231]

[0232] Intermediates such as ddd (where P N is an amine protecting group (eg, Boc, Cbz, or Bn), A is CH2, and A' is O) can be prepared according to Scheme 14. Indazole ggg is reacted with an electrophilic reagent ccc (wherein P N is an amine protecting group (eg, Boc, Cbz, or Bn), A is CH2, and R Yis a leaving group (e.g., Cl, Br, I, OTf, or OMs)) in the presence of a base and, optionally, an iodide salt in a solvent (e.g., potassium carbonate in MeCN; or N,N-diisopropylethylamine and sodium iodide in DMF) to give intermediate hhh. Coupling hhh with methyl acrylate in the presence of a catalyst in a solvent (e.g., aluminum oxide in methyl acrylate) provides intermediate iii, which can be reacted with an isocyanate (e.g., sodium or potassium isocyanate) in a solvent (e.g., potassium isocyanate in acetic acid) to give intermediate ddd (wherein A' is O).

[0233] How to use

[0234] In one embodiment, the compounds described herein have uses as drugs to treat, prevent or improve animal or human conditions. The compounds described herein have uses as drugs to treat, prevent or improve animal or human conditions. Therefore, many uses of the compounds are provided herein, including treating or preventing those diseases described below. In one embodiment, the methods provided herein include administering an effective amount of the compound to a subject in need.

[0235] The methods provided herein comprise administering to a subject in need thereof an effective amount of one or more compounds.

[0236] 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.

[0237] 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.

[0238] On the other hand, provided herein are compounds for use in treating or preventing AR-mediated diseases in a subject, comprising administering an effective amount of a compound as described herein to a subject in need thereof. In some embodiments, provided herein are compounds for use in treating AR-mediated diseases in a subject, comprising administering an effective amount of a compound as described herein to a subject in need thereof. In some embodiments, provided herein are compounds for use in preventing AR-mediated diseases in a subject, comprising administering an effective amount of a compound as described herein to a subject in need thereof.

[0239] 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 from Table 1.

[0240] In some embodiments, the AR-mediated disease is a disease mediated by wild-type AR. In other embodiments, the AR-mediated disease is the result of AR amplification.

[0241] In certain embodiments, the disease mediated by AR is prostate cancer. In some such embodiments, prostate cancer is castration-resistant prostate cancer (CRPC). In some such embodiments, prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In still another embodiment, prostate cancer is non-metastatic CRPC (nmCRPC). In certain embodiments, prostate cancer is hormone-refractory. In certain embodiments, prostate cancer is resistant to treatment with AR antagonists. For example, 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.

[0242] Provided herein is a method for reducing AR levels, the method comprising administering an effective amount of a compound to a subject. Also provided herein is a compound for use in a method for reducing AR levels in vivo, in vitro or in vitro cells, the method comprising contacting the cell with an effective amount of a compound. In one embodiment, the cell is in the patient's body. In one embodiment, the cell is not in the patient's body. In one embodiment, provided herein is a method for reducing wild-type AR levels in a tumor, the method comprising administering a therapeutically effective amount of a compound to reduce wild-type AR levels in the tumor. In one embodiment, provided herein is a method for reducing AR-full length (AR-FL) levels in a tumor, the method comprising administering a therapeutically effective amount of a compound to reduce AR-full length (AR-FL) levels in a tumor. In some embodiments, compared to AR levels before compound administration, AR levels are reduced. In some embodiments, compared to AR levels before compound administration, AR levels are reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

[0243] Also provided herein are methods for regulating the activity of an AR protein in a patient in need thereof, comprising administering a certain amount of a compound to the patient. In some such embodiments, also provided herein are methods for reducing the activity of an AR protein in a patient in need thereof, comprising administering a certain amount of a compound to the patient. In some embodiments, AR protein activity is reduced compared to AR protein activity before compound administration. In some embodiments, AR protein activity is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to AR protein activity before compound administration.

[0244] In some embodiments of the methods described herein, the methods further comprise administering one or more second agents selected from AR antagonists (e.g., cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (e.g., finasteride and dutasteride), CYP17A1 inhibitors (e.g., abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (e.g., leuprolide and cetrorelix), and antigonadotropin drugs (e.g., megestrol acetate and medroxyprogesterone acetate).

[0245] In some embodiments, the compounds provided herein can be used in any of the above methods.

[0246] In some embodiments, the compounds provided herein can be used in any of the above methods.

[0247] Pharmaceutical compositions and routes of administration

[0248] The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional forms of formulations, such as capsules, microcapsules, tablets, granules, powders, dragees, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0249] The compound can be administered orally, topically or parenterally to a subject in the conventional form of a preparation, such as a capsule, microcapsule, tablet, granule, powder, lozenge, pill, suppository, injection, suspension, syrup, patch, cream, lotion, ointment, gel, spray, solution and emulsion. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or The composition may be a pharmaceutical composition comprising a pharmaceutical composition comprising a lubricant (e.g., calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), a flavoring (e.g., citric acid, menthol, glycine, or orange powder), a preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), a stabilizer (e.g., citric acid, sodium citrate, or acetic acid), a suspending agent (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), a dispersant (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and a base wax (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound in the pharmaceutical composition may be at a level that will exert the desired effect, for example, for oral and parenteral administration, a unit dose of about 0.005 mg / kg to about 10 mg / kg of subject body weight.

[0250] The dosage variation range of the compound applied to the subject is quite wide and can be subject to the judgment of the health care practitioner. Generally, the compound can be applied one to four times a day with a dosage of about 0.001mg / kg subject body weight to about 10mg / kg subject body weight, but the above dosage can be appropriately changed based on the age, body weight and medical condition of the subject and the type of application. In one embodiment, the dosage is about 0.001mg / kg subject body weight to about 5mg / kg subject body weight, about 0.01mg / kg subject body weight to about 5mg / kg subject body weight, about 0.05mg / kg subject body weight to about 1mg / kg subject body weight, about 0.1mg / kg subject body weight to about 0.75mg / kg subject body weight or about 0.25mg / kg subject body weight to about 0.5mg / kg subject body weight. In one embodiment, a dosage is given every day. In any given case, the amount of the compound applied will depend on factors such as the solubility of the active ingredient, the formulation used and the route of administration.

[0251] In another embodiment, provided herein are methods for treating or preventing a disease or disorder comprising administering to a subject in need thereof a compound at about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0252] In another embodiment, provided herein are unit dosage formulations comprising between about 0.1 mg and 500 mg, between about 1 mg and 250 mg, between about 1 mg and about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, or between about 1 mg and about 10 mg of the compound.

[0253] In specific embodiments, provided herein are unit dosage formulations containing about 0.1 mg or 100 mg of a compound.

[0254] In another embodiment, provided herein is a unit dose formulation comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of compound.

[0255] The compound can be administered once, twice, three times, four times or more daily. In certain embodiments, a dose of 100 mg or less is administered as a once daily dose and a dose greater than 100 mg is administered twice daily in an amount equal to half the total daily dose.

[0256] For convenience, the compound can be administered orally. In one embodiment, when administered orally, the compound is administered with a meal and water. In another embodiment, the compound is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0257] The compounds can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the health care practitioner and may depend in part on the site of the medical condition.

[0258] In one embodiment, provided herein are capsules containing a compound without additional carriers, excipients, or vehicles.

[0259] 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, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0260] The composition can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions. The composition can be formulated as a portable portion containing a daily dose or a daily dose in a dosage unit, which can be a single tablet or capsule or a liquid of portable volume. In one embodiment, the solution is prepared from a water-soluble salt (e.g., hydrochloride). Generally, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing the compound with a suitable carrier or diluent and filling an amount of the mixture in a capsule. Common carriers and diluents include but are not limited to inert powdery substances, such as various types of starch, powdered cellulose (especially crystallization and microcrystalline cellulose), sugar (e.g., fructose, mannitol and sucrose), cereal flour and similar edible powders.

[0261] Tablets can be prepared by direct compression, wet granulation or dry granulation. Its formulation is usually mixed with diluents, binders, lubricants and disintegrants and the compound. Typical diluents include, for example, different types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride) and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are the following substances, such as starch, gelatin and sugar (such as lactose, fructose, glucose etc.). Natural gums and synthetic gums are also very convenient, including gum arabic, alginate, methylcellulose, polyvinyl pyrrolidone etc. Polyethylene glycol, ethyl cellulose and wax can also be used as binders.

[0262] To prevent the tablet and punch from sticking in the die, lubricants may be necessary in tablet formulations. Lubricants can be selected from smooth solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when exposed to moisture, causing the tablet to disintegrate and release the compound. Tablet disintegrants include starch, clay, cellulose, algin, and gum. More specifically, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange gums, alginic acid, guar gum, citrus pulp, carboxymethyl cellulose, and sodium lauryl sulfate can be used. Tablets can be coated with sugars that act as flavorings and sealants, or with film-forming protective agents to modify the tablet's dissolution characteristics. These compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0263] When it is desired to administer the compound as a suppository, a typical base may be used. Cocoa butter is a traditional suppository base, which may be modified by the addition of waxes to slightly increase its melting point. Water-miscible suppository bases, particularly those containing polyethylene glycols of varying molecular weights, are widely used.

[0264] The effects of the compound can be delayed or prolonged through appropriate formulation. For example, slowly dissolving pellets of the compound can be prepared and incorporated into tablets or capsules, or as an implantable sustained-release device. This technology also includes preparing several pellets with different dissolution rates and filling a capsule with the pellet mixture. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations can be made into long-acting preparations by dissolving or suspending the compound in an oily or emulsifying vehicle, allowing it to slowly disperse in the serum.

[0265] Examples

[0266] The invention can be defined by reference to the following numbered illustrative examples.

[0267] 1. A compound having formula I

[0268]

[0269] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0270] R 1 It is C 1-3 alkyl;

[0271] A is CH2 or C=O;

[0272] A' is NH or O;

[0273] a is 1 or 2;

[0274] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 and the carbon to which they are attached to form substituted or unsubstituted C 3-6 Cycloalkyl;

[0275] m is 0-8;

[0276] 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, form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The groups, together with the non-adjacent carbon atoms to which they are attached, form a substituted or unsubstituted 4-7 membered heterocyclic group;

[0277] L is substituted or unsubstituted -O(C 1-6 Alkyl)-, -(C 1-6 Alkyl)O-, -O(C 1-6 alkyl)O- or -(C 1-9 alkyl)-;

[0278] X is N or CR X ;

[0279] R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl);

[0280] V is

[0281]

[0282] in

[0283] B is N, CH or CR B ;

[0284] Each R B independently selected from halogen, and substituted or unsubstituted C 1-6 alkyl;

[0285] R C is halogen, CF3 or SF5;

[0286] R 5 and R 6 It is C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which they are attached, they form a substituted or unsubstituted C 3-6 cycloalkyl, or 3-6 membered heterocyclic group; and

[0287] b is 0-2.

[0288] 2. The compound of embodiment 1, wherein R 1 It's methyl.

[0289] 3. The compound of embodiment 1 or 2, wherein a is 1, and R 2 and R 3 Both are H.

[0290] 4. The compound of any one of embodiments 1 to 3, wherein A is C═O.

[0291] 5. The compound of any one of embodiments 1 to 3, wherein A is CH2.

[0292] 6. The compound of any one of embodiments 1 to 5, wherein A' is NH.

[0293] 7. The compound of any one of embodiments 1 to 5, wherein A' or O.

[0294] 8. The compound of any one of embodiments 1 to 7, wherein each R 4 is a substituted or unsubstituted methyl group.

[0295] 9. The compound of any one of embodiments 1 to 8, wherein each R 4 Independently selected from methyl and CF3.

[0296] 10. The compound of any one of embodiments 1 to 9, wherein m is 0, 1, 2, 3, or 4.

[0297] 11. The compound of any one of embodiments 1 to 10, wherein m is 1 or 2.

[0298] 12. The compound of any one of embodiments 1 to 11, wherein X is N.

[0299] 13. A compound as described in any one of embodiments 1 to 11, wherein X is CR X ; and R X is hydrogen, halogen, -O(C 1-6 alkyl) or -(C 1-9 alkyl).

[0300] 14. A compound as described in any one of embodiments 1-13, wherein L is substituted or unsubstituted -O(CH2) p -、O(CH2) p O- or -(CH2) p -, and p is 1-4.

[0301] 15. A compound as described in any one of embodiments 1 to 13, wherein L is substituted or unsubstituted -O(CH2) p -, and p is 2 or 3.

[0302] 16. A compound as described in any one of embodiments 1 to 13, wherein L is substituted or unsubstituted -O(CH2) p O-, and p is 2 or 3.

[0303] 17. A compound as described in any one of embodiments 1 to 13, wherein L is substituted or unsubstituted -(CH2) p -, and p is 3 or 4.

[0304] 18. The compound of any one of embodiments 1 to 13, wherein L is -O(CH2)(CH2)-, -O(CH2)(CH2)O-, or -(CH2)(CH2)(CH2)-.

[0305] 19. The compound of any one of embodiments 1 to 18, wherein B is CH.

[0306] 20. The compound of any one of embodiments 1 to 19, wherein B is N.

[0307] 21. The compound of any one of embodiments 1 to 20, wherein b is 0.

[0308] 22. A compound as described in any one of embodiments 1 to 21, wherein R C It is CF3, Cl or SF5.

[0309] 23. A compound as described in any one of embodiments 1 to 22, wherein R C It's CF3.

[0310] 24. A compound as described in any one of embodiments 1 to 23, wherein R 5 and R6 It's methyl.

[0311] 25. The compound of embodiment 1, which has formula II,

[0312]

[0313] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof.

[0314] 26. The compound of embodiment 1, which has formula III,

[0315]

[0316] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0317] R 1 It is a methyl group;

[0318] A is CH2 or C=O;

[0319] Each R 4m are independently hydrogen or substituted or unsubstituted methyl, wherein these substituents, when present, are selected from 1 to 5 halo;

[0320] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0321] V is

[0322]

[0323] B is N or CH;

[0324] R C is halogen, CF3 or SF5; and

[0325] R 5 and R 6 It is C 1-3 alkyl.

[0326] 27. The compound of embodiment 1, which has formula IV,

[0327]

[0328] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0329] L is substituted or unsubstituted -O(C 1-3alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0330] R 1 It is a methyl group;

[0331] A is CH2 or C=O;

[0332] V is

[0333]

[0334] B is N or CH;

[0335] R C is halogen, CF3 or SF5; and

[0336] R 5 and R 6 It is C 1-3 alkyl.

[0337] 28. The compound of embodiment 1, which has formula V,

[0338]

[0339] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0340] R 1 It is a methyl group;

[0341] A is CH2 or C=O;

[0342] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0343] V is

[0344]

[0345] B is N or CH;

[0346] R C is halogen, CF3 or SF5; and

[0347] R 5 and R 6 It is C 1-3 alkyl.

[0348] 29. The compound of embodiment 1, which has formula VI,

[0349]

[0350] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0351] R 1 It is a methyl group;

[0352] A' is NH or O;

[0353] a is 1 or 2;

[0354] Each R 4m are independently hydrogen or substituted or unsubstituted methyl, wherein these substituents, when present, are selected from 1 to 5 halo;

[0355] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)- or -(C 1-4 alkyl)-;

[0356] V is

[0357]

[0358] B is N or CH;

[0359] R C is halogen, CF3 or SF5; and

[0360] R 5 and R 6 It is C 1-3 alkyl.

[0361] 30. The compound of embodiment 1, which has formula VII,

[0362]

[0363] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0364] R 1 It is a methyl group;

[0365] A' is NH or O;

[0366] a is 1 or 2;

[0367] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0368] V is

[0369]

[0370] B is N or CH;

[0371] R C is halogen, CF3 or SF5; and

[0372] R 5 and R 6 It is C 1-3 alkyl.

[0373] 31. The compound of embodiment 1, which has formula VIII,

[0374]

[0375] or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, wherein

[0376] A' is NH or O;

[0377] a is 1 or 2;

[0378] L is substituted or unsubstituted -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-;

[0379] R 1 It is a methyl group;

[0380] V is

[0381]

[0382] B is N or CH;

[0383] R C is halogen, CF3 or SF5; and

[0384] R 5 and R 6 It is C 1-3 alkyl.

[0385] 32. The compound of embodiment 1, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof.

[0386] 33. A pharmaceutical composition comprising an effective amount of the compound of any one of Examples 1 to 32, or a pharmaceutically acceptable salt, tautomer, isotopomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0387] 34. A method for treating an androgen receptor-mediated disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1 to 32.

[0388] 35. A method for treating an androgen receptor-mediated disease, comprising administering an effective amount of the pharmaceutical composition of embodiment 33 to a subject in need thereof.

[0389] 36. The method of embodiment 34 or 35, wherein the androgen-mediated disease is prostate cancer.

[0390] 37. The method of embodiment 36, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

[0391] Examples

[0392] The following examples are provided by way of illustration and not limitation. Compound nomenclature was performed using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures described in the illustrative examples to obtain the desired product.

[0393] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring the product with an acid solution (e.g., aqueous HCl) after chromatographic purification.

[0394] Abbreviations used:

[0395]

[0396]

[0397] The following examples are provided by way of illustration and not limitation. Compound nomenclature was performed using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures described in the illustrative examples to obtain the desired product.

[0398] Salts of the compounds described herein can be prepared by standard methods, such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring the product with an acid solution (e.g., aqueous HCl) after chromatographic purification.

[0399] Abbreviations used:

[0400]

[0401]

[0402] 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

[0403]

[0404] Trans-4-(dibenzylamino)cyclohexane-1-ol. To a mixture of trans-4-aminocyclohexane-1-ol (40 g, 347 mmol, 1.0 equivalent) and cesium carbonate (339 g, 1.04 mol, 3 equivalents) in acetonitrile (900 mL) was added benzyl bromide (119 g, 698 mmol, 2.01 equivalents) dropwise. The reaction solution was stirred at room temperature. After 48 h, the reaction mixture was filtered and concentrated. The resulting residue was diluted with DCM (300 mL), washed with water (100 mL x 3), dried over anhydrous sodium sulfate and concentrated. Trans-4-(dibenzylamino)cyclohexane-1-ol (77 g, 261 mmol, 75% yield) was provided as a light red solid. The crude product was used without further purification. MS (ESI) m / z 116.3 [M+1] + ; 1 H NMR400 MHz DMSO-d6δ7.27-7.34(m,8H),7.19-7.21(m,2H),4.42(d,J=4.8Hz,1H),3.55(s,4H),2.33 -2.36(m,1H),1.74-1.84(m,4H),1.40(dd,J=12.4Hz,2.0Hz,2H),0.98(d,J=13.2Hz,2H).

[0405] 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 solution was heated to 65° C. After 12 h, the reaction solution was poured into ice water (1.0 L) and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude material was purified by column chromatography (SiO , 2%-50% ethyl acetate in petroleum ether) to give trans-N, N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (60 g, 142 mmol, 70% yield) as a colorless oil. 1 H NMR400MHz CDCl3δ7.37-7.39(m,4H),.7.28-7.32(m,4H),7.22(m,2H),4.63-4.67(m,1H),3.57-3.89(m,9H),3.23-3.25(m, 1H),2.55(m,1H),2.08-2.11(m,2H),1.92-1.95(m,5H),1.58-1.64(m,6H),1.54-1.56(m,2H),1.20-1.39(m,2H).

[0406]

[0266] trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine. To a mixture of trans-N,N-dibenzyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (65 g, 153 mmol, 1.0 equiv) in methanol (500 mL) was added 10% palladium on carbon (6.5 g) under N. The suspension was degassed under vacuum and purged with hydrogen three times. The reaction solution was stirred at room temperature under a hydrogen atmosphere (15 psi). After 1 h, the reaction solution was filtered and the filtrate was concentrated to give trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (46 g) as an off-white oil. The crude material was used further without further purification. 1H NMR400MHz CDCl3δ7.34-7.36(m,1H),.4.63-4.65(m,1H),3.82-3.91(m,3H),3.52-3.66(m,5H),3.28(m,1H),2.70-2.71(m,1H) ,2.01-2.04(m,2H),1.85-1.89(m,3H),1.58-1.59(m,1H),1.45-1.56(m,8H),1.29-1.32(m,2H),1.11-1.14(m,2H).

[0407] Methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate. To a mixture of trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexan-1-amine (25 g, 103 mmol, 1.0 equiv) in acetonitrile (175 mL) was added methyl 2-bromo-2-methylpropanoate (37.2 g, 205 mmol, 26.6 mL, 2.0 equiv), potassium carbonate (28.4 g, 205 mmol, 2.0 equiv), and potassium iodide (1.71 g, 10.3 mmol, 0.1 equiv). The reaction solution was heated to 110° C. After 16 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The resulting crude material was purified by column chromatography (SiO , 0-50% ethyl acetate in petroleum ether) to afford 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)δ4.63(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).

[0408]

[0146] 4-(4,4-Dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of methyl 2-methyl-2-((trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)amino)propanoate (18.6 g, 54.2 mmol, 1.0 equiv) in ethyl acetate (130 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (24.7 g, 108 mmol, 2.0 equiv) and N,N-diisopropylethylamine (14.0 g, 108 mmol, 2.0 equiv). The reaction solution was heated to 90°C with stirring. After 12 h, the reaction solution was concentrated and the resulting crude material was purified by silica gel column chromatography (0-50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (25 g, 46.3 mmol, 86% yield) as a yellow oil.

[0409]

[0146] 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 solution was stirred at room temperature. After 1 h, the reaction solution was concentrated and purified by silica gel column chromatography (1%-20% THF in dichloromethane) to give 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (21 g, 46.1 mmol, 59% yield) as a shiny yellow oil. MS (ESI) m / z 456.4 [M+1] + ; 1H NMR(400MHz CDCl3)δ7.95(d,J=8.0Hz,1H),7.85(m,1H),7.72(dd,J=10.0Hz,1.6Hz,1H),3.73-3.77(m,4H),3.60-3.62(m,2H),3.3 7-3.39(m,1H),2.88-2.91(m,2H),2.21-2.24(m,2H),1.97(m,1H),1.83-1.88(m,3H),1.61(s,6H),1.33-1.41(m,2H).

[0410] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a mixture of 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (3.500 g, 7.72 mmol, 1.0 equiv) in dichloromethane (80 mL) was added N,N-dimethylformamide (8 mL) and thionyl bromide (3.201 g, 15.43 mmol, 2.0 equiv) at 0° C. After 12 h, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 x 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] + .

[0411] 1-Methyl-7-nitro-1H-indazol-3-amine. To a mixture of 2-fluoro-3-nitrobenzonitrile (19.50 g, 117.4 mmol, 1 eq) in N,N-dimethylacetamide (30 mL, 3.9 M) was added methylhydrazine (40.56 g, 352.2 mmol, 46.36 mL, 3 eq) and N,N-diisopropylethylamine (16.69 g, 129.13 mmol, 22.49 mL, 1.1 eq). The mixture was stirred at 20 ° C for 30 min. The reaction mixture was diluted with water (1000 mL) 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).

[0412] 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 eq) in 1,4-dioxane (300 mL, 0.52 M) was added aluminum oxide (48.07 g, 471.5 mmol, 3 eq) and acrylic acid (33.97 g, 471.5 mmol, 32.36 mL, 3 eq). 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] +

[0413] 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 solution was stirred at 25° C. for 8 hours. The reaction solution 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 + 0.225% formic acid in water). The product fractions were adjusted to pH=7 with saturated sodium bicarbonate and then extracted with ethyl acetate (3×80 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] + ; 1H NMR(400MHz, DMSO-d6)δ8.16(dd,J=0.8,7.6Hz,1H),8.10(dd,J=1.2,8.0Hz,1H),7.10(t,J=8.0H z,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).

[0414] 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 solution was stirred at 25° C. for 8 hours. The reaction solution 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) δ8.20 (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).

[0415] 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 4M hydrochloric acid (25 mL, 0.02 M) in 1,4-dioxane. The mixture was stirred at 25 ° C for 8 hours. The reaction solution 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] +.

[0416] 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 hydrogen at 15 psi. The mixture was stirred at 25 ° C for 8 hours. The reaction solution 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) δ10.50 (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).

[0417] Tert-Butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate. A solution of tert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate (5.g, 23.33 mmol, 1 eq), methyl bromoacetate (3.57 g, 23.33 mmol, 1 eq) and triethylamine (10.2 mL, 70 mmol, 3 eq) in THF (100 mL, 0.23 M) was stirred at 50°C. After 18 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The resulting crude material was purified by silica gel column chromatography (10%-100% ethyl acetate in hexanes) to give tert-butyl (3R,5S)-4-(2-methoxy-2-oxoethyl)-3,5-dimethylpiperazine-1-carboxylate (6.2 g, 21.6 mmol, 92% yield) as a yellow oil. MS (ESI) m / z 287.2 [M+1] + .

[0418] 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 eq) in THF (20 mL) was added lithium hydroxide (208.8 mg, 8.7 mmol, 1.1 eq) in water (5 mL), and the reaction solution was stirred at room temperature. After 18 h, the reaction solution was concentrated under vacuum 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 used without further purification. MS (ESI) m / z 273.2 [M+1] + .

[0419] 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 eq) and N-(chloro(dimethylamino)methylene)-N-methylmethanium hexafluorophosphate (0.45 g, 1.6 mmol, 2.2 eq) was added acetonitrile (2 mL) followed by 1-methylimidazole (0.18 mL, 2.2 mmol, 3 eq). The reaction solution was stirred at room temperature for 10 min. 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 solution was stirred at room temperature. After 16 h, the reaction solution was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was removed and washed with 100 mL of brine, dried over magnesium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (50 g column, 1%-10% methanol in dichloromethane) to give tert-butyl (3S,5R)-4-(2-((3-(2,4-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]+.

[0420]

[0266] 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) was added 2 ml of dichloromethane followed by 4 M hydrochloric acid in dioxane (1.35 mL, 5.41 mmol, 20 equiv) and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was concentrated and dried under vacuum to afford 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 used further without further purification. MS (ESI) m / z 414.0 [M+1]+.

[0421] 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

[0149] To the solution of 4-[ ... 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)δppm 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).

[0422] 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

[0423]

[0424] Tert-butyl (trans-4-formylcyclohexyl) carbamate. To a mixture of tert-butyl (trans-4-(hydroxymethyl)cyclohexyl) carbamate (240 g, 1.05 mol, 1 equiv) in acetonitrile (1.60 L) was added IBX (352 g, 1.26 mol, 1.2 equiv) at 15 ° C. The reaction was stirred at 65 ° C for 1 h. The two batches were combined for processing 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 product) as a white solid. The crude product was used directly in the next step without further purification. 1H NMR(400MHz CDCl3)δ9.62(s,1H),4.43(s,1H),4.41(s,1H),2.10-2.14(m,3H),2.01-2.05(m,2H),1.45(s,9H),1.38-1.41(m,2H),1.14-1.18(m,2H).

[0425] Ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate. To a mixture of sodium hydride (49.6 g, 1.24 mol, 60% purity, 1.2 equiv) in THF (900 mL) at 0°C was added ethyl 2-(diethoxyphosphoryl)acetate (255 g, 1.14 mol, 1.1 equiv) dropwise. The reaction was stirred at 0°C for 1 h. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (235 g, 1.03 mol, 1 equiv) in THF (500 mL) was added dropwise at 0°C. The reaction was stirred at 25°C for 2 h. The reaction solution was poured into ice water (3.0 L) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (800 mL, 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate and concentrated to give ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (560 g, crude) as a light yellow solid. This material was carried forward without further purification. 1 H NMR(400MHz CDCl3)δ6.88(dd,J=15.6Hz,6.8Hz 1H),5.75-5.79(m,1H),4.40(s,1H),4.12-4.23(m,3H),3.39(s,1H),2.04-2.08(m,3H), 1.81-1.85(m,2H),1.44(s,9H),1.33-1.35(m,1H),1.26-1.30(m,6H),1.10-1.16(m,3H).

[0426] Tert-Butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate. The reaction was set up as two reactions in parallel. To a solution of the compound ethyl (E)-3-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)acrylate (280 g, 942 mmol, 1 eq) in dichloromethane (1.12 L) was added diisobutylaluminum hydride (1 M, 1.88 L, 2 eq) at -78 °C under an argon atmosphere. The reaction was stirred at -78 °C for 1 h. The reaction was quenched with MeOH (280 mL) at -60 °C. The two reaction mixtures were combined and poured into saturated citric acid (1.0 kg citric acid in 4.0 L) at below 10 °C. The mixture was added 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 to 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 light yellow solid. 1 H NMR(400MHz CDCl3)δ5.58-5.60(m,2H),4.39(s,1H),4.06-4.07(m,2H),3.35(s,1H),1.80-2.00(m,3H),1.74-1.78(m,2H),1.42(s,9H),1.08-1.20(m,4H).

[0427] Tert-Butyl ((trans-4-(3-hydroxypropyl)cyclohexyl)carbamate. The reaction was run in parallel for four batches. A mixture of tert-butyl ((trans-4-((E)-3-hydroxyprop-1-en-1-yl)cyclohexyl)carbamate (105 g, 411 mmol, 1 equiv) and palladium on carbon (10.5 g, 10% purity) in MeOH (600 mL) was degassed and purged with H2 three times, and then the mixture was incubated at 25° C. under H2 (15 p The product of 1,2-dimethyl-1-thiazolinone (50mg, 11.8mmol) and 1,2-dimethyl-1-thiazolinone (50mg, 11.8mmol) was stirred for 12h under 40 ℃ of stirring. Four batches were merged for treatment and purification. The reaction solution was filtered and concentrated under reduced pressure. The crude material was passed through column chromatography (SiO , petroleum ether / ethyl acetate=20 / 1 to 0 / 1) purification. It was tert-butyl (trans-4-(3-hydroxypropyl) cyclohexyl) carbamate (82g, 19% yield) and tert-butyl (trans-4-(3-oxopropyl) cyclohexyl) carbamate (200g, 48% yield) as white solid. 1H NMR(400MHz CDCl3)δ4.38(s,1H),3.63(t,J=6.4Hz,2H),3.37(s,1H),1.98-2.01(m,2H),1.60- 1.79(m,2H),1.55-1.59(m,2H),1.44(s,9H),1.22-1.28(m,3H),0.95-1.05(m,4H).

[0428] 3- (trans-4-aminocyclohexyl) propan-1-ol hydrochloride. Two reactions were carried out in parallel. 4M hydrochloric acid in methanol (500mL) was added to a solution of tert-butyl (trans-4-(3-hydroxypropyl) cyclohexyl) carbamate (115g, 447mmol, 1 equivalent) in methanol (200mL). The reaction was stirred at 15°C for 6h. Two batches were combined for processing and purification. The reaction solution was filtered and concentrated to give 3- (trans-4-aminocyclohexyl) propan-1-ol hydrochloride (160g, 92% yield) as a light yellow solid. The material was used without further purification. 1H NMR(400MHz DMSO-d6)δ8.09(s,4H),4.62(s,2H),3.35(t,J=6.8Hz,2H),2.87(d,J=4.4Hz,1H),1.93(d,J=10.8Hz,2 H), 1.73 (d, J = 12.8Hz, 2H), 1.38-1.42 (m, 2H), 1.29-1.31 (m, 3H), 1.13-1.17 (m, 3H), 0.89-0.92 (m, 2H).

[0429] 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 eq) in acetonitrile (750 mL) was added potassium carbonate (428 g, 3.10 mol, 5 eq) and methyl 2-bromo-2-methylpropanoate (449 g, 2.48 mol, 4 eq). The mixture was stirred at 110 ° C for 12 h. The reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (5%-100% ethyl acetate in petroleum ether) to give methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (54 g, 210 mmol, 34% yield) as a yellow oil. MS (ESI) m / z 258.2 [M+1] + .

[0430]

[0266] 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 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (62.2 g, 273 mmol, 1.3 eq) in ethyl acetate (350 mL) was added N,N-diisopropylethylamine (54.2 g, 420 mmol, 2 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 15 / 1 to 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).

[0431]

[0149] 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) at 0 °C was slowly added thionyl bromide (0.752 g, 3.620 mmol, 2 equiv). After stirring at 0° C. for 2 h, the reaction solution was concentrated and purified by silica gel column chromatography (15%-25% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.650 g, 1.259 mmol, 70% yield) as a brown solid. MS (ESI) m / z 516.1 [M+1] + .

[0432] 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 eq) in dichloromethane (3 mL) was added 4M HCl (in 1,4-dioxane) (8.7 mL, 34.9 mmol, 10 eq) and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was concentrated, neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate (5 x 50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to provide methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (510 mg, 2.72 mmol, 78% yield) as a yellow oil. MS (ESI) m / z 187.5 [M+1] + .

[0433] Methyl 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)acetate. To a solution of methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)benzonitrile (500 mg, 0.968 mmol, 1 eq) and methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate (270 mg, 1.45 mmol, 1.5 eq) in N,N-dimethylformamide (4.8 mL, 0.2 M) was added N,N-diisopropylethylamine (0.46 mL, 4.84 mmol, 5 eq) and the reaction solution was stirred at 50°C. After 18 h, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (2 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1%-10% methanol in dichloromethane) to give 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 light yellow oil. MS (ESI) m / z 622.3 [M+1] + .

[0434] 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 eq) in 5:1 THF / water (4 mL, 0.2 M) was added lithium hydroxide (59 mg, 2.46 mmol, 3 eq). The reaction solution was stirred at room temperature. After 12h, the reaction solution was diluted with water (10mL), adjusted to pH 5 by adding 2M HCl and extracted with ethyl acetate (4x 50mL). 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)δ8.33(d,J=8.0Hz,1H),8.19(s,1H),7.97(d,J=8.4Hz,1H),3.83(s,1H),3.37(s,2H),3.14(s,2H),2.89(s,2H),2.73(s,2H),2.40(s,2H ),2.00(s,2H),1.81(d,J=12.0Hz,2H),1.72(d,J=10.4Hz,2H),1.44-1. 54(m,8H),1.15-1.19(m,3H),1.05-1.08(m,2H),1.01(d,J=6.4Hz,6H).

[0435] 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. To a 2-dram vial containing 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.06 g, 0.25 mmol, 1.5 equiv) 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) was added acetonitrile (1.65 mL, 0.2 M). The reaction solution was stirred until all solids dissolved. 1-Methylimidazole (0.07 mL, 0.84 mmol, 5 equiv) was added, followed by N-(chloro(dimethylamino)methylene)-N-methylmethanium hexafluorophosphate (0.1 g, 0.36 mmol, 2.2 equiv) and the reaction solution was stirred at room temperature. After 1 h, the reaction solution 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)δ10.5-10.7(m,1H),9.7-10.1(m,1H),8.1-8.3(m,1 H),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).

[0436] 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

[0437]

[0438] 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 eq) in ethyl acetate (1.3234 mL) was added 2-chloro-4-isothiocyanato-benzonitrile (2.27 g, 11.65 mmol, 2 eq) and N,N-diisopropylethylamine (2.03 mL, 11.65 mmol, 2 eq). The reaction solution was heated to 90° C. with stirring. After 18 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give 2-chloro-4-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (2 g, 3.9521 mmol, 68% yield) as a white solid. MS (ESI) m / z 506.2 [M+1] + .

[0439]

[0266] 2-Chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-l-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-l-yl)benzonitrile (4.0 g, 7.9 mmol, 1 equiv) in chloroform (5.7 mL) was added 4 M HCl in dioxane (39.52 mL, 158.08 mmol, 20 equiv) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-40% ethyl acetate in hexanes) to give 2-chloro-4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.5 g, 2.883 mmol, 36% yield) as an off-white solid. MS (ESI) m / z 422.2 [M+1] + .

[0440] 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 equivalents) and the reaction solution was stirred at room temperature. After 1 h, the reaction solution was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (100 mL), 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 light yellow solid. MS (ESI) m / z 484.0 [M+1]+.

[0441] 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. To a solution of 2-chlorobenzonitrile (400 mg, 0.825 mmol, 1 eq.) and methyl 2-((2R,6S)-2,6-dimethylpiperazin-1-yl)acetate hydrochloride (239 mg, 1.073 mmol, 1.3 eq.) in N,N-dimethylformamide was added N,N-diisopropylethylamine (1.03 mL, 5.94 mmol, 7 eq.) and the reaction solution was stirred at 60 °C. After 18 h, the reaction solution was concentrated and purified by silica gel column chromatography (1%-10% methanol in dichloromethane) to give 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] + .

[0442]

[0266] 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 solution was stirred at room temperature. After 7 h, the reaction solution was diluted with water (10 mL) and adjusted to approximately pH 7 by adding 2M 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 used further without further purification. MS (ESI) m / z 576.0 [M+1]+.

[0443] 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 (100 mg, 0.160 mmol, 1 eq) and (1-(7-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione) (102 mg, 0.390 mmol, 2.4 eq) was added N,N-dimethylformamide (0.82 mL, 0.2 M) and 1-methylimidazole (0.07 mL, 0.830 mmol, 5 eq). The reaction solution was stirred at room temperature until all solids dissolved. After 5 min, N-(chloro(dimethylamino)methylene)-N-methylmethanium hexafluorophosphate (101 mg, 0.360 mmol, 2.2 eq) was added and the reaction was stirred at room temperature. In 40mL 40mL 40mL 40mL 40mL 40mL 30mL 30mL 30mL 30mL 40mL 50mL 80mL 60mL 10mL 20mL 80mL 20mL 10mL 20mL 80mL 20mL 10mL 40mL 20mL 80mL 60mL 20mL 1 ...40mL 20mL 80mL 60mL 20mL 10mL 40mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 60mL 20mL 80mL 6 + ; 1H NMR(DMSO-d6,400MHz)δ10.57(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(brd,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).

[0444] 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

[0445]

[0446]

[0146] 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 h. The reaction was diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (10%-100% ethyl acetate in hexanes) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.5 g, 6.4743 mmol, 33% yield) as a brown solid. MS (ESI) m / z 541.3 [M+1] + .

[0447]

[0266] 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 eq) in dichloromethane (30 mL) was added 4 M hydrochloric acid (16.2 mL, 64.7 mmol, 10 eq) and the reaction solution was stirred at room temperature. After 3 h, the reaction solution 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. The crude material was used further without further purification. MS (ESI) m / z 457.0 [M+1] + .

[0448]

[0146] 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. To a solution of 5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (3.20 g, 6.49 mmol) in dichloromethane (30 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.26 mL, 16.2 mmol, 2.5 equiv) and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was concentrated and the crude material was purified by silica gel column chromatography (5%-80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (2.00 g, 3.85 mmol, 59% yield) as a reddish-brown oil. MS (ESI) m / z 519.8 [M+1] + .

[0449] 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. 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 hydrochloride (0.097 g, 0.23 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 (0.19 mL, 1.08 mmol, 6 equiv). The reaction vial was heated to 60° C. with stirring. After 16 h, the reaction solution was diluted with dimethyl sulfoxide to a total volume of 3 ml 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] + ; 1 H NMR(DMSO-d6,500MHz)δ10.5-10.6(m,1H),9.1-9.2(m,1H),8.7-8.8(m,1 H),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).

[0450] 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

[0451]

[0452] 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 eq) was combined with lithium perchlorate (10.02 g, 93.33 mmol, 4 eq) and ethyl acrylate (26.7 mL, 233.32 mmol, 10 eq) and the reaction solution 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] + .

[0453] 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) was added dichloromethane (1 mL) followed by 4 M hydrochloric acid in 1,4-dioxane (13.52 mL, 54.07 mmol, 25 equiv). The reaction solution was stirred at room temperature. After 15 min, the reaction solution was concentrated to give a yellow solid. The 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 of 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] + .

[0454] 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 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 eq) was added N,N-dimethylformamide (1.1666 mL, 0.48 M) and N,N-diisopropylethylamine (0.59 mL, 3.36 mmol, 6 eq). The reaction solution was heated to 50° C. with stirring. After 14 s, the reaction solution was diluted with 100 ml of ethyl acetate and washed with saturated aqueous sodium bicarbonate (100 mL) and then 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 afford 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] + . 1 H NMR (400MHz, CDCl3) δ7.94 (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(brd,J=10.6H z,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=10.7H z,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)

[0455] 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 (1.478 mL) 1,4-dioxane 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 of water. The reaction solution was stirred at room temperature for 2 hours. The solution was concentrated to afford 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 shiny oil which was used without further purification. MS (ESI) m / z 624.3 [M+1] + .

[0456] 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. (-)-(1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (27.0 mg, 0.10 mmol, 1.3 equiv), 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 solution was diluted with brine (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were 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)δppm 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).

[0457] 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

[0458]

[0459] 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 eq) in toluene (20 mL) was added thiophosgene (5.96 mL, 78.14 mmol, 1.2 eq). The mixture was stirred at 110 ° C. After 16 h, the reaction solution was concentrated and purified by silica gel chromatography (20%-50% ethyl acetate in petroleum ether) to give 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (8.000 g, 40.89 mmol, 63% yield) as a red solid.

[0460]

[0266] 3-Chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)picolinonitrile. To a mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (4.000 g, 20.45 mmol, 1 eq) 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 eq) in ethyl acetate (100 mL, 0.2 M) was added triethylamine (5.7 mL, 40.89 mmol, 2 eq), and the reaction solution was stirred at 90°C. After 6 hours, the reaction solution was concentrated and purified by silica gel chromatography (10%-50% ethyl acetate in petroleum ether) to give 3-chloro-5-(4,4-dimethyl-5-oxo-3-(trans-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)cyclohexyl)-2-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) δ8.92-8.72(m,1H),8.62-8.31(m,1H),4.68-4.50(m,1H),3.91-3.63(m,4H),3.62-3.52(m ,3H),3.50-3.39(m,3H),2.91-2.73(m,3H),2.10-2.03(m,2H),1.75-1.68(m,3H),1.55(s,6H),1.50-1.43(m,4H).

[0461] 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 eq) in methanol (30 mL, 0.27 M) was added 2 M hydrochloric acid (3 mL, 15.78 mmol, 2 eq). The reaction solution was stirred at 25° C. After 2 h, the pH of the mixture was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (% 33-100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-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) δ7.59 (s, 1H), 7.43-7.33 (m, 2H), 7.15 (br d, J = 7.0Hz, 1H), 6.57 (br s,1H),4.40(t,J=6.7Hz,2H),2.98(s,3H),2.70-2.55(m,2H),1.53(s,5H), 1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H),1.54-1.51(m,1H).

[0462] 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 eq) in dichloromethane (5 mL, 1 M) and N,N-dimethylformamide (0.50 mL) was added thionyl bromide (0.65 mL, 10.17 mmol, 2 eq) at 0°C. The mixture was stirred at 25°C for 16 h. The pH of the mixture was adjusted to 8 by saturated sodium carbonate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (150 mL x 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) δ8.90-8.72(m,1H),8.60-8.44(m,1H),3.93-3.81(m,1H),3.79-3.72(m,2H),3.61-3.53(m,2H),3.34(br s,1H),2.90-2.74(m,2H),2.12-2.02(m,2H),1.76-1.67(m,2H),1.59-1.52(m,6H),1.44-1.28(m,2H).

[0463] 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. To a mixture of 5-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-chloropicolinonitrile (0.100 g, 0.206 mmol, 1 equiv) in N,N-dimethylformamide (1.5 mL, 0.14 M) was added N,N-diisopropylethylamine (0.14 mL, 0.820 mmol, 4 equiv) and sodium iodide (0.030 g, 0.210 mmol, 1 equiv). The mixture was stirred at 50° C. After 12 h, the reaction solution was poured into water (20 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by standard methods to give 2-((2R,6S)-4-(2-((trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-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) δ10.58(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).

[0464] 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

[0465]

[0466] 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 eq) in xylene (450 mL, 0.45 M) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (113.28 g, 507.75 mmol, 2.5 eq), tetra-n-butylammonium bromide (13.09 g, 40.62 mmol, 0.2 eq), and potassium hydroxide (52.42 g, 934.26 mmol, 4.6 eq), and the reaction solution was stirred at room temperature. After 24 h, the reaction solution was diluted with ethyl acetate (500 mL) and washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (100% petroleum ether) to give trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (40.0 g, 91.4 mmol, 45% yield) as a light yellow oil. MS (ESI) m / z 438.4 [M+1]+ ; 1 H NMR (400MHz, CDCl3) δ7.38-7.32(m,4H),7.31-7.28(m,4H),7.24-7.22(m,2 H),4.61-4.57(m,1H),3.88-3.84(m,2H),3.63(s,4H),3.55-3.52(m,4H),3 .51-3.16(m,1H),2.54-2.09(m,1H),2.08-2.07(m,2H),1.92-1.90(m,2H), 1.61-1.60(m,2H),1.59-1.57(m,6H),1.55-1.53(m,2H),1.38-1.16(m,2H)

[0467]

[0266] trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine. To a solution of trans-N,N-dibenzyl-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-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 three times, then stirred at room temperature under a hydrogen atmosphere (15 psi). After 12 h, the reaction solution was filtered and the filtrate was concentrated to afford trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexan-1-amine (11.00 g, 42.74 mmol, 94% yield) as a light yellow oil. This material was used further without further purification. 1 H NMR(400MHz,DMSO-d6)δ4.52(m,1H),3.79-3.61(m,2H),3.50-3.30(m,4H),3.18-3.05(m,1H), 1.94-1.83(m,2H),1.77-1.65(m,6H),1.64-1.55(m,1H),1.53-1.38(m,4H),1.20-0.91(m,4H).

[0468] 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 eq) and methyl 2-bromo-2-methyl-propanoate (12.5 mL, 108.79 mmol, 4 eq) in acetonitrile (10 mL) was added potassium iodide (0.451 g, 2.72 mmol, 0.1 eq) and potassium carbonate (7.518 g, 54.4 mmol, 2 eq). The reaction vessel was sealed and heated to 110° C. with stirring. After 12 h, the reaction solution was filtered and concentrated. The crude material was purified by silica gel column chromatography (10%-80% ethyl acetate in petroleum ether) to give methyl 2-methyl-2-((trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)amino)propanoate (8.00 g, 22.4 mmol, 82% yield) as a light yellow oil. MS (ESI) m / z 358.4 [M+1] + .

[0469]

[0266] 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 eq) and 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (6.41 g, 28.0 mmol, 2 eq) in ethyl acetate (50 mL, 0.28 M) was added N,N-diisopropylethylamine (4.62 mL, 28.0 mmol, 2 eq) and the reaction solution was stirred at 90 °C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (10%-50% ethyl acetate in petroleum ether) to give 5-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 90% yield) as a brown oil. 1H NMR(400MHz, CDCl3)δ8.95(s,1H),8.23(s,1H),4.55-4.51(m,1H),3.81-3.78(m,2H),3.70-3.68(m,1H),3.57-3.54(m,2H),3.4 8-3.45(m,2H),3.29-2.87(m,1H),2.85(d,J=10.8Hz,2H),1.85-1.80(m,8H),1.60(s,6H),1.56-1.52(m,4H),1.32-1.29(m,2H).

[0470] 5-(3-(trans-4-(3-hydroxypropyloxy)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)propyloxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (7.00 g, 12.6 mmol, 1 equiv) in methanol (50 mL) was added 1 M hydrogen chloride (5.0 mL, 5 mmol) and the reaction solution was stirred at room temperature. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 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] + .

[0471] 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 eq) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (1.7 mL, 21.3 mmol, 2 eq) at 0° C. After stirring for 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (10%-20% ethyl acetate in petroleum ether) to give 5-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile as a light yellow solid. (ESI) m / z 535.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.98(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),3.76-3.65(m,1H),3.62(t,J=5.6Hz,2H),3.53(t,J=6.4Hz,2H ),3.40-3.29(m,1H),2.89(s,2H),2.30-2.18(m,2H),2.16-2.05(m,2H),1.83(d,J=12.4Hz,2H),1.63(s,6H),1.45-1.24(m,2H).

[0472] 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 5-(3-(trans-4-(3-bromopropyloxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-( To a solution 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 (0.208 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 h, the reaction solution 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] + ; 1 H NMR (400MHz, DMSO-d6) δ10.57(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).

[0473] 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

[0474]

[0475]

[0146] 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 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (6.4 g, 28.0 mmol, 2 eq) in ethyl acetate (50 mL) was added N,N-diisopropylethylamine (4.6 mL, 28.0 mmol, 2 eq) and the reaction solution was stirred at 90 °C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (10%-50% ethyl acetate in petroleum ether) to give 4-(4,4-dimethyl-5-oxo-3-(trans-4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (6.5 g, 11.7 mmol, 84% yield) as a brown oil. MS (ESI) m / z 554.4 [M+1] + ; 1 H NMR(400MHz, CDCl3) δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1 H),4.60-4.58(m,1H),3.84-3.82(m,2H),3.71-3.61(m,1H),3.60-3.52(m,2H),3.5 0-3.49(m,2H),3.47-3.32(m,1H),2.22-2.20(m,2H),2.19(d,J=12.0Hz,2H),1.88- 1.87(m,6H),1.85-1.84(m,2H),1.60(s,6H),1.56-1.55(m,2H),1.54-1.35(m,2H).

[0476] 4-(3-(trans-4-(3-hydroxypropyloxy)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)propyloxy)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 solution was stirred at room temperature. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 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] + .

[0477] 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 eq) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added thionyl bromide (1.7 mL, 21.3 mmol, 4 eq) and the reaction solution was gradually warmed to room temperature. After 12 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The 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 light yellow oil. MS (ESI) m / z 534.1 [M+1] + ; 1H NMR (400MHz, CDCl3) δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.74-7.71(m,1H),3.71-3.61(m,1H),3.60-3.53(m,2H),3.52(t,J=6.4 Hz,2H),3.35-3.32(m,1H),2.21(d,J=12.0Hz,2H),2.19-2.05(m,2H),1.83(d,J=12.0Hz,2H),1.65(s,2H),1.60(s,6H),1.35-1.32(m,2H).

[0478] 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 4-(3-(trans-4-(3-bromopropyloxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) To a solution of 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 solution was heated to 50° C. with stirring. After 13 h, the reaction solution was filtered and purified by standard methods to provide 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-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) δ10.58(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=6.8 Hz,2H),3.88-3.79(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).

[0479] 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

[0480]

[0481]

[0146] 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 eq) in ethyl acetate (100 mL, 0.28 M) were added 2-chloro-4-cyanophenyl isothiocyanate (10.9 g, 56.0 mmol, 2 eq) and triethylamine (7.8 mL, 56.0 mmol, 2 eq), and the reaction solution was stirred at 80°C. After 8 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (9%-20% ethyl acetate in petroleum ether) to give 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] + .

[0482] 4-(3-(trans-4-(3-hydroxypropyloxy)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)propyloxy)cyclohexyl)-2-thioxoimidazolidin-1-yl)benzonitrile (6.80 g, 13.1 mmol) in methanol (50 mL) was added 1 M hydrochloric acid (5 mL, 13.07 mmol) and the reaction solution was stirred at 25° C. After 2 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The 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. 1H NMR (400MHz, DMSO-d6) δ8.12(d,J=8.4Hz,1H),7.92(d,J=1.6Hz,1H),7.61(dd,J=2.0,8.4Hz,1H),3.89-3.76(m,1H),3.48-3.42(m,4H),3. 24-3.16(m,1H),2.79(d,J=11.2Hz,2H),2.04(d,J=10.8Hz,2H),1.70(d,J=10.8Hz,2H),1.65-1.59(m,2H),1.53(s,6H),1.34-1.25(m,2H).

[0483] 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile. To a solution of 4-(3-(trans-4-(3-hydroxypropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (5.8 g, 13.3 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (5 mL) was added thionyl bromide (2.1 mL, 26.6 mmol, 2 equiv) at 0°C. After 8 h, the reaction solution was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (4.8 g, 9.6 mmol, 72% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.14-8.11(m,1H),7.93(d,J=1.6Hz,1H),7.61(dd,J=1.6,8.0Hz,1H),3.84(s,1H),3.58-3.51(m, 4H), 3.27-3.21 (m, 1H), 2.81 (d, J = 11.6Hz, 2H), 2.06 (m, 2H), 1.71 (d, J = 11.6Hz, 2H), 1.53 (s, 6H), 1.33 (d, J = 13.2Hz, 2H).

[0484] 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 2-chlorobenzonitrile (0.100 g, 0.200 mmol, 1 eq.) in N,N-dimethylformamide (1 mL, 0.2 M) were 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 eq.) and N,N-diisopropylethylamine (0.17 mL, 1 mmol, 5 eq.), and the mixture was stirred at 50°C. After 16 h, the reaction solution was filtered and purified by standard methods to give 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-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] + ; 1 H NMR (400MHz, DMSO-d6) δ10.83(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).

[0485] 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

[0486]

[0487]

[0266] 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 eq) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (1.44 g, 6.28 mmol, 1.1 eq) in ethyl acetate (15 mL, 0.38 M) was added N,N-diisopropylethylamine (2.21 g, 17.13 mmol, 3 eq) and the reaction solution was stirred at 80 °C. After 16 h, the reaction solution was concentrated under reduced pressure and the crude material was purified by standard methods to give 5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.80 g, 3.96 mmol, 69% yield) as a brown solid. MS (ESI) m / z 455.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.99(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),2.72-2.7 0(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).

[0488] 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 eq) in dichloromethane (18 mL, 0.22 M) and N,N-dimethylformamide (1.8 mL) was slowly added thionyl bromide (1.650 g, 7.92 mmol, 2 eq) at 0°C. The reaction solution was stirred at 0°C. After 12 h, the reaction solution was diluted with water (30 mL) and extracted with dichloromethane (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (5%-80% ethyl acetate in hexanes) to give 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (1.75 g, 3.38 mmol, 85% yield) as a brown solid. MS (ESI) m / z 516.9 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.99(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).

[0489] 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 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) To a solution of 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 solution was heated to 50° C. with stirring. After 12 h, the reaction solution was filtered and concentrated. The crude material was purified by standard methods to afford 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] + ; 1 H NMR(400MHz,DMSO-d6)δ10.58(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).

[0490] 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

[0491]

[0492]

[0266] 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 eq) and 2-chloro-4-cyanophenylisothiocyanate (1.08 g, 5.57 mmol, 1.1 eq) in ethyl acetate (25 mL) was added N,N-diisopropylethylamine (2.51 mL, 15.18 mmol, 3 eq) and the reaction mixture was stirred at 80 °C. After 18 h, the reaction solution was concentrated and purified by column chromatography (15%-50% ethyl acetate in petroleum ether) to give 2-chloro-4-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)benzonitrile (1.26 g, 3.01 mmol, 59% yield) as a brown oil. MS (ESI) m / z 420.1 [M+1] + .

[0493]

[0149] 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) at 0 °C was slowly added thionyl bromide (1.88 g, 9.03 mmol, 3 equiv). After 12 h, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (15%-30% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (1.21 g, 2.50 mmol, 83% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ7.79(d,J=8.4Hz,1H),7.58(d,J=2.0Hz,1H),7.42(dd,J=8.4,2.0Hz,1H),3.87(m,1H) ,3.43(t,J=6.8Hz,2H),2.70(s,2H),1.94-1.82(m,6H),1.59(s,6H),1.39-1.36(m,3H),1.12-1.03(m,2H).

[0494] 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 4-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-chlorobenzonitrile (0. To a solution of 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 solution 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] + . 1H NMR(400MHz,DMSO-d6)δ11.36(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,3H),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).

[0495] 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

[0496]

[0497] 3-Chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile. To a mixture of methyl 3-chloro-5-isothiocyanato-pyridine-2-carbonitrile (1.600 g, 8.18 mmol, 1 eq) and methyl 2-((trans-4-(3-hydroxypropyl)cyclohexyl)amino)-2-methylpropanoate (2.320 g, 9 mmol, 1.1 eq) in ethyl acetate (100 mL) was added triethylamine (2.28 mL, 16.36 mmol, 2 eq). The reaction was stirred at 90°C. After 6 h, the reaction solution was concentrated and purified by silica gel column chromatography (10%-100% ethyl acetate in petroleum ether) to give 3-chloro-5-(3-(trans-4-(3-hydroxypropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)picolinonitrile (2.000 g, 4.75 mmol, 58% yield) as a yellow solid. MS (ESI) m / z 421.2 [M+1] + ; 1HNMR(400MHz, CDCl3)δ8.67-8.50(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).

[0498] 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 eq) in dichloromethane (5 mL, 0.1 M) and N,N-dimethylformamide (0.50 mL) at 0° C. was added thionyl bromide (0.61 mL, 9.5 mmol, 2 eq). The reaction solution was stirred at 25° C. After 16 h, the pH of the reaction solution was adjusted to 8 by adding saturated sodium carbonate. The aqueous phase was extracted with ethyl acetate (2 x 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) δ8.73-8.50(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).

[0499] 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 5-(3-(trans-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) 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 (184 mg, 0.37 mmol, 1.5 equiv) in 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 solution 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] + ; 1 H NMR (400MHz, DMSO-d6) δ10.68-10.49(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),2.8 6-2.67(m,5H),1.91-1.67(m,7H),1.61-1.52(m,6H),1.41-1.05(m,12H).

[0500] 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

[0501]

[0502] (2S,6R)-1-Benzyl-2,6-dimethylpiperidin-4-one. To a solution of 3-oxoglutaric acid (100.0 g, 684.5 mmol, 1 eq) in water (200 mL) at 20°C was added acetaldehyde (150.8 g, 1368.9 mmol, 2 eq). The reaction was stirred at 20°C for 20 min, then cooled to 0°C and benzylamine (74.61 mL, 684.5 mmol, 1 eq) was added dropwise. The reaction solution was allowed to warm to room temperature and stirred for 48 h. The reaction solution was extracted with 3000 mL of ethyl acetate (1000 mL x 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. 1 H NMR (400MHz, CDCl3) δ7.42 (d, J = 7.2Hz, 2H), 7.37-7.29 (m, 2H), 7.27-7.20 (m, 1H), 3.8 6(s,2H),3.17-3.09(qd,J=6.4,13.2Hz,2H),2.42-2.28(m,4H),1.16(d,J=6.4Hz,6H).

[0503] 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) at 0°C was added ethyl 2-(diethoxyphosphoryl)acetate (40.23 g, 179.5 mmol, 1.3 equiv) in THF (100 mL) dropwise. The mixture was stirred at 0°C for 30 min. (2S,6R)-1-benzyl-2,6-dimethylpiperidin-4-one (30.00 g, 138.1 mmol, 1 equiv) in THF (200 mL) was added dropwise to the above solution, and the reaction solution was warmed to room temperature. After 12 h, the reaction solution was neutralized by adding saturated ammonium chloride solution and poured into ice water (200 mL). The aqueous phase was extracted with ethyl acetate (3x 500mL). The combined organic layers were washed with brine (300mL), 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 purified again by semi-preparative reverse phase HPLC (55%-85% acetonitrile + 0.05% ammonium hydroxide in water, within 20min). The collected fractions were concentrated, and the aqueous phase was extracted with ethyl acetate (3x 500mL). The combined organic layers were washed with brine (300mL), dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 2-((2R, 6S)-1-benzyl-2,6-dimethylpiperidin-4-ylidene) acetate (11.7g, 40.7mmol, 30% yield) as a yellow oil. MS (ESI) m / z 288.2[M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.45-7.35(m,2H),7.30(t,J=7.6Hz,2H),7.26-7.16(m,1H),5.63(s,1H),4.15(q,J=7.2Hz,2H),3.82( s,2H),3.57(dd,J=2.8,14.0Hz,1H),2.84-2.62(m,2H),2.29-2.08(m,3H),1.33-1.23(m,3H),1.14(dd,J=6.4,16.4Hz,6H).

[0504] Tert-Butyl (2S,6R)-4-(2-ethoxy-2-oxoethyl)-2,6-dimethylpiperidin-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)δ4.26(s,1H),4.21(m,1H),4.17-4.10(m,2H),2.26-2.18(m,2H),2.13-2.05(m,1H),1.99-1.84 (m,1H),1.66-1.55(m,1H),1.47(s,9H),1.36-1.29(m,1H),1.29-1.25(m,3H),1.24-1.19(m,6H),1.15-1.02(m,2H).

[0505] Tert-butyl (2S,6R)-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 solution was slowly heated to room temperature over 1 h. The reaction solution was quenched by adding 0.5 mL of water, 15% sodium hydroxide solution (1 mL), 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 100 mL of ethyl acetate x 3. The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to provide tert-butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 96% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ4.40-4.25(m,1H),4.24-4.07(m,1H),3.77-3.65(m,2H),2.12-2.03(m,1H),1.68 -1.56(m,2H),1.55-1.49(m,2H),1.49-1.42(m,9H),1.33-1.26(m,1H),1.25-1.17(m,6H),1.05(m,1H).

[0506] Tert-Butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2S,6R)-4-(2-hydroxyethyl)-2,6-dimethylpiperidine-1-carboxylate (2.180 g, 8.470 mmol, 1 eq) and triphenylphosphine (3.332 g, 12.71 mmol, 1.5 eq) in dichloromethane (40 mL, 0.21 M) was added carbon tetrabromide (4.214 g, 12.71 mmol, 1.5 eq) at 0°C. The reaction mixture was slowly heated to room temperature. After 2 h, the reaction solution was poured into saturated sodium bicarbonate solution (100 mL) and the aqueous phase was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to afford 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) δ4.45-4.27(m,1H),4.26-4.06(m,1H),3.51-3.29(m,2H),2.18-1.96(m,2H),1.89-1. 75(m,2H),1.73-1.53(m,2H),1.48-1.39(m,9H),1.33-1.25(m,1H),1.24-1.19(m,6H),1.13-0.97(m,1H).

[0507]

[0146] tert-Butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of trans-4-(dibenzylamino)cyclohexanol (12.18 g, 41.22 mmol, 2 equiv) and tert-butyl (2S,6R)-4-(2-bromoethyl)-2,6-dimethylpiperidine-1-carboxylate (6.600 g, 20.61 mmol, 1 equiv) in 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. In 40mL 40mL 40mL 40mL 40mL 30mL 30mL 40mL 80mL 20mL 10mL 20mL 80mL 20mL 10mL 40mL 80mL 20mL 10mL 20mL 30mL 40mL 80mL 20mL 1 ... 1 H NMR (400MHz, CDCl3) δ7.42-7.33(m,4H),7.33-7.27(m,4H),7.24-7.17(m,2H),4.36-4.23(m,2H),4.22 -4.15(m,1H),3.62(s,4H),3.48(t,J=6.4Hz,1H),3.45-3.37(m,1H),3.19-3.06(m,1H),2.53(m,1H),2 .09-2.04(m,3H),2.01-1.86(m,3H),1.63-1.59(m,1H),1.57-1.51(m,2H),1.47-1.46(m,9H),1.43-1. 33(m,2H),1.28-1.24(m,2H),1.21(s,2H),1.17(d,J=7.0Hz,6H),1.14-1.08(m,1H),1.07-0.92(m,1H).

[0508] Tert-Butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2R,6S)-4-(2-((trans-4-(dibenzylamino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 5.240 mmol, 1 equiv) in methanol (60 mL) was added palladium on carbon (2.000 g) under nitrogen. The reaction was stirred at room temperature under hydrogen (15 psi) for 12 hours. The reaction mixture was filtered and concentrated to give tert-butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 98% yield) as a yellow oil which was carried forward without further purification. 1 H NMR (400MHz, DMSO-d6) δ4.23-4.08(m,2H),4.08-3.93(m,1H),3.50-3.40(m,2H),3.40-3.33(m,1H),3.18-3.04(m,1H),2.55-2.51(m,2H),2.49(br s,1H),2.05-1.83(m,4H),1.82-1.68(m,2H),1.67-1.47(m,2H),1.46- 1.32(m,16H),1.29-1.15(m,2H),1.15-1.07(m,9H),1.07-0.87(m,3H).

[0509]

[0146] tert-Butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate. To a solution of tert-butyl (2R,6S)-4-(2-((trans-4-aminocyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.837 g, 5.180 mmol, 1 eq) 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 eq) and methyl 2-bromo-2-methylpropanoate (3.75 mL, 25.91 mmol, 5 eq). The reaction was stirred at 110 °C. After 48 h, the reaction solution was filtered and concentrated to give tert-butyl (2S,6R)-4-(2-((trans-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 5.279 mmol, crude) as a yellow oil, which was used without further purification. MS (ESI) m / z 455.5 [M+1] + .

[0510] Tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate and tert-butyl (2R,4r,6S)-4-(2-((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 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.084 g, 4.750 mmol, 1 eq) in ethyl acetate (10 mL, 0.47 M) was added N,N-diisopropylethylamine (1.660 mL, 9.500 mmol, 2 eq). The reaction was stirred at 90 °C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash silica gel column chromatography to give a diastereomeric mixture, which was separated by SFC (DAICEL CHIRAL PAK IG: 250 mm*30 mm.10 um, 20% methanol + 0.1% .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 tert-butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.553 mmol, 12% yield). Tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1H NMR (400MHz, CDCl3) δ7.95(d,J=8.0Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0Hz,1H),4.38- 4.22(m,2H),3.72-3.59(m,1H),3.54(t,J=6.4Hz,2H),3.37-3.24(m,1H),3.03-2.75(m,2H),2.21(br d, J = 12.4 Hz, 2H), 2.03-1.90 (m, 1H), 1.89-1.77 (m, 2H), 1.61 (s, 6H), 1.58 (m, 2H), 1.54-1.48 (m, 2H), 1.47 (s, 9H), 1.40-1.26 (m, 4H), 1.19 (d, J = 7.2 Hz, 6H). tert-Butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate: 1 HNMR(400MHz, CDCl3) δ7.95(d,J=8.4Hz,1H),7.85(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),4. 28-4.10(m,2H),3.76-3.58(m,1H),3.49(t,J=6.0Hz,2H),3.30(m,1H),3.03-2.76(m,2H),2.19(br d,J=12.0Hz,2H),2.12-1.98(m,2H),1.89-1.76(m,2H),1.61(s,6H),1.52(br t,J=6.4Hz,2H),1.47(s,9H),1.40-1.25(m,3H),1.22(d,J=6.8Hz,6H),1.03(m,2H).

[0511]

[0146] 4-(3-(trans-4-(2-((2R,4s,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl (2R,4s,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (1.060 g, 1.630 mmol, 1 equiv) in dichloromethane (5 mL) was added 4 M hydrochloric acid in 1,4-dioxane (20 mL, 80.00 mmol), and the reaction solution was stirred at room temperature. After 2h, the reaction solution was concentrated. The resulting yellow solid was absorbed in saturated aqueous sodium bicarbonate (50mL) and extracted with ethyl acetate (3x100mL). The combined organic layer was washed with brine (50mL), 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 (0.920g, 1.67mmol, 99% yield) as a yellow solid, which was used without further purification. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 2.0, 8. 0Hz,1H),3.74-3.59(m,1H),3.51(t,J=6.8Hz,2H),3.31(m,1H),2.92(m,4H),2.20(br d,J=12.0Hz,2H),2.02-1.92(m,1H),1.82(br d,J=12.0Hz,2H),1.70(q,J=6.8Hz,2H),1.64-1.56(s,6H),1.51(br d,J=12.8Hz,2H),1.40-1.27(m,4H),1.09(br d,J=6.0Hz,6H).

[0512] Benzyl 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)acetate. To a mixture of 5-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.080 g, 0.150 mmol, 1 eq.) and benzyl 2-bromoacetate (0.040 g, 0.170 mmol, 1.2 eq.) in acetonitrile (0.5 mL, 0.3 M) was added N,N-diisopropylethylamine (0.08 mL, 0.440 mmol, 3 eq.) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was filtered and concentrated, and the crude material was purified by preparative TLC (dichloromethane:methanol=10:1, Rf=0.7) to give benzyl 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)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)δ8.33(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,3 H), 1.56 (s, 6H), 1.45-1.35 (m, 2H), 1.30-1.25 (m, 4H), 0.95 (d, J = 6.0Hz, 6H).

[0513]

[0156] 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 benzyl 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)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 solution was stirred at 25 ° C for 3h. Hydrochloric acid (1M) was added to the reaction solution and its pH was adjusted to 5-6. The mixture was concentrated in vacuo and purified by semi-preparative reverse phase HPLC (30%-60% acetonitrile + 0.225% formic acid in water, 10min) 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 (0.042g, 0.069mmol, 59% yield) as a yellow liquid. MS (ESI) m / z 609.4 [M + 1] + .

[0514] 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 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0. To a mixture of 1 mL of pyridine (0.06 M) 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 eq) was added EDCI (0.023 g, 0.120 mmol, 2 eq). The reaction solution was stirred at 50°C. After 12 h, the reaction solution was diluted with DMSO and purified by standard methods to give 2-((2R,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) δ10.73-10.68(m,1H),10.67-10.60(m,1H),9.12-9.10(m,1H),8.34(d,J=7.6Hz,1H),8.19(s,1 H),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),4.38(s,1H),4.26-4.18(m,1H),4.1 2-4.05(m,3H),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).

[0515] 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

[0516]

[0517]

[0266] 4-(3-(trans-4-(2-((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl (2R,4r,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidine-1-carboxylate (0.360 g, 0.550 mmol, 1 equiv) in dichloromethane (3 mL, 0.12 M) was added 4 M hydrochloric acid in 1,4-dioxane (12 mL, 48 mmol), and the reaction solution was stirred at 15°C. In 40mL 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 (0.330g, 0.56mmol) ) is added into 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 (0.330g, 0.56mmol) ) is added into 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 (0.330g, 0.56mmol) ) , It is not further purified and is continued to use. MS (ESI) m / z 551.4 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.95(d,J=8.4Hz,1H),7.84(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.4Hz,1H),3.73-3.59(m ,1H),3.52(t,J=6.4Hz,2H),3.30(m,1H),3.03-2.80(m,2H),2.74(m,2H),2.20(brd,J=12.4Hz,2H),1.82(br d,J=11.6Hz,2H),1.68(br d,J=13.2Hz,2H),1.61(s,6H),1.54-1.48(m,2H),1.41-1.27(m,3H),1.14(br d,J=6.4Hz,6H),0.92-0.76(m,2H).

[0518] Benzyl 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)acetate. To a mixture of 5-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.060 g, 0.110 mmol, 1 eq.) and benzyl 2-bromoacetate (0.030 g, 0.130 mmol, 1.2 eq.) in acetonitrile (0.5 mL, 0.2 M) was added N,N-diisopropylethylamine (0.06 mL, 0.330 mmol, 3 eq.) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was filtered and concentrated, and the crude material was purified by preparative TLC (dichloromethane:methanol=10:1, Rf=0.7) to give benzyl 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)acetate (0.063 g, 0.090 mmol, 83% yield) as a yellow solid. MS (ESI) m / z 699.4 [M+1] + .

[0519]

[0146] 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 benzyl 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)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 solution was stirred at 25 ° C for 3h. Hydrochloric acid (1M) was added to the reaction solution and its pH was adjusted to 5-6. The mixture was concentrated in vacuo and purified by semi-preparative reverse phase HPLC (30%-60% acetonitrile + 0.225% formic acid in water, 10min) 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 (0.028g, 0.046mmol, 51% yield) as a yellow liquid. MS (ESI) m / z 609.1 [M + 1] + .

[0520] 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 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (14.3 To a mixture of 1 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 solution was stirred at 50°C. After 12 h, the reaction solution was diluted with DMSO and purified by standard methods to give 2-((2R,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) δ10.85-10.78(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),4.12-4.05(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).

[0521] 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

[0522]

[0523] 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 eq) in dichloromethane (50 mL) at 0 °C was added triethylamine (4.2 mL, 30.20 mmol, 1.5 eq) dropwise followed by 2-chloroacetyl chloride (1.76 mL, 22.15 mmol, 1.1 eq) dropwise and the reaction mixture was stirred at 0 °C. After 2 h, the reaction solution 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. 1H NMR (400MHz, CDCl3) δ7.41-7.34(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).

[0524] 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 solution was stirred at 70°C. After 12 h, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were 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 HNMR (400MHz, CDCl3) δ7.36-7.31(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).

[0525] 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 eq) in THF (80 mL) was added borane-dimethyl sulfide complex (5.81 mL, 58.14 mmol, 3.5 eq) and the reaction solution 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 the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 x 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) δ7.52-7.50(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,2 H),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).

[0526]

[0146] Benzyl (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 solution was diluted with ethyl acetate (150 mL), filtered, and concentrated. The resulting material was purified by semi-preparative reverse phase HPLC (20%-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] + .

[0527]

[0266] 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. 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 eq) in acetic acid (30 mL) was added potassium cyanate (1.220 g, 15.07 mmol, 3 eq) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution 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] + ; 1H NMR (400MHz, CDCl3) δ7.40-7.30(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).

[0528] 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 solution was concentrated. The resulting crude material was purified by semi-preparative reverse phase HPLC (0%-20% acetonitrile in water + 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) δ12.49(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),4.2 0(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).

[0529] 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. To a flask containing 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) was added. The reaction was stirred at 50°C. After 15 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((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] + ; 1 H NMR (400MHz, DMSO-d6) δ10.55(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(brd,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).

[0530] 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

[0531]

[0532] Benzyl (3R,5S)-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 eq) and 1,3-dibromopropane (40.65 g, 201.35 mmol, 10 eq) in acetonitrile (50 mL) was added potassium carbonate (8.350 g, 60.410 mmol, 3 eq) and the reaction mixture was stirred at 100° C. After 12 h, the reaction solution was diluted with ethyl acetate (100 mL), filtered, and concentrated. The resulting 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) δ7.39-7.30(m,5H),5.13(s,2H),3.96-3.91(m,2H),3.39-3.36(t,J=6.4 Hz, 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).

[0533] 7-Methoxy-1-methyl-1H-indazol-3-amine. To a solution of 2-fluoro-3-methoxybenzonitrile (20.00 g, 132.33 mmol, 1 eq) in N,N-dimethylacetamide (200 mL) was added methylhydrazine (76.20 g, 661.64 mmol, 5 eq) and N,N-diisopropylethylamine (20.52 g, 158.79 mmol, 1.2 eq) and the reaction solution was stirred at 130° C. After 3 h, the reaction solution was diluted with ice water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate and 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) δ7.25-7.23(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).

[0534] 3-amino-1-methyl-1H-indazole-7-ol. To a solution of 7-methoxy-1-methyl-1H-indazole-3-amine (18.00 g, 101.58 mmol, 1 eq) in dichloromethane (200 mL) was added aluminum chloride (54.18 g, 406.32 mmol, 4 eq) and the reaction mixture was stirred at 45 ° C. After 12 h, the reaction solution was slowly poured into water (500 mL) and extracted with ethyl acetate (3 x 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-indazole-7-ol (6.500 g, 39.833 mmol, 39% yield) as a brown solid. MS (ESI) m / z 164.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ9.81 (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).

[0535] Benzyl (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 eq) and (3R,5S)-benzyl 4-(3-bromopropyl)-3,5-dimethylpiperazine-1-carboxylate (2.400 g, 6.500 mmol, 1 eq) in acetonitrile (20 mL) was added potassium carbonate (2.690 g, 19.50 mmol, 3 eq) and the reaction mixture was stirred at 60° C. After 12 h, the reaction solution was diluted with water (80 mL) and extracted with ethyl acetate (3 x 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] + .

[0536] 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 eq) and ethyl acrylate (4.430 g, 44.290 mmol, 8 eq) was added aluminum oxide (1.410 g, 13.840 mmol, 2.5 eq) and the reaction suspension was stirred at 110° C. After 70 h, the reaction solution 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 + 0.1% TFA in water, 20 min). The pH 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) δ7.40-7.31(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).

[0537] 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 eq) in acetic acid (12 mL) was added potassium isocyanate (0.478 g, 5.890 mmol, 2 eq) and the reaction mixture was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by semi-preparative reverse phase HPLC (15%-45% acetonitrile in water + 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] + ; 1H NMR (400MHz, DMSO-d6) δ7.39-7.31(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).

[0538]

[0149] 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 equiv) in hydrogen chloride (17. mL, 541.70 mmol) was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by semi-preparative reverse phase HPLC (1%-30% acetonitrile in water + 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) δ12.06(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).

[0539] 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. To a flask containing 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) was added. The reaction was stirred at 50°C. After 14 h, the reaction solution 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] + ; 1 H NMR (400MHz, DMSO-d6) δ10.54(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 (brd, J = 9.90Hz, 2H), 1.73 (br d, J = 10.88Hz, 2H), 1.55 (s, 6H), 1.28-1.49 (m, 8H).

[0540] 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

[0541]

[0542] 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 eq) and N,O-dimethylhydroxylamine hydrochloride (0.830 g, 8.550 mmol, 1.1 eq) 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 eq) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclohexyl)carbamate (2.200 g, 7.323 mmol, 94% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ4.41(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).

[0543] 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 eq) in dichloromethane (10 mL) at 0° C. was added a 70% solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (4.08 mL, 14.65 mmol, 2 eq). After stirring for 2 h, the reaction solution was diluted with water (20 mL) and saturated aqueous ammonium chloride (10 mL). The solution was extracted with dichloromethane (3 x 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was purified by silica gel column chromatography (0-25% ethyl acetate in petroleum ether) to give tert-butyl (trans-4-(2-oxoethyl)cyclohexyl)carbamate (1.450 g, 6.008 mmol, 82% yield) as a white solid. 1 H NMR(400MHz, CDCl3)δ9.65-9.64(t,J=2.0Hz,1H),6.69-6.64(m,1H),3.19-3.13(m,1H),2.55-2.5 2(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).

[0544]

[0146] 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-(triphenylphosphinilidene)acetate (2.300 g, 6.610 mmol, 1.1 equiv) and the reaction mixture was stirred at 80°C. After 12 h, the reaction solution was concentrated and the resulting crude material was purified by silica gel column chromatography (0-20% ethyl acetate in hexanes) to give ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.858 mmol, 48% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ6.95-6.88(m,1H),5.82-5.78(m,1H),4.36(s,1H),4.24-4.14(m,2H),3.37(s,1H),2.12-2.0 8(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).

[0545] 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 min. To the reaction solution was added a solution of ethyl (E)-4-(trans-4-((tert-butoxycarbonyl)amino)cyclohexyl)but-2-enoate (0.890 g, 2.860 mmol, 1 equiv) in THF (8 mL) and the reaction solution was stirred at 15°C. After 12 h, the reaction solution was quenched by the slow addition of 1 M aqueous hydrochloric acid (10 mL) and extracted with ethyl acetate (3 x 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) δ4.37 (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).

[0546] 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 eq) in dichloromethane (2 mL) was added 4 M hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol, 5.8 eq) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated to remove the organic solvent, then diluted with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 x 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 used without further purification. 1 H NMR (400MHz, CDCl3) δ3.62-3.59(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).

[0547]

[0266] 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) were added potassium carbonate (0.993 g, 7.180 mmol, 3 equiv) and sodium iodide (0.072 g, 0.480 mmol, 0.2 equiv) and the reaction solution was stirred at 80°C. After 12 h, the reaction solution was diluted with ethyl acetate, filtered, and concentrated to afford 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] + .

[0548] 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 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.556 g, 2.440 mmol, 1.1 eq) in ethyl acetate (12 mL) was added N,N-diisopropylethylamine (1.15 mL, 6.960 mmol, 3 eq) and the reaction mixture was stirred at 80° C. After 3 h, the reaction solution was diluted with ethyl acetate (20 mL) and concentrated. The resulting crude oil was purified by silica gel column chromatography (0-35% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360 g, 0.736 mmol, 32% yield) as a brown solid. MS (ESI) m / z 468.1 [M+1] + .

[0549]

[0266] 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 4-(3-(trans-4-(4-hydroxybutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.360.g, 0.770mmol, 1 eq) in dichloromethane (3 mL) were added N,N-dimethylformamide (0.30 mL) and thionyl bromide (0.400 g, 1.920mmol, 2.5 eq) and the reaction solution was stirred at 15 °C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography (0-20% ethyl acetate in petroleum ether) to give 4-(3-(trans-4-(4-bromobutyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.280 g, 0.517 mmol, 67% yield) as a brown solid. MS (ESI) m / z 530.0 [M+1] + ; 1H NMR (400MHz, CDCl3) δ7.96-7.94(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=6.8H z,2H),2.69(s,2H),1.95-1.92(m,2H),1.88-1.83(m,4H),1.61(s,6H),1. 50-1.44(m,2H),1.36-1.34(m,1H),1.27-1.25(m,2H),1.11-1.01(m,2H).

[0550] 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 4-(4-(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 eq) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.065 g, 0.500 mmol, 3.3 eq) and the reaction solution was stirred at 50° C. After 12 h, the reaction solution 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 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] + .

[0551] 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

[0552]

[0553] 1-Methyl-7-nitro-1H-indazol-3-amine. To a solution of 2-fluoro-3-nitrobenzonitrile (20.000 g, 120.400 mmol, 1 eq) in N,N-dimethylacetamide (200 mL) was added methylhydrazine (48 mL, 361.210 mmol, 3 eq) and N,N-diisopropylethylamine (23 mL, 132.050 mmol, 1.1 eq) and the reaction solution was stirred at room temperature. After 30 min, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (2 x 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) δ8.16 (dd, J = 7.6, 1.2 Hz, 1H), 8.08 (dd, J = 7.6, 1.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 5.91 (s, 2H), 3.81 (s, 3H).

[0554] 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 eq) in 1,4-dioxane (50 mL) was added aluminum oxide (20.214 g, 198.260 mmol, 3 eq), tris(trifluoromethylsulfonyloxy)ytterbium (2.050 g, 3.304 mmol, 5 mol%), and acrylic acid (14.29 g, 198.260 mmol, 3 eq), and the reaction solution was stirred at 110° C. After 24 h, the reaction solution was filtered and concentrated. The resulting crude material was purified by semi-preparative reverse phase HPLC (20%-50% acetonitrile + 0.225% formic acid in water, 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]+ .

[0555] 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 eq) in toluene (80 mL) and methanol (80 mL) was added diazomethyl(trimethyl)silane (72 mL, 45.410 mmol, 1 eq) dropwise at 0° C. under a nitrogen atmosphere. The mixture was heated to 25° C. and stirred for 12 hours. The reaction solution 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%-65% acetonitrile in water + 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] + ; 1 H NMR (400MHz, CDCl3) δ8.09 (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).

[0556] 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 eq) in acetic acid (80 mL) was added potassium isocyanate (7.521 g, 92.720 mmol, 3 eq) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 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%-46% acetonitrile in water + 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 light orange solid. MS (ESI) m / z 322.1 [M+1] + ; 1H NMR (400MHz, CDCl3) δ8.17 (dd, J=7.6, 1.2Hz, 1H), 7.99 (dd, J=8.0, 0.8Hz, 1H), 7.27-7.31 ( m,1H),4.92(s,2H),4.20(s,3H),4.17(t,J=6.8Hz,2H),3.61(s,3H),2.75(t,J=6.8Hz,2H).

[0557] 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) was added palladium hydroxide (1.000 g, 28.530 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum, purged with hydrogen three times, and stirred at room temperature under a hydrogen atmosphere (15 psi). After 5 h, the reaction solution 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 light yellow oil. MS (ESI) m / z 292.1 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.08 (dd, J=8.0, 0.8Hz, 1H), 6.93-7.01 (m, 1H), 6.65 (d, J=7.2Hz, 1H) ,4.77(s,2H),4.34(s,3H),4.07-4.17(m,2H),3.91(s,2H),3.59(s,3H),2.65-2.78(m,2H).

[0558]

[0146] 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. To a solution of benzyl (3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazine-1-carboxylate (0.200 g, 0.680 mmol, 1 eq) and N,N-diisopropylethylamine (0.36 mL, 2.050 mmol, 3 eq) in acetonitrile (4 mL) at 0 °C was added a solution of trifluoromethanesulfonic anhydride (0.14 mL, 0.820 mmol, 1.2 eq) in acetonitrile (1 mL). After stirring at 0°C for 2 h, methyl 3-(1-(7-amino-1-methyl-1H-indazol-3-yl)ureido)propanoate (0.199 g, 0.680 mmol, 1 eq) in acetonitrile (10 mL) was added, and the reaction solution was slowly warmed to room temperature. After 12 h, the reaction solution 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 give 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) δ7.46-7.29(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).

[0559]

[0266] 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 h, the reaction was acidified with 1 M aqueous hydrochloric acid (10 mL) and the solution was adjusted to pH 8 by the addition of saturated aqueous sodium bicarbonate. The aqueous solution was extracted with ethyl acetate (3 x 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 give 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) δ10.49(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),4.23(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).

[0560]

[0266] 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 under a hydrogen atmosphere (15 psi) at room temperature. After 12 h, the reaction solution 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) δ10.89-10.00(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).

[0561] 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. To a flask containing nitrile (150 mg, 0.29 mmol, 1 eq) was added 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 eq), N,N-diisopropylethylamine (0.2 mL, 1.16 mmol, 4 eq), sodium iodide (52 mg, 0.35 mmol, 1.2 eq), and N,N-dimethylformamide (2.0 mL 0.15 M). The reaction was stirred at 50 °C. After 18 h, the reaction solution was diluted with DMSO (1 mL) and purified by standard methods to give 4-(3-(trans-4-(2-((3R,5S)-4-(2-((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]; 1 H NMR (400MHz, DMSO-d6) δ10.51(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).

[0562] 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

[0563]

[0564] Tert-Butyl (R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate. To a 40 mL vial were added tert-butyl (R)-3-(trifluoromethyl)piperazine-1-carboxylate (0.5 g, 1.97 mmol), N,N-diisopropylethylamine (0.69 mL, 3.93 mmol, 2 eq), methyl bromoacetate (1.09 mL, 11.8 mmol, 6 eq), and THF (20 mL, 0.1 M). The reaction solution was stirred at room temperature. After 18 s, the solution was diluted with 100 mL of ethyl acetate and 100 mL of water. The organic layer was removed, and the aqueous layer was extracted with 2 x 50 mL of ethyl acetate. The combined organic layers were then dried over magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (1%-50% ethyl acetate in hexanes) to provide tert-butyl (R)-4-(2-methoxy-2-oxoethyl)-3-(trifluoromethyl)piperazine-1-carboxylate (0.557 g, 1.71 mmol, 88% yield) as a yellow oil. MS (ESI) m / z 227 [M-99] + .

[0565] Methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate. Tert-Butyl (R)-3-(trifluoromethyl)piperazine-1-carboxylate (250 mg, 0.7 mmol) and trifluoroacetic acid (0.58 mL, 7.6 mmol, 10 equiv) were combined in dichloromethane (7.6 mL, 1 M) and stirred at room temperature in a screw-capped scintillation vial. After 1 h, the solution was concentrated to give methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (255 mg, 0.75 mmol, 98% yield) as a yellow oil, which was used without further purification. MS (ESI) m / z 227 [M+1] + .

[0566] Methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetate. To a 1-dram vial containing (trifluoromethyl)benzonitrile (0.5 g, 0.96 mmol, 1 equiv), methyl (R)-2-(2-(trifluoromethyl)piperazin-1-yl)acetate (0.33 g, 0.96 mmol, 1 equiv), and sodium iodide (2.7 mg, 0.02 mmol, 0.1 equiv) was added acetonitrile (5 mL), followed by N,N-diisopropylethylamine (0.8 mL, 4.82 mmol, 5 equiv). The reaction vial was heated to 60°C with stirring. After 16 h, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in 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]+.

[0567] 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. At 0°C, methyl 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl) To a cooled solution of 2-(trifluoromethyl)piperazin-1-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)-4-(4-(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 eq) 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 eq) in one portion. The resulting solution was stirred at room temperature. After 3 h, the reaction solution was diluted with water (20 mL) and extracted with 10% methanol in dichloromethane (4 x 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 used without further purification. MS (ESI) m / z 650.2 [M+1]+.

[0568] 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 2-dram vial containing 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.06 g, 0.22 mmol, 1.2 equiv) and 5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-1-(cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)acetic acid (0.12 g, 0.19 mmol, 1 equiv) was added acetonitrile (1.5 mL) and dimethylformamide (1.5 mL), and the solution was stirred until all solids dissolved. 1-Methylimidazole (0.07 mL, 0.84 mmol, 5 equiv) was added, followed by N-(chloro(dimethylamino)methylene)-N-methylmethanium hexafluorophosphate (0.12 g, 0.41 mmol, 2.2 equiv) and the reaction solution was stirred at room temperature. After 1 h, the reaction solution was diluted with dimethyl sulfoxide to a total volume of 3 ml, filtered, and purified by standard methods to give 2-((R)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-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)δ10.4-10.6(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).

[0569] Example 21: 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ 6 (2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

[0570]

[0571] 4-Bromo-3-(pentafluoro-λ 6 -sulfanyl)aniline. Under nitrogen atmosphere, at 0 ° C, to 3-(pentafluoro-λ 6 To a solution of 4-bromo-3-(pentafluoro-λ- thioalkyl)aniline (2.0 g, 9.12 mmol, 1 eq) in dimethylformamide (15 mL) was added N-bromosuccinimide (1.9 g, 10.95 mmol, 1.2 eq) in one portion. The resulting mixture was stirred at room temperature for 4 h. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (2 x 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- thioalkyl)aniline. 6 -sulfanyl)aniline (1.7 g, 5.7 mmol, 59% yield). 1 H NMR (CDCl3, 400MHz) δ7.4-7.5(m,1H),7.1-7.2(m,1H),6.6-6.7(m,1H),3.8-4.0(m,2H).

[0572] 4-amino-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. Under stirring, 4-bromo-3-(pentafluoro-λ 6 -sulfanyl) aniline (1.7 g, 5.7 mmol, 1 eq) and copper (I) cyanide (0.61 g, 6.84 mmol, 1.2 eq) in a 100 mL round-bottom flask was heated to 180 ° C. After 4 h, the reaction solution 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. The residue was purified by silica gel chromatography (0-20% ethyl acetate in hexane on a 50 g column) to give 4-amino-2-(pentafluoro-λ6-sulfanyl)benzonitrile (1.0 g, 4.09 mmol, 72% yield) as a white solid. MS (ESI) m / z 244.8 [M + 1] +.

[0573] 4-isothiocyanato-2-(pentafluoro-λ 6 To a 100 mL round bottom flask containing thiophosgene (0.94 mL, 12.29 mmol, 1.2 equiv) in water (10 mL) was added 4-amino-2-(pentafluoro-λ- thiophene)-1,2-dichloro ... 6 -sulfanyl)benzonitrile (2.5 g, 10.24 mmol, 1 eq). The resulting mixture was stirred at room temperature for 16 h. 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)-1,2-difluoro-1,2-difluoro-2,3-difluoro-1,3 ... 6 -sulfanyl)benzonitrile (1.3 g, 4.54 mmol, 44% yield) which was used without further purification. MS (ESI) m / z 286.9 [M+1]+.

[0574] 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 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 -sulfanyl)benzonitrile (1.67 g, 5.82 mmol, 1.2 eq) and N,N-diisopropylethylamine (1.02 mL, 5.82 mmol, 3 eq). The reaction solution was stirred at 80 ° C. After 18 h, the reaction solution was concentrated and purified by column chromatography (0-50% ethyl acetate / hexane) to give a white solid 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. The intermediate solid was suspended in dichloromethane (1.5 mL), followed by addition of 4M hydrochloric acid in dioxane (4 mL, 16 mmol, 3 equivalents) and stirred at 25 ° C for 12 h. The reaction solution was concentrated, the solid was dissolved in dichloromethane and purified by silica gel column chromatography (0-40% ethyl acetate in hexane) to give 4- (3- (trans-4- (2-hydroxyethoxy) cyclohexyl) -4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) -2- (pentafluoro-λ 6-sulfanyl)benzonitrile (0.80 g, 1.33 mmol, 46% yield). MS (ESI) m / z 513.8 [M+1] +.

[0575] 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 -sulfanyl)benzonitrile. To 4-(3-(trans-4-(2-hydroxyethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ 6 To a solution of 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ-imidazolidin-1-yl)-3-nitro-1-ol (1.0 g, 1.95 mmol, 1 equivalent) in dichloromethane (30 mL) was added dimethylformamide (5 mL) and thionyl bromide (1.0 g, 4.87 mmol, 2.5 equivalents). The reaction solution was stirred at room temperature overnight. After 16 h, the reaction solution was diluted with brine (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to obtain 4-(3-(trans-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(pentafluoro-λ-imidazolidin-1-yl)-2-nitro-1-ol (1.0 g, 1.95 mmol, 1 equivalent). 6 -sulfanyl)benzonitrile (0.59 g, 1.02 mmol, 53% yield). MS (ESI) m / z 578.8 [M+1] +.

[0576] 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. 6To 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 h, the reaction solution was diluted with dimethyl sulfoxide to a total volume of 3 ml and purified by standard methods to give 2-((2S,6R)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-λ)- 6 1H-indazol-7-yl)acetamide hydrochloride (0.07 g, 0.07 mmol, 34% yield). MS (ESI) m / z 910.3 [M+1] + ; 1 H NMR(DMSO-d6,400MHz)δ10.5-10.5(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).

[0577] 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

[0578]

[0579]

[0266] (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 solution 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] + .

[0580]

[00146] (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 solution 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 used without further purification. MS (ESI) m / z 454.2 [M+1] + .

[0581] 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 5-(3-((trans)-4-(3-bromopropyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl) 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 hydrobromide (0.107 g, 0.200 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.060 g, 0.460 mmol) were added and the reaction solution was stirred at 50°C. After 12 h, the reaction solution 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] + . 1 HNMR(400MHz,DMSO-d6)δ10.83(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,2 H),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).

[0582] 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.

[0583]

[0584] 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 (R)-N-(3-(2,4-dioxotetrahydropyrimidin-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 solution was stirred at 50°C. After 8 h, the reaction solution 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) δ10.58(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).

[0585] 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

[0586]

[0587] 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. Under nitrogen, 5-(3-((trans)-4-(3-bromopropyloxy)cyclohexyl)-4,4-dimethyl-5-oxo-2- 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 hydrobromide (1.235 g, 2.310 mmol) in DMF (15 mL) was added N,N-dimethylformamide (1.39 mL, 7.970 mmol) in one portion and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (4 x 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 afford 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 / z 906.2 [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(brd,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).

[0588] 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

[0589]

[0590] Benzyl 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)acetate. To a solution of 2-(4-((2 ... After 12 h, the reaction solution was concentrated and purified by flash silica gel column chromatography (0-3% methanol in dichloromethane) to give benzyl 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)acetate (350 mg, 0.5001 mmol, 92% yield) as a clear, colorless oil. MS (ESI) m / z: 700.5 [M+1] + .

[0591] 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 benzyl 2-((2R,4s,6S)-4-(2-(((trans)-4-( To a solution of 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)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 at 25° C. under a hydrogen atmosphere. After 6 h, 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] + .

[0592] 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 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.083 g, 0.3 To a mixture 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)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 solution was stirred at 50° C. After 12 h, the reaction solution 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 afford 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) δ11.32-10.96(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).

[0593] 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

[0594]

[0595] 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 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 solution was stirred at 50°C. After 12 h, the reaction solution 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] + ; 1 HNMR(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).

[0596] 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

[0597]

[0598] 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 5-(3-((trans)-4-(2-bromoethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2- To a solution of (R)-N-(3-(2,4-dioxotetrahydropyrimidin-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 solution was stirred at 50°C. After 12 h, the reaction solution was diluted with DMSO and purified by standard methods to afford 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) δ10.95-10.91(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).

[0599] 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

[0600]

[0601] Benzyl 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)acetate. To a solution of 2-(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 (10 mL) was added diisopropylethylamine (0.28 mL, 1.63 mmol) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by standard methods to provide benzyl 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)acetate (370 mg, 0.5287 mmol, 97% yield) as a yellow oil. MS (ESI) m / z 722.4 [M+23] + .

[0602] 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 5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-(cyclohexyl)oxy)ethyl)-2,6-dimethylpiperidin-1-yl)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 solution was stirred at room temperature under a hydrogen atmosphere. After 6 h, the reaction slurry was filtered and concentrated to afford 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]+ .

[0603] 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 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.128 g, 0.49 To a mixture of 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)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 solution was stirred at 50° C. After 12 h, the reaction solution 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 afford 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) δ10.60(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,3H),3.90(t,J=6.6Hz,2H),3.67(d,J=8.4Hz,2H),3.42-3.18(m,2H),2.89-2.7 5(m,4H),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).

[0604] 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

[0605]

[0606] (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)cyclohexylamine (6.290 g, 15.70 mmol) in xylene (45 mL) were added tetrabutylammonium bromide (0.840 g, 2.620 mmol) and potassium hydroxide (3.5 mL, 65.41 mmol), and the reaction solution was stirred at 30° C. After 12 h, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to afford (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. 1H NMR (400MHz, DMSO-d6) δ7.34-7.26(m,8H),7.21-7.16(m,2H),4.15-4.02(m,2H),3.57-3.52(m,5H),2.39-2.31(m,1H),1. 81(d,J=11.6Hz,2H),1.76-1.68(m,6H),1.53-1.26(m,15H),1.23(d,J=7.2Hz,6H),1.16-1.11(m,3H),0.77-0.66(m,2H).

[0607] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(dibenzylamino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (5.300 g, 9.657 mmol) in methanol (100 mL) and ammonium hydroxide (2 mL) was added 10% palladium on activated carbon (3.000 g, 28.19 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at 25° C. under hydrogen (15 Psi) for 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give crude (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (3.000 g, 8.140 mmol, 84% yield) which was used further without further purification. 1 H NMR(400MHz, DMSO-d6)δ4.17-4.03(m,2H),3.56(q,J=4.0Hz,1H),3.35(s,2H),2.47-2.39(m, 1H),1.77-1.60(m,8H),1.52-1.44(m,2H),1.39(s,9H),1.27-1.12(m,9H),1.01-0.79(m,4H).

[0608]

[0266] (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-aminocyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.500 g, 4.070 mmol) and methyl 2-bromo-2-methylpropanoate (3.680 g, 20.35 mmol) in acetonitrile (5 mL) was added sodium iodide (0.060 g, 0.410 mmol) and potassium carbonate (1.690 g, 12.21 mmol). The mixture was stirred at 110°C. After 12 h, the reaction solution was filtered and concentrated to afford crude (2R,4r,6S)-tert-butyl 4-(3-((1r,4R)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)propoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 4.054 mmol, 99.6% yield), which was used without further purification. MS (ESI) m / z 469.4 [M+1] + .

[0609] (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-dimethylpiperidin-1-carboxylate. To a solution of 2-(4-(2-yl)amino)cyclohexyl)propyloxy)-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 solution was stirred at 90°C. After 12 h, the reaction solution was filtered and concentrated and purified by standard methods to afford (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. 1H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.97(d d,J=1.6,8.4Hz,1H),4.14-4.06(m,2H),3.90-3.74(m,1H),3.59-3.54(m,1H ),3.40-3.37(m,2H),2.80-2.63(m,2H),1.80(d,J=12.0Hz,2H),1.75-1.70( m,6H),1.56-1.47(m,8H),1.39(s,9H),1.27-1.23(m,9H),1.18-1.16(m,2H).

[0610] 4-(3-((trans)-4-(3-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrobromide. To a solution of (2R,4r,6S)-tert-butyl 4-(3-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyloxy)-2,6-dimethylpiperidine-1-carboxylate (2.400 g, 3.610 mmol) in dichloromethane (20 mL) was added 33% hydrogen bromide in acetic acid (20 mL, 3.610 mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated to afford 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 used without further purification. MS (ESI) m / z 565.3 [M+1] + .

[0611] Benzyl 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)acetate. To a solution of (4-(trifluoromethyl)benzonitrile, (5-(4-piperidin-4-yl)oxy)propyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile and benzyl 2-bromoacetate (1.220 g, 5.310 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (3.080 mL, 17.71 mmol) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by standard methods to afford benzyl 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)acetate (0.800 g, 1.122 mmol, 32% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.4Hz,1H),8.20(d,J=2.0Hz,1H),7.97(d d,J=1.6,8.4Hz,1H),7.38-7.32(m,5H),5.09(s,2H),3.83(s,1H),3.53(s,2H ),3.23-3.15(m,1H),2.79-2.66(m,4H),1.88-1.77(m,4H),1.71(d,J=10.4Hz ,2H),1.54(s,6H),1.50-1.42(m,3H),1.23-1.15(m,4H),1.06-0.95(m,10H).

[0612] 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 (4-(2-(4-fluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)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 h, the reaction solution was adjusted to pH = 7 by the addition of aqueous HCl and concentrated to afford 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 used further without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd,J=1.6,8.4Hz,1H),3.83(s,1H),3.36(s,3H),3.18(s,4H),2.67(d,J=2 .0Hz,2H),1.88(d,J=12.4Hz,2H),1.81-1.78(m,2H),1.70(d,J=11.6Hz,2H ), 1.54 (s, 6H), 1.48 (d, J = 7.2Hz, 2H), 1.18 (s, 3H), 1.09 (d, J = 6.4Hz, 10H).

[0613] 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 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 h, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3 x 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 afford 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 / z 864.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ10.95-10.76(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),7.97(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).

[0614] 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

[0615]

[0616] 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 1-(5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-(4-(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 solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (20 mL) and washed with ethyl acetate (3 x 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 afford 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) δ11.26-10.80(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).

[0617] 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

[0618]

[0619] (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-dimethylpiperidin-1-carboxylate. To a solution of 4-(4-(2-(4-thiocyanato-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 solution was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-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) δ7.97-7.95(d,J=8.0Hz,1H),7.87(d,J=1.6Hz,1H),7.76-7.73(dd ,J=8.0,1.6Hz,1H),4.29-4.25(m,2H),3.87(s,1H),3.61-3.56(m,1H),3.49-3.46(t,J= 6.0Hz,2H),2.69(s,2H),1.98-1.91(m,4H),1.88-1.85(m,2H),1.75-1.69(m,2H),1.63 (s,6H),1.54-1.51(m,3H),1.49(s.9H),1.35-1.34(d,J=6.8Hz,6H),1.18-1.07(m,2H).

[0620]

[0266] 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 (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 2h, the reaction solution was concentrated, and the resulting material was absorbed in a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (4x 50mL). The combined organic layers were washed with brine (50mL), 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 (0.870g, 1.580mmol, 90% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.96-7.95(d,J=8.0Hz,1H),7.86(d,J=1.6Hz,1H),7.75-7.72(dd,J=8.0,1.6Hz,1H),3.86(s,1H),3.52-3.49(m,2H),3.35-3. 27(m,1H),2.75-2.59(m,4H),2.02-1.92(m,4H),1.86-1.83(m,2H),1.61( s, 6H), 1.52-1.49 (m, 3H), 1.16-1.14 (d, J = 6.4Hz, 6H), 1.10-0.96 (m, 4H).

[0621] Benzyl 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)acetate. To a solution of 4-(trifluoromethyl)benzonitrile (0.870.g, 1.580mmol) in acetonitrile (9mL) were added benzyl 2-bromoacetate (0.723g, 3.160mmol) and N-ethyl-N-isopropylpropan-2-amine (0.83mL, 4.740mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by standard methods to provide benzyl 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (1.100 g, 1.574 mmol) as a brown solid. MS (ESI) m / z 699.3 [M+1] + .

[0622] 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 benzyl 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 (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-(cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)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 solution was stirred at 50° C. After 12 h, the reaction solution was concentrated and extracted with 10:1 DCM / methanol (3 x 30 mL). The combined organic layers were dried over sodium sulfate and concentrated to provide 2-((2R,4r,6S)-4-(2-((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-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 forward without further purification. MS (ESI) m / z 609.3 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ8.34-8.32(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.98-7.96(dd,J=8.0,1.6Hz,1H),3.79(s,2H),3.16(s,2H),2.72 -2.67(m,2H),2.03-2.00(m,2H),1.81-1.70(m,4H),1.54(s,6H),1.45 -1.38(m,5H),1.27-1.19(m,7H),1.15-1.01(m,3H),0.87-0.80(m,2H).

[0623] 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 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) were 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 solution was concentrated and the resulting crude material was purified by standard methods to afford 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] + ; 1 H NMR (400MHz, DMSO-d6) δ11.11-10.92(m,1H),10.60(s,1H),9.20-9.15(m,2H),8.75(d,J=1.6Hz,1 H),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,2 H),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).

[0624] 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

[0625]

[0626]

[0266] (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)cyclohexylamine (5.660 g, 14.65 mmol) and (2S,4r,6R)-tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate (2.800 g, 12.21 mmol) in o-xylene (60 mL) were added potassium hydroxide (3.080 g, 54.95 mmol) and tetra-n-butylammonium bromide (0.790 g, 2.440 mmol) and the reaction mixture was stirred at 15 °C. After 12 h, the reaction solution was concentrated and purified by standard methods to afford (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)δ7.43-7.36(m,5H),7.30-7.26(m,4H),7.22-7.18(m,1H), 4.28-4.20(m,2H),3.63(s,3H),3.56-3.52(m,1H),3.42-3.39(m,2H),2.50-2. 44(m,1H),1.97-1.87(m,4H),1.80-1.77(m,2H),1.72-1.66(m,2H),1.62-1.55 (m,2H),1.47(s,9H),1.44-1.38(m,4H),1.32-1.30(m,6H),0.90-0.82(m,2H).

[0627]

[0147] (2R,4r,6S)-tert-Butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(dibenzylamino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (3.500 g, 6.540 mmol) in methanol (40 mL) were 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 at 20 °C under a molecular hydrogen atmosphere (15 Psi) for 12 h. The reaction mixture was poured into methanol (50 mL) and 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)δ4.12-4.08(m,2H),3.57-3.55(m,1H),3.41-3.38(m,5H),2.45-2.3 9(m,1H),1.73-1.65(m,8H),1.39-1.35(m,11H),1.25(d,J=6.8Hz,6H),0.98-0.84(m,4H).

[0628]

[0266] (2R,4r,6S)-tert-Butyl 4-(2-((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-aminocyclohexyl)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (1.900 g, 5.360 mmol) and methyl 2-bromo-2-methylpropanoate (3.880 g, 21.44 mmol) in acetonitrile (6 mL) were added potassium carbonate (2.220 g, 16.08 mmol) and sodium iodide (0.080 g, 0.540 mmol), and the reaction solution was stirred at 110°C. After 15 h, the reaction solution was diluted with ethyl acetate (15 mL), filtered and concentrated to afford 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 used further without further purification.

[0629] (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 5-(4-(2-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 solution was concentrated and purified by standard methods to provide (2R,4r,6S)-tert-butyl 4-(2-((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-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)δ8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),4.29-4.2 1(m,2H),3.82(m,1H),3.59-3.54(m,1H),3.48-3.45(t,J=6.4Hz,2H),2.68-2.5 9(m,2H),1.97-1.89(m,4H),1.85-1.82(m,2H),1.73-1.67(m,2H),1.63(s,6H), 1.54-1.49(m,3H),1.47(s,9H),1.34-1.32(d,J=7.2Hz,6H),1.14-1.05(m,2H).

[0630]

[0266] 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 (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 and the pH was adjusted to 7-8 by saturated sodium bicarbonate solution, extracted with ethyl acetate (50 mL×4), and 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) δ8.98(d,J=2.0Hz,1H),8.25(d,J=2.0Hz,1H),3.85(m,1H),3.51-3.49(m,2H),3.36-3.28(m,1H),2.78 -2.59(m,4H),2.03-1.92(m,5H),1.86(m,2H),1.63(s,6H),1.54-1.50(m,3H),1.17-1.16(d,J=6.4Hz,6H),1.10-1.00(m,4H).

[0631] 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. To a solution of 4-(4-(2-(4-(2-(4-(2-thiazolyl)-4-(ethyl)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.650 g, 1.180 mmol) in acetonitrile (12 mL) were 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 solution 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] + .

[0632]

[0146] 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 solution 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] + .

[0633] 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 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) were 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 solution was stirred at 50°C. After 12 h, the reaction solution was concentrated, taken up in DMSO and purified by standard methods to afford 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) δ11.08-10.91(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=1.6Hz,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 ),1.84-1.82(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).

[0634] 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

[0635]

[0636] (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)cyclohexylamine (3.680 g, 9.157 mmol) in xylene (30 mL) was added tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to afford (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.600 g, 4.721 mmol, 77% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.41-7.24(m,8H),7.23-7.13(m,2H),4.18-4.01(m,2H),3.63-3.52(m,5H),3.47(dd,J=2.8,9.2Hz,4H),3.19(t, J=10.8Hz,1H),2.39(t,J=11.6Hz,1H),1.98(d,J=10.2Hz,2H),1.85-1.66(m,6H),1.39(s,11H),1.24(d,J=7.2Hz,6H),1.01-0.88(m,2H).

[0637] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.600 g, 1.089 mmol) in methanol (5 mL) and THF (5 mL) was added 10% palladium on activated carbon (0.115 g, 1.089 mmol) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred at 25° C. under hydrogen (15 Psi) for 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give crude (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) as a colorless oil which was carried forward without further purification. MS (ESI) m / z 371.3 [M+1] + .

[0638]

[0266] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.400 g, 1.080 mmol) and methyl 2-bromo-2-methylpropanoate (0.977 g, 5.400 mmol) in acetonitrile (1 mL) were added potassium carbonate (0.448 g, 3.239 mmol) and sodium iodide (0.016 g, 0.108 mmol), and the reaction solution was stirred at 110°C. After 12 h, the reaction solution was filtered and concentrated to afford crude (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol), which was used without further purification. MS (ESI) m / z 471.4 [M+1] + .

[0639]

[0266] (2R,4r,6S)-tert-Butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.500 g, 1.062 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.242 g, 1.062 mmol) in ethyl acetate (5 mL) was added N,N-diisopropylethylamine (0.55 mL, 3.19 mmol) and the reaction solution was stirred at 90°C. After 12 h, the reaction solution was concentrated and purified by silica gel column chromatography to afford (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.470 g, 0.705 mmol, 66% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.0Hz,1H),8.19(d,J=1.6Hz,1H),7.97(dd, J=1.6,8.0Hz,1H),3.82(s,1H),3.62-3.60(m,2H),3.57-3.54(m,2H),3.31-3.2 5(m,1H),2.81(d,J=12.8Hz,2H),2.04(d,J=10.8Hz,2H),1.89(d,J=11.2Hz,2H ),1.75-1.72(m,5H),1.54(s,6H),1.39(s,9H),1.26(s,6H),1.20-1.15(m,4H).

[0640]

[0266] 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (0.470 g, 0.705 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2.0 mL, 25.78 mmol). The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated in vacuo to give crude 4-(3-((trans)-4-(2-(((2R,4r,6S)-2,6-dimethylpiperidin-4-yl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.400 g, 0.706 mmol) which was used further without further purification.

[0641] Tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate. To a solution of 4-(4-(2-(4-(2-(4-(2-thiazolyl)oxy)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.400 g, 0.706 mmol) and tert-butyl 2-bromoacetate (0.206 g, 1.059 mmol) in acetonitrile (5 mL) was added N,N-dimethylformamide (0.61 mL, 3.530 mmol) and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated and purified by standard methods to afford tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.150 g, 0.220 mmol, 31% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ8.33(d,J=8.4Hz,1H),8.19(d,J=1.6Hz,1H),7.97(d d,J=1.6,8.4Hz,1H),3.83(s,1H),3.49(s,4H),3.29-3.22(m,2H),2.83-2.7 1(m,4H),2.04(d,J=10.8Hz,2H),1.88(dd,J=4.0,11.6Hz,2H),1.70(d,J=10 .4Hz,2H),1.54(s,6H),1.40(s,9H),1.36-1.25(m,2H),1.06-0.92(m,10H).

[0642] 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid. To a solution of tert-butyl 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetate (0.150 g, 0.220 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.0 mL, 12.89 mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was concentrated to afford crude 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)acetic acid (0.150 g, 0.240 mmol) which was used further without further purification.

[0643] 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. To a solution of 1-(7-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.062 g, 0.240 mmol) in pyridine (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.123 g, 0.640 mmol) and the reaction solution was stirred at 50° C. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (2 x 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 afford 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 (0.048 g, 0.055 mmol, 34% yield) as an off-white solid. MS (ESI) m / z: 866.5 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.57 (s, 1H), 9.89 (s, 1H), 8.33 (d, J = 8.2Hz, 1H), 8.19 (d, J = 1.2Hz, 1H), 7.97 (dd, J=1.5,8.2Hz,1H),7.50(d,J=8.1Hz,1H),7.31(d,J=7.2Hz,1H),7.08(t,J=7.8Hz,1H),4.09(s,3H),3.89(t, J=6.7Hz,2H),3.87-3.77(m,1H),3.52(s,4H),3.32-3.23(m,4H),2.89-2.74(m,4H),2.69-2.59(m,2H),2.0 7-2.01(m,2H),1.95-1.85(m,2H),1.75-1.67(m,2H),1.54(s,6H),1.39-1.19(m,4H),1.17(d,J=6.2Hz,6H).

[0644] Example 34: 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0645]

[0646] (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)cyclohexylamine (3.680 g, 9.157 mmol) in xylene (30 mL) was added tetrabutylammonium bromide (0.394 g, 1.221 mmol) and potassium hydroxide (1.713 g, 30.53 mmol), and the reaction solution was stirred at room temperature. After 12 h, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude material was purified by standard methods to afford (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-(dibenzylamino)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate (2.600 g, 4.721 mmol, 77% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.41-7.24(m,8H),7.23-7.13(m,2H),4.18-4.01(m,2H),3.63-3.52(m,5H),3.47(dd,J=2.8,9.2Hz,4H),3.19(t, J=10.8Hz,1H),2.39(t,J=11.6Hz,1H),1.98(d,J=10.2Hz,2H),1.85-1.66(m,6H),1.39(s,11H),1.24(d,J=7.2Hz,6H),1.01-0.88(m,2H).

[0647] (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-aminocyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidine-1-carboxylate. To a solution of (2R,4r,6S)-tert-butyl 4-(2-(((trans)-4-...

Claims

1. A compound having formula I or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 1-3 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 selected from H; m is 1 or 2; Each R 4 are independently methyl or trifluoromethyl; L is -O(CH2) p -、-(C 1-6 Alkyl)O-, -O(C 1-6 alkyl)O- or -(CH2) p -, and p is 1-4; X is N or CR X ; R X It is hydrogen; V is in B is N or CH; R C is halogen, CF3 or SF5; R 5 and R 6 It is C 1-3 alkyl; and b is 0.

2. The compound of claim 1, wherein R 1 It's methyl.

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

4. The compound of claim 1, wherein each R 4 It's methyl.

5. The compound of claim 1, wherein L is -O(CH2) p -、O(CH2) p O- or -(CH2) p -, and p is 1-4.

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

7. The compound of claim 1, wherein R C It is CF3, Cl or SF5.

8. The compound of claim 1, wherein R 5 and R 6 It's methyl.

9. A compound having the formula II, or a pharmaceutically acceptable salt thereof, in R 1 It is a methyl group; A is CH2 or C=O; A' is NH or O; a is 1 or 2; R 2 and R 3 It is H; Each R 4m are independently H, methyl or trifluoromethyl; L is -O(C 1-3 alkyl)-, -O(C 1-3 alkyl)O- or -(C 1-4 alkyl)-; V is in B is N or CH; R C is Cl, CF3 or SF5; R 5 and R 6 is methyl; and b is 0.

10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide, 2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide, and 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 2-((S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide, 2-((R)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide, 2-((R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-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, 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, 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, and 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.

12. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 2-(4-(2-(((trans)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide, and 2-(4-(2-(((trans)-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide.

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

14. Use of an effective amount of a compound as claimed in any one of claims 1 to 12 or a pharmaceutical composition as claimed in claim 13 in the preparation of a medicament for treating an androgen receptor-mediated disease in a subject in need thereof, wherein the androgen receptor-mediated disease is prostate cancer.

15. The use of claim 14, wherein the prostate cancer is castration-resistant prostate cancer.

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