Substituted 3-((3-aminophenyl) amino) piperidine-2, 6-dione compounds, compositions thereof and methods of treatment using same

Abstract

Provided herein are piperidinedione compounds having the following structure (I) wherein RN, R1, R2, R3, R4, L, V, m and n are as defined herein; a composition comprising an effective amount of a piperidinedione compound; and methods for treating or preventing androgen receptor mediated diseases. # imgabs0 #

Description

[0001] Related applications

[0002] This application is a divisional application of the Chinese invention patent application filed on December 18, 2019, with the invention name “Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof and treatment methods using the same” and application number 201980092358.2.

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 782,298, filed December 19, 2018, and U.S. Provisional Application No. 62 / 879,900, filed July 29, 2019, the disclosures of each of which are incorporated herein by reference in their entirety. Technical Field

[0004] Provided herein are certain 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions comprising effective amounts of such compounds, and methods for treating or preventing androgen receptor-mediated diseases, comprising administering to a subject in need thereof an effective amount of such 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds. Also provided herein are compounds and compositions for use in such methods. Background Art

[0005] It is known that androgen receptor signaling plays a key role in the pathogenesis of prostate cancer and is associated with the emergence 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 using antiandrogens that have an antagonistic effect on androgen receptors has been used or proposed for the treatment of prostate cancer.

[0006] The androgen receptor normally resides in the cytoplasm bound to chaperones such as HSP90 (Brinkmann AO et al., J Steroid Biochem Mol Biol, 1999, 69:307-13). After binding to dihydrotestosterone (DHT), the androgen receptor changes its conformation and translocates to the nucleus where it binds to androgen response elements (AREs) that drive transcription of typical targets such as KLK3 (also known as prostate-specific antigen PSA), TMPRSS2 and KLK2 (Tran C et al., Science, 2009, 324:787-90; Murtha P et al., Biochemistry (Mosc.), 1993, 32:6459-64).

[0007] Prostate cancer (PCa) is one of the most commonly diagnosed non-skin cancers in American men and the second leading cause of cancer death in the United States, with more than 200,000 new cases and over 30,000 deaths each year.

[0008] 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 by bilateral orchiectomy. Regardless of the initial response to ADT, disease progression is inevitable, and the cancer manifests as castration-resistant prostate cancer (CRPC). Up to 30% of prostate cancer patients who undergo primary treatment with radiation or surgery will develop metastatic disease within 10 years of primary treatment. Approximately 50,000 patients a year will develop a metastatic disease known as metastatic CRPC (mCRPC).

[0009] There remains a great need for safe and effective methods to treat, prevent, and manage AR-mediated diseases, particularly those that are refractory to standard treatments such as surgery, radiotherapy, chemotherapy, and hormone therapy, while reducing or avoiding the toxicities and / or side effects associated with conventional therapies.

[0010] 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

[0011] Provided herein are compounds having the following formula (I):

[0012]

[0013] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein R N 、R 1 、R 2 、R 3 、R 4 , X, L, V, m and n are as defined herein.

[0014] A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof (each referred to herein as a "piperidinedione compound") can be used to treat or prevent an androgen receptor-mediated disease in a subject.

[0015] In one aspect, provided herein are piperidinedione compounds as described in the present disclosure (such as in Table 1).

[0016] 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 piperidinedione compound as described herein and a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical compositions are suitable for oral, parenteral, transmucosal, transdermal, or topical administration.

[0017] In one aspect, provided herein are methods for treating or preventing an androgen receptor-mediated disease in a subject, the methods 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 an androgen receptor-mediated disease in a subject, the methods comprising administering to a subject in need thereof: an effective amount of a piperidinedione compound as described herein; and a pharmaceutically acceptable carrier, excipient, or vehicle. In another aspect, provided herein are compounds suitable for use in methods of treating androgen receptor-mediated diseases. In another aspect, provided herein are piperidinedione compounds suitable for use in methods of treating androgen receptor-mediated diseases.

[0018] In another aspect, provided herein are methods for preparing the compounds as described herein. In another aspect, provided herein are methods for preparing the piperidinedione compounds as described herein.

[0019] The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments. DETAILED DESCRIPTION

[0020] definition

[0021] 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 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 examples 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.

[0022] The term "consisting of" means that the subject matter comprises at least 90%, 95%, 97%, 98%, or 99% of its features or components. In another embodiment, the term "consisting of" excludes any other features or components from any subsequently listed category, except for features or components that are not essential for the technical effect to be achieved.

[0023] 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 of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." An exception to this definition would only occur if a combination of elements, functions, steps, or actions are inherently mutually exclusive in some way.

[0024] "Alkyl" is a saturated, partially saturated, or unsaturated straight or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. In some embodiments, the alkyl group is an unsaturated alkyl group, also known as an alkenyl or alkynyl group. "Alkenyl" is an alkyl group containing one or more carbon-carbon double bonds. "Alkynyl" 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(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. The alkyl group may be substituted or unsubstituted. When an alkyl group described herein is referred to as "substituted," the alkyl group may be substituted with any one or more substituents, such as those present in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocyclylalkyloxy, cycloalkylalkoxy, aralkyloxy, heterocyclylalkoxy, heteroarylalkoxy, heterocyclylalkylalkoxy; oxo (═O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocyclylalkylamino, cycloalkyl ... Alkylamino, heterocyclylalkylamino, heteroaralkylamino, heterocyclylalkylalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxyamino; alkoxyamino; aralkyloxyamino; hydrazine; hydrazide; hydrazono; azido; nitro; sulfenyl (-SH), alkylsulfenyl; =S; sulfoxide; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxyl; ester; carbamate; amide; cyano; isocyanate; isothiocyanate; cyanate; thiocyanate; or -B(OH)2.In certain embodiments, when an alkyl group described herein is referred to as "substituted," the alkyl group may be substituted with any one or more substituents, such as those present in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfoxide; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)2 or O(alkyl)aminocarbonyl.

[0025] "Cycloalkyl" is a saturated or partially saturated cycloalkyl group having 3 to 10 carbon atoms, with a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. In some embodiments, the cycloalkyl group is a saturated cycloalkyl group. Such saturated cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like; or polycyclic or bridged ring structures such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. In other embodiments, the cycloalkyl group is an unsaturated cycloalkyl group. Examples of unsaturated cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and other groups. The cycloalkyl group may be substituted or unsubstituted. Such substituted cycloalkyl groups include, for example, cyclohexanol and the like.

[0026] "Aryl" is an aromatic carbocyclic group having 6 to 14 carbon atoms, having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthracenyl). In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The term "aryl" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0027] "Heteroaryl" is an aromatic ring system having one to four heteroatoms as ring atoms in the heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 3 to 6 ring atoms, and in other embodiments, contains 6 to 9 or even 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, 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), imidazolyl The heteroaryl group may be substituted or unsubstituted.

[0028] "Heterocyclyl" is an aromatic (also known as heteroaryl) or non-aromatic cycloalkyl group in which one to four ring carbon atoms are independently replaced by heteroatoms from the group consisting of O, S, and N. In some 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 may also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocycle). The heterocycloalkyl group may be substituted or unsubstituted. Heterocyclyl encompasses unsaturated, partially saturated, and saturated ring systems such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dione). The term heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 1-aminotetralin 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 term also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidine.Representative examples of heterocyclyl include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-one or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, 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-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxy, dithianyl, pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridinyl, dihydrodithiinyl, dihydrodisulfinyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidine, indolyl (e.g., indolyl-2-onyl or isoindolyl-1-onyl), indolyl, isoindolyl, isoindolyl, azaindolyl (pyrrolopyridinyl or 1H-pyrrolo[2,3-b]pyridinyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzo Thiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl), imidazopyridinyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridinyl), triazolopyridinyl, isoxazolopyridinyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-one), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, etc. Representative non-aromatic heterocyclic groups include pyridinyl, pteridinyl, thiapyridinyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolinyl, dihydrobenzodioxinyl, tetrahydroindolinyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridinyl, tetrahydropyrazolopyridinyl, tetrahydroimidazopyridinyl, tetrahydrotriazolopyridinyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl. Representative non-aromatic heterocyclic groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclic groups include aziridinyl, azetidinyl, azepanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decyl, homopiperazinyl, quinuclidinyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclic groups may be monosubstituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl, which are 2-, 3-, 4-, 5-, or 6-substituted or disubstituted with various substituents such as those listed below.

[0029] As used herein and unless otherwise specified, "cycloalkylalkyl" is a radical having the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups may be substituted on the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the radical. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0030] As used herein and unless otherwise specified, an "aralkyl" group is a group having the formula: -alkyl-aryl, in which the alkyl and aryl groups are as defined above. Substituted aralkyl groups 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, as well as aralkyl groups in which the aryl group is fused to a cycloalkyl group, such as indan-4-ylethyl.

[0031] As used herein and unless otherwise specified, "heterocyclylalkyl" is a radical of the formula: -alkyl-heterocyclyl, in which alkyl and heterocyclyl are as defined above. "Heteroarylalkyl" is a radical of the formula: -alkyl-heteroaryl, in which alkyl and heteroaryl are as defined above. "Heterocycloalkylalkyl" is a radical of the formula: -alkyl-heterocycloalkyl, in which alkyl and heterocycloalkyl are as defined above. Substituted heterocyclylalkyls may be substituted on the alkyl, heterocyclyl, or both the alkyl and heterocyclyl portions of the radical. Representative heterocyclylalkyls 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.

[0032] "Halogen" is fluorine, chlorine, bromine or iodine.

[0033] "Hydroxyalkyl" is an alkyl group as described above substituted with one or more hydroxy groups.

[0034] "Alkoxy" is -O-(alkyl) where alkyl is as defined above.

[0035] "Alkoxyalkyl" is -(alkyl)-O-(alkyl) where alkyl is as defined above.

[0036] "Amino" is a group having the formula: -NH2, -NH(R # ) or -N(R # )2, where each R # is independently alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) as defined above, each of which is independently substituted or unsubstituted.

[0037] In one embodiment, "amino" is "alkylamino", which is a group having the following formula: -NH-alkyl or -N(alkyl), wherein each alkyl group is independently as defined above. The term "cycloalkylamino", "arylamino", "heterocyclylamino", "heteroarylamino", "heterocycloalkylamino" or the like is as described above for "alkylamino", wherein the term "alkyl" is replaced by "cycloalkyl", "aryl", "heterocyclyl", "heteroaryl", "heterocycloalkyl" or the like, respectively.

[0038] A "carboxy" group is a group having the formula: -C(O)OH.

[0039] 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 #As defined above. "Formyl" is a group having the formula: -C(O)H.

[0040] 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 as defined above.

[0041] In one embodiment, "amido" is "aminocarbonyl," which is a group having the formula: -C(O)-NH2, -C(O)-NH(R # )、-C(O)-N(R # )2, where each R # are independently as defined above.

[0042] In one embodiment, "amido" is "acylamino," 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 as defined above.

[0043] "Sulfonylamino" is a radical having the formula: -NHSO2(R # ) or -N(alkyl)SO2(R # ), wherein each alkyl group and R # As defined above.

[0044] 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.

[0045] When groups described herein other than alkyl are referred to as "substituted," they may be substituted with any one or more suitable substituents. Illustrative examples of substituents are those present in the exemplary compounds and embodiments disclosed herein as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxyl; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfoxide; sulfone; sulfonamide; ketone; aldehyde; ester; urea; carbamate; oxime; hydroxylamine; alkoxyamine; aralkyloxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (=O); B(OH)2, O(alkyl)aminocarbonyl ; cycloalkyl, which can be a monocyclic or fused or non-fused polycyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), or heterocyclyl, which can be a monocyclic or fused or non-fused polycyclic ring (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, pyridyl, quinolyl, isoquinolyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl); aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclylalkoxy.

[0046] As used herein, the term "piperidinyldione compound" refers to compounds of formula (I) and other embodiments provided herein. In one embodiment, the "piperidinyldione compound" is a compound as described in Table 1. The term "piperidinyldione compound" includes pharmaceutically acceptable salts, tautomers, isotopomers, and stereoisomers of the compounds provided herein.

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, 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, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Examples of specific salts therefore include hydrochlorides, formates, and mesylates. 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).

[0048] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of a piperidinedione compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having 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. The piperidinedione compounds may have chiral centers and may exist as racemates, single enantiomers or diastereomers and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0049] The embodiments disclosed herein encompass the use of stereoisomerically pure forms of such piperidinedione compounds as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular piperidinedione compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetric synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and OpticalResolutions page 268 (EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0050] It should also be noted that the piperidinedione compound may include an E isomer and a Z isomer or a mixture thereof, and a cis isomer and a trans isomer or a mixture thereof. In certain embodiments, the piperidinedione compound is separated in the form of an E isomer or a Z isomer. In other embodiments, the piperidinedione compound is a mixture of an E isomer and a Z isomer.

[0051] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms will depend on the environment in which the compound is present and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0052]

[0053] As those skilled in the art readily appreciate, various functional groups and other structures may exhibit tautomerism, and all tautomers of compounds of formula (I) are within the scope of the present invention.

[0054] It should also be noted that the piperidinedione compounds may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or may be isotopically enriched, such as deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N). 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" may also refer to a compound containing at least one of the following atoms, each of which has an isotopic composition other than the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds can be used as therapeutic agents (e.g., cancer therapeutic agents), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the piperidinedione compounds as described herein (whether or not radioactive) are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, an isotopologue of a piperidinedione compound is provided, for example, an isotopologue is a piperidinedione compound enriched in deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" means a substance in which at least one hydrogen (H) has been deuterated (by D or 2 H represents) substituted compounds, i.e., the compounds are enriched in deuterium at at least one position.

[0055] It will be understood that, independently of the stereoisomeric composition or isotopic composition, each piperidinedione compound mentioned herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Similarly, it will be understood that the isotopic composition can be varied independently of the stereoisomeric composition of each piperidinedione compound mentioned herein. In addition, although the isotopic composition is limited to those elements present in each piperidinedione compound or its salt, the isotopic composition can be varied in other ways independently of the selection of the pharmaceutically acceptable salt of each piperidinedione compound.

[0056] It should be noted that if a depicted structure is inconsistent with the name of the structure, the depicted structure is given greater consideration.

[0057] As used herein, "treating" means the complete or partial relief of a condition, disease, or disorder, or one or more symptoms associated with the condition, disease, or disorder, or the slowing or arresting of further progression or worsening of those symptoms, or the alleviation or eradication of the cause of the condition, disease, or disorder itself. In one embodiment, the condition is an androgen receptor-mediated disease or a symptom thereof as described herein.

[0058] As used herein, "prevention" means a method of: delaying and / or preventing the complete or partial onset, recurrence, or spread of a condition, disease, or disorder; preventing a subject from developing a condition, disease, or disorder; or reducing the risk of a subject developing a condition, disease, or disorder. In one embodiment, the condition is an androgen receptor-mediated disease or a symptom thereof as described herein.

[0059] The term "effective amount" with respect to a piperidinedione compound means an amount capable of treating or preventing a condition, disease or disorder disclosed herein, or a symptom thereof.

[0060] 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, in one embodiment mammals, in another embodiment humans. In one embodiment, the subject is a human having a disease mediated by an androgen receptor, or having symptoms thereof, or being at risk of developing the disease.

[0061] 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).

[0062] 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 to 3), the hinge domain (exon 4), and the C-terminal ligand binding domain (LBD, exons 4 to 8).

[0063] The term "castration-resistant prostate cancer" (CRPC) refers to advanced prostate cancer that worsens or progresses while the patient remains on androgen ablation therapy or other therapies to lower testosterone, or is considered hormone-refractory, hormone-naive, androgen-independent, or resistant to chemical or surgical castration. Castration-resistant prostate cancer (CRPC) is advanced prostate cancer that develops despite ADT and / or surgical castration. Castration-resistant prostate cancer is defined as prostate cancer that has progressed despite prior surgical castration with gonadotropin-releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamicin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib), or gefitinib Cabozantinib ( Also known as XL184)) or other prostate cancer therapies (e.g., vaccines (sipuleucel-T) GVAX, etc.), herbal remedies (PC-SPES) and resolvase inhibitors (abiraterone), but the prostate cancer continues to progress or worsen or adversely affects the patient's health status, as evidenced by increased or higher prostate specific antigen (PSA) serum levels, cancer metastasis, bone cancer metastasis, pain, lymph node metastasis, increased size or serum markers of tumor growth, worsening of prognostic diagnostic markers or disease condition.

[0064] Piperidinedione compounds

[0065] Provided herein are compounds having the following formula (I):

[0066]

[0067] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof,

[0068] in:

[0069] R N is H;

[0070] Each R 1 independently selected from halogen, CN and C 1-3 alkyl;

[0071] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is connected forms a substituted or unsubstituted C 3-6 Cycloalkyl;

[0072] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0073] X is N;

[0074] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0075] n is 0 to 4;

[0076] m is 0 to 8;

[0077] V is

[0078]

[0079] in

[0080] A is N, CH or CR A ;

[0081] B is N, CH or CR B ;

[0082] Each R Aare independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0083] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0084] R C is halogen or CF3;

[0085] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0086] a is 0 to 3; and

[0087] b is 0 to 2.

[0088] Provided herein are compounds having the following formula (I):

[0089]

[0090] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof,

[0091] in:

[0092] R N is H;

[0093] Each R 1 independently selected from halogen, CN and C 1-3 alkyl;

[0094] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is connected forms a substituted or unsubstituted C 3-6 Cycloalkyl;

[0095] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0096] X is N;

[0097] L is -O(CH2) p -or-(CH2) p -;

[0098] n is 0 to 4;

[0099] m is 0 to 8;

[0100] p is 1 to 3;

[0101] V is

[0102]

[0103] in

[0104] A is N, CH or CR A ;

[0105] B is N, CH or CR B ;

[0106] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0107] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0108] R C is halogen or CF3;

[0109] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-5 Cycloalkyl or 3- to 5-membered heterocyclic group;

[0110] a is 0 to 3; and

[0111] b is 0 to 2.

[0112] In one embodiment of the compound of formula (I), the compound is

[0113]

[0114] In another embodiment of the compound of formula (I), the compound is

[0115]

[0116] In some embodiments of compounds of Formula (I), Formula (IIa), and Formula (IIb), each R 1 independently selected from halogen and C 1-3 In some embodiments of the compounds of Formula (I), Formula (IIa), and Formula (IIb), each R 1 In other embodiments, each R 1 In some other embodiments, each R 1 Independently selected from Cl, F and CN.

[0117] In some embodiments of the compound of formula (I), n is 0. In other embodiments, n is 1 or 2.

[0118] In some embodiments of the compound of formula (I), the compound is

[0119]

[0120] In other embodiments of the compound of formula (I), the compound is

[0121]

[0122] In yet other embodiments of the compound of formula (I), the compound is

[0123]

[0124] In some embodiments, the compound is of formula (III), formula (IV), or formula (V), wherein each R 1 In some such embodiments, the compound is of formula (III), formula (IV) or formula (V), wherein R 1 is F or Cl. In some embodiments of the compound of formula (III), R 1 is F, Cl or CN. In some embodiments of the compound of formula (IV), R 1 For F.

[0125] In some embodiments of the compound of Formula (I), R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R3 In some such embodiments, R 2 and R 3 are each independently selected from H and methyl, or R 2 and R 3 In some other embodiments, R 2 and R 3 Both are H or methyl, or R 2 and R 3 and the carbon to which it is attached to form an unsubstituted cyclopropyl group. 2 and R 3 For H.

[0126] In some embodiments of the compound of Formula (I), each R 4 are independently selected from substituted or unsubstituted methyl and ethyl, or two R 4 The groups, taken together with the same carbon atom to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl group. 4 are independently substituted or unsubstituted methyl, or two R 4 The groups together with the same carbon atom to which they are attached form an unsubstituted cyclopropyl group. In yet other embodiments, each R 4 are independently selected from methyl, CF3 and CH2OH, or two R 4 The groups together with the same carbon atom to which they are attached form an unsubstituted cyclopropyl group. In yet other embodiments, R 4 In some embodiments, R 4 For ethyl.

[0127] In some embodiments of the compound of Formula (I), m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, or 2.

[0128] In some embodiments of the compound of Formula (I), both R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms an unsubstituted 4- to 7-membered heterocyclic group. In some such embodiments, the compound is

[0129]

[0130] In some such embodiments, the compound is

[0131]

[0132] In some such embodiments, the compound is

[0133]

[0134] In some embodiments of compounds of Formula (I), (IIa)-, (IIb), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), exemplary L groups include, but are not limited to, -O(CH)(CH)-, -O(CH)(CH(CH3))-, -O(CH)(C(CH3))-, -O(CH(CH3))(CH2)-, -O(C(CH3))(CH2)-, -O(CH(CH3))(CH(CH3))-, -O(CH(CH3))(CH(CH3))-, -O(CH(CH3))(C(CH3))- , -(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(C(CH3)2)(C(CH3)2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CH(CH3))(CH(CH3))-, -(CH(CH3))(C(CH3 )2)-, -(C(CH3)2)(CH(CH3))-, -(C(CH3)2)(C(CH3)2)-, -(CH3)(CH3)(CH(CH3))-, -(CH2)(CH(CH3))(CH2)-, -(CH(CH3))(CH2)(CH2)-, -(CH2)(CH 2)(C(CH2)2)-, -(CH2)(C(CH2)2)(CH2)-, -(C(CH2)2)(CH2)(CH2)-, -(CH2)(CH(CH3))(CH(CH3))-, -(CH(CH3))(CH(CH3))(CH(CH3))-, -(CH(CH3) )(CH(CH3))(CH2)-, -(CH(CH3))(CH2)(CH(CH3))-, -(CH2)(CH(CH3))(C(CH3)2)-, -(CH(CH3))(CH2)(C(CH2)2)-, -(C(CH3)2)(CH2)(C(CH3)2)-,- (CH2)(C(CH3)2)(C(CH3)2)-, -(CH2)(C(CH3)2)(CH(CH3))-, -(CH(CH3)(C(CH3)2)(CH2)-, -(C(CH3)2)(CH2)(CH(CH3))-, -(C(CH3)2)(CH(CH3))( CH2)-, -(C(CH3)2)(C(CH3)2)(CH2)-, -(CH(CH3))(CH(CH3))(C(CH3)2)-, -(CH(CH3))(C(CH3)2)(C(CH3)2)-, -(C(CH3)2)(CH(CH3))(C(CH3)2)-,-(CH(CH3))(C(CH3)2)(CH(CH3))-, -(C(CH3)2)(C(CH3)2)(CH(CH3))-, -(C(CH3)2)(CH(CH3))(CH(CH3))-, and -(C(CH3)2)(C(CH3)2)(C(CH3)2)-. ,

[0135] In some embodiments of the compound of formula (I), L is -O(CH2)(CH2)-, -O(CH2)(CH(CH3))-, -O(CH2)(C(CH3)2)-, -O(CH(CH3))(CH2)-, O(CH(CH3))(CH(CH3))-, -O(CH(CH3))(CH(CH3))-, -O(CH(CH3)(C(CH3)2)-, -O(C(CH3)2)(CH2)-, -(CH2)-, -(CH2)(CH2)-, or -(CH2)(CH2)(CH2)-. In some embodiments of the compound of formula (I), L is -O(CH2)(CH2)-, -O(CH2)(CH(CH3))(CH2)-, -O(CH2)(CH(CH3))(CH2)-, -O(CH2)(CH(CH3))(CH2)-, -O(CH2)(CH(CH2))(CH2)-, -O(CH2)(CH(CH2))(CH2)-, -O(CH2)(CH(CH2))(CH2)-, -O(CH2)(CH(CH2))(CH2)-, -O(CH2)(CH(CH3 ...3))(CH2)-, -O(CH2)(CH(CH3))(CH2)-, -O(CH2)(CH(CH3))(CH2)-, -O(CH2)(CH(CH3))(CH2)-, - In some embodiments of the compound of formula (I), L is -O(CH)(CH)-, -O(CH)(CH(CH3))-, -O(CH(CH3))(CH2)-, or -(CH)(CH)(CH2)-. In other embodiments, L is -O(CH)(CH)- or -(CH)(CH)(CH2)-. In still other embodiments, L is -O(CH)(CH)-. In some embodiments of the compound of formula (I), L is -O(CH)(CH)-, -O(CH)(CH(CH3))-, -O(CH(CH3))(CH2)-, or -(CH)(CH)(CH2)-.

[0136] In some embodiments of compounds of formula (I), A is CH. In some other embodiments of compounds of formula (I), B is CH. In some other embodiments, B is N.

[0137] In some embodiments of the compound of Formula (I), a is 0, 1 or 2.

[0138] In some embodiments of the compound of Formula (I), each R A R is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3)CH(CH3)2, CF3, CF(CH3)2, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl, and cyclopentyl. In some such embodiments, each R AR is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl. In some embodiments, wherein B is CH, each R A In other embodiments, wherein B is N, each R A R is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, cyclopropyl, and cyclobutyl. In some such embodiments, each R A Independently selected from ethyl, isopropyl and cyclopropyl.

[0139] In some embodiments of the compound of Formula (I), b is 0 or 1. In some embodiments of the compound of Formula (I), R B In some embodiments of the compound of formula (I), R C It is CF3 or Cl.

[0140] In some embodiments of the compound of Formula (I), R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, tetrahydrofuranyl, or tetrahydropyranyl group. 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a cyclobutyl or tetrahydrofuranyl group. In some embodiments, R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl group.

[0141] In some embodiments of the compound of Formula (III), Formula (IV), or Formula (V), each R 1 are independently selected from Cl, F, CN and CH3, and R 2 and R 3 is H. In some such embodiments, each R 4 are independently selected from methyl, CF3 and CH2OH, or two R 4The groups, taken together with the same carbon atom to which they are attached, form an unsubstituted cyclopropyl group. In some such embodiments, R 4 In some such embodiments, R 4 In some other such embodiments, L is -O(CH2)(CH2)- or -(CH2)(CH2)(CH2)-. In some other such embodiments, L is -O(CH2)(CH(CH3))-, -O(CH(CH3))(CH2)-. In still other such embodiments, A is CH. In still other such embodiments, B is CH, and each R A R is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, cyclopropyl, cyclobutyl and cyclopentyl. In other such embodiments, B is N, and each R A is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, and cyclopropyl. In some other such embodiments, each R A is ethyl, isopropyl or cyclopropyl. In yet other such embodiments, R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a cyclobutyl or tetrahydrofuranyl group. In some embodiments, R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl group.

[0142] In some embodiments of compounds of Formula (I), Formula (IIa), and Formula (IIb),

[0143] R N is H;

[0144] Each R 1 Independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl;

[0145] R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 Forming a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl group with the carbon to which it is attached;

[0146] Each R4 are independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 The group and the same carbon atom or adjacent carbon atoms to which it is attached together form a substituted or unsubstituted cyclopropyl or cyclobutyl group, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0147] X is N;

[0148] L is -O(C 1-5 alkyl)- or -(C 1-5 alkyl)-;

[0149] n is 0 to 4;

[0150] m is 0 to 2;

[0151] V is

[0152]

[0153] in

[0154] A is N, CH or CR A ;

[0155] B is N, CH or CR B ;

[0156] Each R A independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3)CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl;

[0157] Each R B independently selected from halogen and methyl;

[0158] R C is halogen or CF3;

[0159] R 5 and R 6 is methyl, or R 5 and R 6 together with the carbon atom to which it is attached, form a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl group;

[0160] a is 0 to 3; and

[0161] b is 0 to 2.

[0162] In some embodiments of compounds of Formula (I), Formula (IIa), and Formula (IIb),

[0163] R N is H;

[0164] Each R 1 Independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl;

[0165] R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 Forming a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl group with the carbon to which it is attached;

[0166] Each R 4 are independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 The group and the same carbon atom or adjacent carbon atoms to which it is attached together form a substituted or unsubstituted cyclopropyl or cyclobutyl group, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0167] X is N;

[0168] L is -O(CH2) p -or-(CH2) p -;

[0169] n is 0 to 4;

[0170] m is 0 to 2;

[0171] p is 1 to 3;

[0172] V is

[0173]

[0174] in

[0175] A is N, CH or CR A ;

[0176] B is N, CH or CR B ;

[0177] Each R Aindependently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3)CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl;

[0178] Each R B independently selected from halogen and methyl;

[0179] R C is halogen or CF3;

[0180] R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cyclobutyl or tetrahydrofuranyl group;

[0181] a is 0 to 3; and

[0182] b is 0 to 2.

[0183] In some embodiments of the compounds of Formula (III), Formula (IV), and Formula (V),

[0184] R N is H;

[0185] Each R 1 Independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl;

[0186] R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 Forming a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl group with the carbon to which it is attached;

[0187] Each R 4 are independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 The group and the same carbon atom or adjacent carbon atoms to which it is attached together form a substituted or unsubstituted cyclopropyl or cyclobutyl group, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0188] X is N;

[0189] L is -O(C 1-5 alkyl)- or -(C 1-5 alkyl)-;

[0190] n is 0 to 4;

[0191] m is 0, 1, or 2;

[0192] V is

[0193]

[0194] in

[0195] A is N, CH or CR A ;

[0196] B is N, CH or CR B ;

[0197] Each R A independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3)CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl;

[0198] Each R B independently selected from halogen and methyl;

[0199] R C is halogen or CF3;

[0200] R 5 and R 6 is methyl, or R 5 and R 6 together with the carbon atom to which it is attached, form a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl group;

[0201] a is 0 to 3; and

[0202] b is 0 to 2.

[0203] In some embodiments of the compounds of Formula (III), Formula (IV), and Formula (V),

[0204] R N is H;

[0205] Each R 1 Independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl;

[0206] R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 Forming a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl group with the carbon to which it is attached;

[0207] Each R 4 are independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 The group and the same carbon atom or adjacent carbon atoms to which it is attached together form a substituted or unsubstituted cyclopropyl or cyclobutyl group, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic ring;

[0208] X is N;

[0209] L is -O(CH2) p -or-(CH2) p -;

[0210] n is 0 to 4;

[0211] m is 0, 1, or 2;

[0212] p is 1 to 3;

[0213] V is

[0214]

[0215] in

[0216] A is N, CH or CR A ;

[0217] B is N, CH or CR B ;

[0218] Each R A independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3)CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl;

[0219] Each R B independently selected from halogen and methyl;

[0220] R Cis halogen or CF3;

[0221] R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted cyclobutyl or tetrahydrofuranyl group;

[0222] a is 0 to 3; and

[0223] b is 0 to 2.

[0224] Other embodiments provided herein include any combination of one or more of the specific embodiments set forth above.

[0225] In some embodiments of the compound of Formula (I), the compound is a compound from Table 1.

[0226] Representative compounds of Formula (I)-(II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), or Formula (X) are described in Table 1.

[0227] The piperidinedione compounds described in Table 1 were tested in the AR-mediated assays described herein and found to be active in the assays. In one embodiment, the piperidinedione compound is as described herein, wherein a 1 μM concentration of the compound causes AR protein degradation by at least about 50% or more.

[0228] Method for preparing piperidinedione compounds

[0229] The piperidinedione compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or methods provided herein. For example, but not limited to, piperidinedione compounds of formula (I) can be prepared as outlined in Schemes 1 to 8 shown below and in the Examples described herein, wherein R N 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R A 、R B 、R c , L, V, X, n, m, p, a and b are as defined herein. It should be noted that one skilled in the art will know how to modify the procedures set forth in the illustrative schemes and examples to obtain the desired products.

[0230]

[0231] As shown in Scheme 1, the piperidinedione compound of formula (I) (wherein L is -O(C 1-6 Alkyl)-): phenol (A is CH or CR A ) or a pyridone (A is N) derivative V-OH with an appropriately derivatized and N-protected piperazinyl (e.g., wherein P N Boc and detached from LG 1 is Br, Cl, OTs or OMs) at high temperature (e.g., temperature between about 40°C and about 70°C) in a solvent in the presence of a base (e.g., in DMF in the presence of CsCO3 or in acetonitrile in the presence of K2CO3) to give intermediate a. Alternatively, when LG 1 When V-OH is -OH, treatment of V-OH under Mitsunobu conditions (e.g., at room temperature in a solvent such as THF with PPh3 and DIAD or DEAD) affords intermediate a. In another approach, V-OH can first be reacted with LG 2 -L-Hal reaction, wherein Hal is Cl, Br, OMs or OTs, and wherein LG 2 For Br, Cl, OH, and when LG 2 When Br or Cl, the reaction is carried out at an elevated temperature, for example, between about 40° C. and about 70° C., in a solvent such as DMF or NMP, in the presence of a base such as CsCO 3 or K 2 CO 3 ; or when LG 2 When OH is present, the Mitsunobu reaction is performed (using PPh3 and DIAD or DEAD at room temperature in a solvent such as THF) to produce VL-Hal, which reacts with an appropriately protected piperazinyl (at elevated temperatures such as between about 40°C and about 70°C in a solvent such as DMF or NMP in the presence of a base such as CsCO3 or K2CO3) to afford intermediate a. Removal of the N-protecting group P from intermediate a is accomplished by the following steps: N (For example, when P N When it is Boc, it is treated with an acid (such as hydrochloric acid in dioxane or EtOAc) at room temperature in a solvent, or with TFA in DCM at room temperature) to give intermediate b. Intermediate b is reacted with Br-C(R 2 )(R 3 )COOR (where R is C 1-4alkyl, such as methyl, ethyl or tert-butyl) optionally in the presence of NaI or KI, optionally at elevated temperature (e.g., a temperature between about 20° C. and about 80° C.), in a solvent such as THF, NMP or DMF, in the presence of a base such as TEA, DBU or DIEA to provide intermediate c. Alternatively, intermediate c can be obtained by reacting VL-Hal (wherein Hal is Cl, Br, OMs or OTs) with an appropriately derivatized 2-(piperazin-1-yl)acetate (wherein R is C 1-4 Intermediate c is prepared by reacting a methyl or ethyl group with a tert-butyl group (e.g., a methyl, ethyl, or tert-butyl group) in a solvent such as DMF or NMP in the presence of a base such as DIEA, TEA, or DBU at room temperature. Intermediate d is obtained by deprotecting the carboxylate group in intermediate c by treating it with a base such as LiOH or NaOH in a solvent such as a THF / H2O mixture or a dioxane / H2O mixture when R is methyl or ethyl, or by treating it with an acid in a solvent such as HCl in a dioxane / DCM mixture or TFA in DCM when R is tert-butyl.

[0232] By R 1 Derivatized 3-nitroaniline to prepare appropriately derivatized 3-((3-aminophenyl)amino)piperidine-2,6-dione h, the R 1 The derived 3-nitroaniline is protected by an amine group P N Protection (where for example P N When the intermediate is Boc, treatment with Boc2O in a solvent such as THF, NMP or DMF in the presence of a base such as TEA, DIEA or DBU forms intermediate e. Reduction of the nitro group in intermediate e (treatment with a reducing agent such as H2 in a solvent such as EtOH or MeOH in the presence of a catalyst such as Pd / C; or treatment with Fe and NH4Cl in a solvent such as EtOH and H2O) provides the monoprotected derivatized diphenylamine intermediate f. Intermediate f is coupled with 3-bromopiperidine-2,6-dione in a solvent in the presence of a base (e.g., in DMF or NMP at an elevated temperature, such as between about 50°C and about 80°C, in the presence of NaHCO3, CsCO3 or K2CO3; or in DMF or NMP at an elevated temperature, such as about 150°C, in the presence of DIEA), followed by removal of the protecting group P. N (For example, when P NWhen it is Boc, treatment with an acid in a solvent such as TFA in DCM or HCl in dioxane or EtOAc provides intermediate h. Alternatively, intermediate e is reacted with 3-bromopiperidine-2,6-dione by iron-catalyzed reductive coupling (e.g., at elevated temperatures, for example, between about 80° C. and about 100° C., in a solvent such as NMP, in the presence of Zn, TMSCl, FeCl2*4H2O), followed by removal of the protecting group P. N (For example, when P N In the case of Boc, treatment with an acid in a solvent such as TFA in DCM or HCl in dioxane or EtOAc provides intermediate h.

[0233] Intermediate d is coupled with intermediate h, for example in a solvent such as DCM, DMF or NMP or mixtures thereof, in the presence of a base such as DIEA, NMM or TEA, in the presence of a coupling agent such as HATU, HBTU or EDC or DCC optionally in combination with HOBt, to give a compound of formula (I) wherein L is -O(C 1-6 alkyl)-.

[0234]

[0235] An alternative method for the synthesis of compounds of formula (I) is shown in Scheme 2. In one method, the common intermediate h is reacted with Hal 2 -C(R 2 )(R 3 )COY(where Hal 2 is Cl or Br) to give intermediate i under the following conditions: when Y is OH, in a solvent (e.g., DCM, DMF, NMP or a mixture thereof), in the presence of a coupling agent (e.g., HATU, HBTU or EDC or DCC optionally in combination with HOBt) and a base (e.g., DIEA, TEA or NMM); or when Y is Cl, at a temperature between about 0°C and about 25°C, in a solvent such as DMF or NMP, in the presence of a base such as TEA or DIEA. Intermediate i is treated with intermediate b, optionally in the presence of NaI or KI, at an elevated temperature, for example, between about 40°C and about 60°C, in a solvent such as DMF or NMP, in the presence of a base such as DIEA, TEA or NMM, to give the target compound of formula (I). In a second method, intermediate h is reacted with an appropriately derivatized N-protected 2-(piperazin-1-yl)acetic acid (wherein P is Cl). NBoc) by reaction in a solvent (e.g., DCM, DMF, NMP or mixtures thereof) in the presence of a coupling agent (e.g., HATU, HBTU or EDC or DCC optionally in combination with HOBt) and a base (e.g., DIEA, TEA or NMM) to afford intermediate j. Alternatively, intermediate i is reacted with a suitably derivatized protected piperazine (wherein P N For example, Boc) is optionally in the presence of NaI or KI, at an elevated temperature, for example, between about 40°C and about 80°C, in a solvent such as DMF or NMP, in the presence of a base such as DIEA, TEA or NMM to prepare intermediate j. In another method, intermediate j is prepared by starting with intermediate ae (wherein P N 'For example, Cbz) and Hal-C(R 2 )(R 3 )COY (wherein Hal is Cl or Br) when Y is OH, in a solvent (e.g., DCM, DMF, NMP or mixtures thereof) in the presence of a coupling agent (e.g., HATU, HBTU or EDC or DCC optionally in combination with HOBt) and a base (e.g., DIEA, TEA or NMM) to give intermediate af. The reaction is carried out with an N-protected appropriately functionalized piperazine (wherein P is OH) in a solvent such as DCM, DMF, NMP or mixtures thereof in the presence of a coupling agent (e.g., HATU, HBTU or EDC or DCC optionally in combination with HOBt) and a base (e.g., DIEA, TEA or NMM) optionally in the presence of NaI or KI at elevated temperature, for example, between about 60° C. and about 90° C. in the presence of a base such as DIEA or TEA. N For example, Boc) is used to treat intermediate af to obtain intermediate ag. N When ' is Cbz, intermediate ag is deprotected, for example, with a reducing agent such as H2, in the presence of a catalyst (e.g., Pd / C, Pt / C, or Pd(OH)2) in a solvent such as MeOH or EtOAc to provide intermediate ah. Intermediate ah is coupled with 3-bromopiperidine-2,6-dione in a solvent in the presence of a base (e.g., at an elevated temperature, for example, between about 50°C and about 80°C, in DMF or NMP, in the presence of NaHCO3, CsCO3, or K2CO3; or at an elevated temperature, for example, about 150°C, in DMF or NMP, in the presence of DIEA) to provide intermediate j. Deprotection of intermediate j (when P N is Boc, treated with an acid in a solvent, such as TFA in DCM, or HCl in dioxane / DCM or EtOAc), followed by reaction with VL-Hal (wherein Hal is Cl, Br, OMs or OTs) at an elevated temperature, such as between about 50° C. and about 70° C., in a solvent such as DMF or NMP, in the presence of a base such as DIEA, TEA or NMM to provide a compound of formula (I).

[0236]

[0237] Scheme 3 shows an alternative synthesis of intermediate a, wherein L is -O(C 1-6 Alkyl) -. Make appropriate derivatization 4-nitrophenol or 5-nitropyridine-2-ol and intermediate 1 (wherein LG 2 is Br, Cl or OH) and when LG 2 When LG is Br or Cl, the reaction is carried out at high temperature in a solvent in the presence of a base (for example, the base is CsCO3 or K2CO3, the solvent is acetonitrile, DMF or NMP, and the temperature is between about 50°C and about 80°C) to obtain the intermediate n. 2 When A is OH, the Mitsunobu reaction (using PPh3 and DIAD or DEAD at room temperature in a solvent such as THF) provides intermediate n. Alternatively, when A is N, an appropriately derivatized 2-halogeno-5-nitropyridine is reacted with intermediate m at an elevated temperature, for example, between about 50°C and about 70°C, in a solvent such as acetonitrile, DMF, THF, or NMP, in the presence of a base such as CsCO3 or K2CO3, to provide intermediate n. The nitro group in intermediate n is reduced with a reducing agent in a solvent (e.g., H2 in EtOH in the presence of a catalyst such as Pd / C; or Fe and NH4Cl in EtOH and H2O at an elevated temperature, for example, about 80°C) to provide intermediate o. Intermediate o is reacted with R'OOC-C(R 5 )(R 6 )Hal (wherein Hal is Br or Cl and R' is C 1-3 alkyl) at elevated temperature (e.g., elevated temperature between 110° C. and about 130° C.) in the presence of a base (e.g., DIEA or TEA) to provide intermediate p. Intermediate p is reacted with an appropriately derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile at elevated temperature, e.g., between about 70° C. and about 90° C., in a solvent such as EtOAc in the presence of a base such as TEA to provide intermediate a, which can be further reacted as described in the above scheme to provide compounds of formula (I), wherein L is —O(C 1-6 alkyl)-.

[0238] Alternatively, intermediate o is reacted with CN-C(R 5 )(R 6 )OH at an elevated temperature, for example, between about 50°C and about 70°C, in the presence of MgSO4 to give intermediate q. 5 )(R 6 ) reacts with TMSCN and TMSOTf in a solvent such as DCM to form the reagent CN-C(R 5 )(R 6)OH. Reaction of intermediate q with an appropriately derivatized 4-isothiocyanatobenzonitrile or 5-isothiocyanatopicolinonitrile in a solvent such as DMF or DMA followed by treatment with an acid such as HCl in a solvent such as MeOH or EtOH at elevated temperature, for example, between about 70° C. and about 80° C., provides intermediate a, which is used as described above to provide compounds of formula (I) wherein L is —O(C 1-6 alkyl)-.

[0239] The synthesis of intermediates is shown in Schemes 4, 5 and 6, where R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 Cycloalkyl.

[0240]

[0241] The reaction can be carried out using R in the presence of a catalyst and a ligand (e.g., CPhosPdG3 and CPhos) at low temperatures, for example, between about 0°C and about 25°C, in a solvent such as toluene. A -Zn-Br treatment intermediate r (where P O is a phenol protecting group, such as acetyl or benzyl), to obtain intermediate s. O (When P O When acetyl, treatment with a base such as K2CO3 in a solvent such as MeOH or EtOH; or when P O is benzyl, treatment with a reducing agent such as H2 in a solvent such as EtOH or MeOH in the presence of a catalyst such as Pd / C, or with a dealkylating agent such as BBr3 in a solvent such as DCM at low temperatures, for example, about -70°C) to provide the intermediate V-OH, wherein R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 Alternatively, intermediate s is formed starting from A is CH or CR by the following method: A Protection of the hydroxyl group of an appropriately derivatized phenol with an alkylating agent such as bromomethylbenzene in the presence of a base such as K2CO3 in a solvent such as acetonitrile at elevated temperature such as about 80°C affords intermediate aw, wherein A is CH or CR A And P O is a phenol protecting group such as benzyl. At an elevated temperature such as about 100°C, in a solvent such as a mixture of toluene and water, in the presence of a catalyst and a base (e.g., Pd(dppf)2Cl2 and Cs2CO3), the phenol protecting group is reacted with R AIntermediate aw is treated with -B(OH)2 to obtain intermediate ax. The nitro group in intermediate ax can be selectively reduced using a reducing agent such as iron in the presence of a Lewis acid such as ammonium chloride at an elevated temperature such as about 60°C. Intermediate ay is reacted with CN-C(R 5 )(R 6 )OH is reacted at an elevated temperature, for example, between about 50° C. and about 70° C., in the presence of MgSO 4 to provide intermediate az. Intermediate az is reacted with an appropriately derivatized 4-isothiocyanatobenzonitrile (wherein B is CH or CR B ) or 5-isothiocyanatopicolinonitrile (wherein B is N) in a solvent such as DMF or DMA, followed by treatment with an acid such as HCl in a solvent such as MeOH or EtOH at elevated temperature, for example, between about 70° C. and about 80° C., to provide intermediate s. The protecting group P is removed as described above. O , to obtain a compound of formula V-OH, wherein R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 Cycloalkyl.

[0242]

[0243] Alternatively, as shown in Scheme 5, the intermediate t can be reacted with R A -Zn-Br is reacted at low temperatures, for example, between about 0°C and about 25°C, in a solvent such as toluene, in the presence of a catalyst and a ligand such as CPhosPdG3 and CPhos and R A , to obtain the intermediate u, where R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 Cycloalkyl, and it can be used in the above scheme similarly to intermediate a.

[0244]

[0245] Intermediates x suitable for use in the above schemes can be prepared as shown in Scheme 6, wherein L is -O(C 1-6 alkyl)- and R A As defined below. In the first step, 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridine-2-ol is reacted with a suitably derivatized and N-protected piperazinyl (e.g., wherein P N Boc and detached from LG 3is Br, Cl, OTs or OMs) at high temperature (e.g., high temperature between about 40°C and about 70°C) in a solvent in the presence of a base (e.g., in DMF, NMP or acetonitrile in the presence of CsCO3 or K2CO3) to give intermediate v. Alternatively, when LG 3 When is -OH, 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol is treated under Mitsunobu conditions (e.g., with PPh3 and DIAD or DEAD at room temperature in a solvent such as THF) to provide intermediate v. In another approach, 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol is reacted with Hal-L-Hal (wherein Hal is Br) at elevated temperatures, e.g., between about 80°C and about 100°C, in a solvent such as acetonitrile or DMF, in the presence of a base such as K2CO3 or CsCO3, followed by coupling with an appropriately derivatized and protected piperazinyl at elevated temperatures, e.g., between about 50°C and about 70°C, in a solvent such as DMF or NMP, in the presence of a base such as DIEA or TEA, to provide intermediate v. Intermediate v is prepared by reacting intermediate v with a boronate ester R A '[B(OR + )2]2(where R A ' is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkenyl, and R + Together with the boron atom and the atom to which it is attached, a cyclic boronate ester is formed, for example, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)) is reacted in a solvent (such as a 1,4-dioxane / water mixture) in the presence of a palladium catalyst (such as Pd(dppf)Cl2) and a base (such as K3PO4) to introduce R A , to obtain the intermediate w, where R A ' is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 The nitro group and R in intermediate w are reduced using a reducing agent such as H2 in a solvent such as MeOH or EtOH in the presence of a catalyst such as Pd / C at a temperature between about 20°C and about 30°C. A 'alkenyl or cycloalkenyl, to obtain intermediate x, wherein R A is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkyl, the intermediate x can be used in the above process to obtain a compound of formula (I), wherein L is -O(C 1-6 alkyl)- and RA is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Alternatively, the cycloalkyl radical is prepared at elevated temperatures, for example, between about 90°C and about 110°C, in a solvent such as a toluene / water mixture, in the presence of a base such as Cs2CO3 or K2CO3, in the presence of a catalyst and a ligand (e.g., A Palladacycle Gen.3 and butyl di-1-adamantyl phosphine) in the presence of R A BF3 - K + (where R A is substituted or unsubstituted C 1-6 alkyl) to produce intermediate y, wherein R A is substituted or unsubstituted C 1-6 As previously described, the nitro group in intermediate y is reduced using a reducing agent such as H2 in a solvent such as MeOH or EtOH in the presence of a catalyst such as Pd / C at a temperature between about 20°C and about 30°C to provide intermediate x, wherein R A is substituted or unsubstituted C 1-6 Alkyl, the intermediate x can be used in the above process to obtain a compound of formula (I), wherein L is -O(C 1-6 alkyl)- and R A is substituted or unsubstituted C 1-6 alkyl.

[0246]

[0247] Scheme 7 describes a method for synthesizing compounds of formula (I) wherein L is -(C 2-9 The synthesis of intermediates ad of (alkyl)-). The starting material V-OH is treated with Tf2O in a solvent such as DCM in the presence of a base such as DIEA or TEA to give intermediate aa. The intermediate aa is prepared by reacting the starting material V-OH with THP-OC in the presence of a catalyst and a ligand (e.g., CPhosPdG3 and CPhos) at a low temperature, for example, about 0°C, in a solvent such as toluene. 2-9Treatment of intermediate aa with an alkyl-zinc(II) affords THP-protected intermediate ab. After removal of THP (by treatment with an acid such as TsOH in a solvent such as a DCM / EtOH mixture), oxidation of intermediate ac using an oxidizing agent (e.g., Dess-Martinperiodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodooxolan-3(1H)-one) at low temperatures, e.g., about 0°C, in a solvent such as DCM) followed by reductive amination with a N-protected appropriately derivatized piperazinyl using a reducing agent such as sodium triacetoxyborohydride in a solvent such as MeOH affords intermediate ad, which can be used as described for intermediate a in Schemes 1 and 2 to afford compounds of formula (I) wherein L is -(C 2-9 alkyl)-.

[0248]

[0249] Intermediate c can also be prepared as shown in Scheme 8, where L is -O(C 1-6 alkyl)- or -(C 1-9 In one approach, the appropriately derivatized intermediate ai is reacted with an alkylating agent such as an O-protected LG 4 -L-Hal (e.g., wherein the O-protecting group P O is benzyl, LG 4 is O, and Hal is Br or Cl)) is reacted at an elevated temperature (e.g., an elevated temperature between about 40° C. and about 70° C.) in a solvent in the presence of a base (e.g., in DMF in the presence of CsCO 3 , or in acetonitrile in the presence of K 2 CO 3 ) to give an intermediate aj. The intermediate aj is reacted with Hal-C(R 2 )(R 3 )COOR (where R is C 1-4 alkyl, such as methyl, ethyl or tert-butyl, and Hal is Cl or Br) is reacted in the presence of NaI or KI, optionally at elevated temperature (e.g., a temperature between about 20° C. and about 80° C.), in a solvent such as THF, NMP or DMF, in the presence of a base such as TEA, DBU or DIEA to give intermediate ak. The O-protecting group P in the intermediate ak is removed using a reducing agent such as H 2 under pressure, for example, at a pressure level of 15 psi, at a temperature between about 20° C. and about 30° C., in a solvent such as MeOH or EtOH, in the presence of a catalyst such as Pd / C and Pd(OH) 2. O , where P O For benzyl, to obtain intermediate ao.

[0250] Alternatively, a suitably derivatized N-protected piperazinyl group is reacted with Hal-C(R 2 )(R 3 )COOR (where R is C 1-4 Alkyl, such as methyl, ethyl or tert-butyl, P N is an N-protecting group such as Boc, and Hal is Br or Cl) optionally in the presence of NaI or KI, optionally at elevated temperature (e.g., a temperature between about 20° C. and about 80° C.), in a solvent such as THF, NMP or DMF, in the presence of a base such as TEA, DBU or DIEA to give intermediate am. Deprotection of intermediate am (when P N In the case of Boc, treatment with an acid in a solvent, such as TFA in DCM, or HCl in dioxane / DCM, MeOH or EtOAc) followed by reaction with LG in the presence of a base, such as DIEA, TEA or NMM, in a solvent such as DMF or NMP at elevated temperature, such as between about 50°C and about 70°C. 4 -L-Hal (LG 4 is Br, Cl or OH, and Hal is Br or Cl) to give the intermediate ao.

[0251] The intermediate ao reacts with the phenol derivative V-OH to obtain the intermediate c, wherein when LG 4 When the leaving group LG in the intermediate ao is -OH, the reaction is carried out under Mitsunobu conditions (for example, at room temperature, in a solvent such as THF, in the presence of PPh3 and DIAD or DEAD). 4 When V-OH is Br, Cl, OTs or OMs (prepared from the corresponding alcohol), the reaction with V-OH is carried out at an elevated temperature (e.g., an elevated temperature between about 40° C. and about 70° C.) in a solvent in the presence of a base (e.g., in DMF in the presence of CsCO 3 , or in acetonitrile in the presence of K 2 CO 3 ) to afford intermediate c.

[0252] Alternatively, 4-nitrophenol (where LG) may be derivatized with an appropriately derivatized 4-nitrophenol (where LG) at elevated temperature (e.g., elevated temperature between about 0° C. and about 90° C.) in a solvent (e.g., acetonitrile, DMF, or NMP) in the presence of a base (e.g., NaOtBu, CsCO 3 , or K 2 CO 3 ). 5 is OH, and A is CH or CR A ) or 5-nitropyridin-2-ol (where LG 5 is OH, and A is N) (intermediate ar) treating intermediate ao (wherein LG 4 is Br, Cl or OH), to obtain the intermediate as. Alternatively, the intermediate ao (wherein LG 4 is OH) and the intermediate ar (where LG5 OH) under Mitsunobu conditions (by reacting in the presence of PPh3 and DIAD or DEAD at room temperature in a solvent such as THF) to give the intermediate as. In the third method, the intermediate ao (wherein LG 4 is OH) with an appropriately derivatized 2-halogeno-5-nitropyridine (where LG 5 is F or Cl, and A is N) or 1-halogeno-4-nitrobenzene (where LG 5 is F or Cl and A is CH or CR A ) at an elevated temperature, for example, between about 0° C. and about 70° C., in a solvent such as acetonitrile, DMF, THF, or NMP, in the presence of a base such as NaOtBu, CsCO 3 , or K 2 CO 3 to provide intermediate as.

[0253] In another approach, a suitably derivatized 4-nitrophenol (where A is CH or CR A ) or 5-nitropyridin-2-ol (wherein A is N) (intermediate ap) and LG 6 -L-Hal (LG 6 is Br or Cl, and Hal is Cl or Br) at elevated temperature (e.g., elevated temperature between about 0° C. and about 90° C.) in a solvent (e.g., acetonitrile, DMF, or NMP) in the presence of a base (e.g., NaOtBu, CsCO 3 , or K 2 CO 3 ) to afford intermediate aq. Intermediate ap can also be reacted with LG 6 -L-Hal (LG 6 is OH) under Mitsunobu conditions (using PPh3 and DIAD or DEAD in a solvent such as THF at room temperature) to provide intermediate aq. Intermediate an can then be alkylated with intermediate aq in the presence of a base such as NaOtBu, CsCO3 or K2CO3 in a solvent such as acetonitrile, DMF, THF or NMP at elevated temperatures, for example, between about 0°C and about 70°C, to provide intermediate as.

[0254] The nitro group in the intermediate as is reduced with a reducing agent (e.g., H2 in MeOH or EtOH; or Fe and NH4Cl in EtOH and H2O) in a solvent at an elevated temperature, e.g., about 80°C, in the presence of a catalyst, e.g., Pd / C, under a pressure, e.g., 50 psi) to give the intermediate at. The intermediate at is reacted with R'OOC-C(R 5 )(R 6 )Hal (wherein Hal is Br or Cl and R' is C 1-3alkyl) at elevated temperature (e.g., elevated temperature between about 90° C. and about 130° C.) in the presence of a base (e.g., NaHCO 3 , DIEA, or TEA) to provide intermediate av. Intermediate av is reacted with an appropriately derivatized 4-isothiocyanatobenzonitrile (wherein B is CH or CR B ) or 5-isothiocyanatopicolinonitrile (wherein B is N) at an elevated temperature, for example, between about 60° C. and about 90° C., in a solvent such as EtOAc, in the presence of a base such as TEA, to similarly afford intermediate c (wherein L is —O(C 1-6 alkyl)-), which can be used as described above.

[0255] Alternatively, the intermediate at is reacted with CN-C(R 5 )(R 6 )OH is reacted in the presence of MgSO4 at an elevated temperature, for example, between about 50°C and about 70°C, to give the intermediate au. The intermediate au is reacted with an appropriately derivatized 4-isothiocyanatobenzonitrile (wherein B is CH or CR B ) or 5-isothiocyanatopicolinonitrile (wherein B is N) in a solvent such as DMF or DMA, followed by treatment with an acid such as HCl in a solvent such as MeOH or EtOH at an elevated temperature, for example, between about 70° C. and about 80° C., to similarly provide intermediate c, wherein L is —O(C 1-6 alkyl)-.

[0256] The intermediate as (when R A When Br) the intermediate as (where R A is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkyl): make the intermediate as (when R A is Br) with borate ester R A '[B(OR + )2]2(where R A ' is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkenyl, and R + Together with the boron atom and the atom to which it is attached, a cyclic boronate ester is formed, such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)) in a solvent such as a 1,4-dioxane / water mixture in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as K3PO4 to give an intermediate as, wherein R A is substituted or unsubstituted C 2-6alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 The nitro group and R in the intermediate as are reduced using a reducing agent such as H2 in a solvent such as MeOH or EtOH in the presence of a catalyst such as Pd / C at a temperature between about 20°C and about 30°C. A alkenyl or cycloalkenyl, to obtain the intermediate at, wherein R A is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkyl, the intermediate at can be used in the above process to obtain a compound of formula (I), wherein L is -O(C 1-6 alkyl)-.

[0257] In some embodiments, the enantiomers of the compound of formula (I) are chiral separated (by standard methods and as described herein) to provide compounds of formula (IIa) and formula (IIb)

[0258]

[0259] Alternatively, chiral separation of intermediate h or i used as described in the schemes above provides compounds of formula (IIa) or (IIb) by standard methods.

[0260] The term "protected" with respect to amine and hydroxy groups refers to forms in which these functional groups are protected to prevent undesired reactions by protecting groups known to those skilled in the art, such as those described in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY (5th ed., 2014), which can be added or removed using the procedures described in that literature.

[0261] In one aspect, provided herein are methods for preparing compounds of formula (I):

[0262]

[0263] The method comprises making a compound of formula (h)

[0264]

[0265] With the compound of formula (d)

[0266]

[0267] contacting under conditions suitable for obtaining a compound of formula (I) in a solvent in the presence of a coupling agent and a base; wherein

[0268] R N is H;

[0269] Each R 1 independently selected from halogen, CN and C 1-3 alkyl;

[0270] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is connected forms a substituted or unsubstituted C 3-6 Cycloalkyl;

[0271] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0272] X is N;

[0273] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0274] n is 0 to 4;

[0275] m is 0 to 8;

[0276] V is

[0277]

[0278] in

[0279] A is N, CH or CR A ;

[0280] B is N, CH or CR B ;

[0281] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl or substituted and unsubstituted C 3-6 Cycloalkyl;

[0282] Each R Bare independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0283] R C is halogen or CF3;

[0284] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0285] a is 0 to 3; and

[0286] b is 0 to 2.

[0287] In one embodiment, the coupling agent is HATU, HBTU, EDC, or DCC, optionally in combination with HOBt. In one embodiment, the coupling agent is HATU. In another embodiment, the base is DIEA, NMM, or TEA. In one embodiment, the base is DIEA. In another embodiment, the solvent is DCM, DMF, NMP, or a mixture thereof. In one embodiment, the solvent is DMF.

[0288] In the following embodiments, unless otherwise specified, the variable R N 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R A 、R B 、R C , L, V, A, B, n, m, p, a and b are as defined herein.

[0289] In some embodiments, the method additionally comprises preparing a compound of formula (h)

[0290]

[0291] The method comprises deprotecting the compound of formula (g) under conditions suitable for obtaining the compound of formula (h)

[0292]

[0293] Among them, P N It is an amine protecting group.

[0294] In some embodiments, P Nis a Boc group. In some such embodiments, the deprotection step is performed by treating with an acid in a solvent. In some embodiments, the acid is TFA and the solvent is DCM. In other embodiments, the acid is HCl and the solvent is dioxane or EtOAc.

[0295] In some embodiments, the method additionally comprises preparing a compound of formula (g)

[0296]

[0297] The method comprises making a compound of formula (f)

[0298]

[0299] contacting with 3-bromopiperidine-2,6-dione under conditions suitable for obtaining the compound of formula (g), at elevated temperature, in a solvent, in the presence of a base.

[0300] In some such embodiments, the base is NaHCO 3 , CsCO 3 or K 2 CO 3 , and the solvent is DMF or NMP. In one embodiment, the base is NaHCO 3 and the solvent is DMF. In some such embodiments, the contacting step is carried out at a temperature between about 50° C. and about 80° C. In other embodiments, the base is DIEA. In some such embodiments, the solvent is DMF or NMP. In some such embodiments, the contacting step is carried out at a temperature of about 150° C.

[0301] In some embodiments, the method additionally comprises preparing a compound of formula (f)

[0302]

[0303] The method comprises reducing the nitro group in the compound of formula (e) using a reducing agent in a solvent under conditions suitable for obtaining the compound of formula (f) and optionally in the presence of a catalyst.

[0304]

[0305] In some such embodiments, the reducing agent is H2 and the catalyst is Pd / C. In some such embodiments, the solvent is EtOH or MeOH. In other embodiments, the reducing agent is Fe and NH4Cl. In some such embodiments, the solvent is EtOH and H2O.

[0306] In some embodiments, the method additionally comprises preparing a compound of formula (e)

[0307]

[0308] The method comprises protecting the amine group P by N Protect the nitroaniline

[0309]

[0310] The nitroaniline is reacted with a protecting agent in a solvent in the presence of a base under conditions suitable for obtaining the compound of formula (e).

[0311] In some such embodiments, the amine protecting group P N In some embodiments, the solvent is THF, NMP, or DMF. In some embodiments, the solvent is THF.

[0312] In some other embodiments, the method additionally comprises preparing a compound of formula (g)

[0313]

[0314] The method comprises making a compound of formula (e)

[0315]

[0316] contacting with 3-bromopiperidine-2,6-dione under conditions suitable for obtaining the compound of formula (g), at elevated temperature, in a solvent, in the presence of Zn, TMSCl and FeCl2*4H2O.

[0317] In some embodiments, the solvent is NMP. In some embodiments, the temperature is between about 80°C and about 100°C.

[0318] In some embodiments, the method additionally comprises preparing a compound of formula (d)

[0319]

[0320] The method comprises deprotecting the compound of formula (c) under conditions suitable for obtaining the compound of formula (d)

[0321]

[0322] Where R is C 1-4 alkyl.

[0323] In some embodiments, where R is methyl or ethyl, the deprotection step is performed by treating with a base in a solvent. In some embodiments, the base is LiOH or NaOH. In other embodiments, the solvent is a THF / H2O mixture or a dioxane / H2O mixture. In other embodiments, where R is tert-butyl, the deprotection step is performed by treating with an acid in a solvent. In some such embodiments, the acid is HCl and the solvent is a dioxane / DCM mixture. In other embodiments, the acid is TFA and the solvent is DCM.

[0324] In some embodiments, the method additionally comprises preparing a compound of formula (c)

[0325]

[0326] The method comprises making a compound

[0327]

[0328] contacting with VL-Hal (wherein Hal is Cl, Br, OMs or OTs) in a solvent in the presence of a base under conditions suitable to obtain a compound of formula (c).

[0329] In some embodiments, the base is DIEA, TEA, or DBU. In some embodiments, the base is DIEA. In other embodiments, the solvent is DMF or NMP. In some such embodiments, the solvent is DMF. In some embodiments, the contacting step is carried out at room temperature. In one embodiment, Hal is Cl or Br.

[0330] In some other embodiments, the method additionally comprises preparing a compound of formula (c)

[0331]

[0332] The method comprises making a compound of formula (b)

[0333]

[0334] With Br-C(R 2 )(R 3 )COOR in a solvent in the presence of a base under conditions suitable to obtain the compound of formula (c).

[0335] In some embodiments, the base is TEA, DBU, or DIEA. In some embodiments, the base is TEA. In other embodiments, the solvent is THF, NMP, or DMF. In some such embodiments, the solvent is THF. In some embodiments, the contacting step is carried out at an elevated temperature, for example, at a temperature between about 20° C. and about 80° C. In some embodiments, the contacting step is carried out in the presence of NaI or KI.

[0336] In some embodiments, the method additionally comprises preparing a compound of formula (b)

[0337]

[0338] The method comprises deprotecting the compound of formula (a) under conditions suitable for obtaining the compound of formula (b)

[0339]

[0340] Among them, P N It is an amine protecting group.

[0341] In some embodiments, P N is Boc. In some such embodiments, the deprotection step is performed by treatment with an acid in a solvent. In some embodiments, the acid is HCl and the solvent is dioxane or EtOAc. In other embodiments, the acid is TFA and the solvent is DCM.

[0342] In some embodiments, the method additionally comprises preparing a compound of formula (a)

[0343]

[0344] The method comprises making a compound

[0345]

[0346] contacting with VL-Hal (wherein Hal is Cl, Br, OMs or OTs) in a solvent in the presence of a base under conditions suitable to obtain a compound of formula (a).

[0347] In some embodiments, the base is CsCO 3 or K 2 CO 3 . In some embodiments, the base is CsCO 3 . In other embodiments, the solvent is DMF or NMP. In some such embodiments, the solvent is DMF. In some embodiments, the contacting step is carried out at an elevated temperature, for example, at a temperature between about 40° C. and about 70° C. In one embodiment, Hal is Cl or Br.

[0348] In some embodiments, the method additionally comprises preparing compound VL-Hal, wherein L is -O(C 1-6 alkyl)-, the method comprising reacting a compound V-OH with LG 2 -L-Hal (LG 2 is a leaving group selected from Br, Cl and OH) under conditions suitable to obtain compound VL-Hal.

[0349] In some embodiments, wherein LG 2 is Br or Cl, and the contacting step is carried out in a solvent in the presence of a base. In some embodiments, the base is CsCO3 or K2CO3. In some such embodiments, the base is CsCO3. In other embodiments, the solvent is DMF or NMP. In some such embodiments, the solvent is DMF. In some embodiments, the contacting step is carried out at an elevated temperature, for example, at a temperature between about 40°C and about 70°C. In other embodiments, LG 2 In some embodiments, the contacting step is carried out at room temperature in the presence of PPh and DIAD or DEAD.

[0350] In some embodiments, the method additionally comprises preparing a compound of formula (a)

[0351]

[0352] The method comprises making a compound

[0353]

[0354] With V-OH (where LG 1 is a leaving group selected from OH, Br, Cl, OTs and OMs) under conditions suitable to obtain the compound of formula (a).

[0355] In some embodiments, LG 1 is Br, Cl, OTs or OMs, and the contacting step is carried out in a solvent in the presence of a base. In some such embodiments, the base is CsCO3 and the solvent is DMF. In other embodiments, the base is K2CO3 and the solvent is acetonitrile. In some embodiments, the contacting step is carried out at an elevated temperature. In some such embodiments, the temperature is between about 40°C and about 70°C. In some embodiments, wherein LG 1 In some embodiments, the contacting step is carried out at room temperature in the presence of PPh and DIAD or DEAD.

[0356] Also provided is a method for preparing a compound of formula (I)

[0357]

[0358] The method comprises making a compound of formula (k)

[0359]

[0360] with VL-Hal (wherein Hal is Br, Cl, OMs or OTs) under conditions suitable for obtaining a compound of formula (I), in a solvent, in the presence of a base; wherein

[0361] R N is H;

[0362] Each R 1 independently selected from halogen, CN and C 1-3 alkyl;

[0363] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is connected forms a substituted or unsubstituted C 3-6 Cycloalkyl;

[0364] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0365] X is N;

[0366] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0367] n is 0 to 4;

[0368] m is 0 to 8;

[0369] V is

[0370]

[0371] in

[0372] A is N, CH or CR A ;

[0373] B is N, CH or CR B ;

[0374] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 Cycloalkyl;

[0375] Each R B are independently selected from halogen or substituted or unsubstituted C 1-6 alkyl;

[0376] R C is halogen or CF3;

[0377] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0378] a is 0 to 3; and

[0379] b is 0 to 2.

[0380] In one embodiment, the base is DIEA, TEA, or NMM. In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF or NMP. In one embodiment, the contacting step is carried out at an elevated temperature. In one such embodiment, the temperature is between about 50° C. and about 70° C. In one embodiment, Hal is Br or Cl.

[0381] In some embodiments, the method additionally comprises preparing a compound of formula (k)

[0382]

[0383] The method comprises deprotecting the compound of formula (j) under conditions suitable for obtaining the compound of formula (k)

[0384]

[0385] Among them, P N It is an amine protecting group.

[0386] In some embodiments, P Nis a Boc group. In some embodiments, the deprotection step is performed by treating with an acid in a solvent. In some such embodiments, the acid is TFA and the solvent is DCM. In other embodiments, the acid is HCl and the solvent is dioxane / DCM or EtOAc.

[0387] In some embodiments, the method additionally comprises preparing a compound of formula (j)

[0388]

[0389] The method comprises making a compound of formula (h)

[0390]

[0391] With compound

[0392]

[0393] The contacting is carried out under conditions suitable for obtaining a compound of formula (j) in a solvent in the presence of a coupling agent and a base.

[0394] In one embodiment, the coupling agent is HATU, HBTU, EDC, or DCC, optionally in combination with HOBt. In one embodiment, the coupling agent is HATU. In another embodiment, the base is DIEA, NMM, or TEA. In one embodiment, the base is DIEA. In another embodiment, the solvent is DCM, DMF, NMP, or a mixture thereof. In one embodiment, the solvent is DMF.

[0395] Also provided is a method for preparing a compound of formula (I)

[0396]

[0397] The method comprises making a compound of formula (i)

[0398]

[0399] With the compound of formula (b)

[0400]

[0401] contacting in a solvent in the presence of a base under conditions suitable for obtaining a compound of formula (I), wherein Hal 2 is Br or Cl;

[0402] R N is H;

[0403] Each R 1 independently selected from halogen, CN and C 1-3 alkyl;

[0404] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is connected forms a substituted or unsubstituted C 3-6 Cycloalkyl;

[0405] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0406] X is N;

[0407] L is -O(C 1-6 alkyl)- or (C 1-9 alkyl)-;

[0408] n is 0 to 4;

[0409] m is 0 to 8;

[0410] V is

[0411]

[0412] in

[0413] A is N, CH or CR A ;

[0414] B is N, CH or CR B ;

[0415] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0416] Each R B are independently selected from halogen or substituted and unsubstituted C 1-6 alkyl;

[0417] R C is halogen or CF3;

[0418] R 5 and R 6 C 1-3 Alkyl, or R 5 and R6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0419] a is 0 to 3; and

[0420] b is 0 to 2.

[0421] In one embodiment, the base is DIEA, TEA, or NMM. In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF or NMP. In one embodiment, the contacting step is carried out at an elevated temperature. In one such embodiment, the temperature is between about 40° C. and about 60° C. In one embodiment, the contacting step is carried out in the presence of NaI or KI.

[0422] In some embodiments, the method additionally comprises preparing a compound of formula (i)

[0423]

[0424] The method comprises making a compound of formula (h)

[0425]

[0426] With Hal 2 -C(R 2 )(R 3 )COY (wherein Y is OH or Cl) under conditions suitable to obtain a compound of formula (i).

[0427] In some embodiments, where Y is OH, the contacting step is carried out in a solvent in the presence of a coupling agent and a base. In one embodiment, the coupling agent is HATU, HBTU, EDC, or DCC, optionally in combination with HOBt. In one embodiment, the coupling agent is HATU. In some embodiments, the base is DIEA, TEA, or NMM. In one embodiment, the base is DIEA. In one embodiment, the solvent is DCM, DMF, NMP, or a mixture thereof. In one embodiment, the solvent is DMF. In other embodiments, where Y is Cl, the contacting step is carried out in a solvent in the presence of a base. In some such embodiments, the base is TEA or DIEA. In other embodiments, the solvent is DMF or NMP. In some embodiments, the contacting step is carried out at a temperature between about 0°C and about 25°C.

[0428] In some embodiments, the method additionally comprises preparing a compound of formula (j)

[0429]

[0430] The method comprises making a compound of formula (i)

[0431]

[0432] With compound

[0433]

[0434] Among them, P N is an amine protecting group,

[0435] In one embodiment, P N It is a Boc group.

[0436] In one embodiment, the base is DIEA, NMM, or TEA. In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF, NMP, or a mixture thereof. In one such embodiment, the contacting step is performed at a temperature between about 40° C. and about 80° C. In one embodiment, the contacting step is performed in the presence of NaI or KI.

[0437] In one embodiment, the methods provided herein comprise preparing a compound of formula (j)

[0438]

[0439] wherein the method comprises making compound (ah)

[0440]

[0441] Among them, P N is an amine protecting group,

[0442] and 3-bromopiperidine-2,6-dione in a solvent in the presence of a base under conditions suitable for obtaining a compound of formula (j). N It is a Boc group.

[0443] In one embodiment, the base is NaHCO 3 , CsCO 3 or K 2 CO 3 . In another embodiment, the solvent is DMF, NMP or a mixture thereof. In one such embodiment, the contacting step is carried out at a temperature between about 50° C. and about 80° C. In one embodiment, the base is NaHCO 3 , CsCO 3 or K 2 CO 3 and the solvent is DMF or NMP, and the contacting step is carried out at a temperature between about 50° C. and about 80° C.

[0444] In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF, NMP, or a mixture thereof. In one such embodiment, the contacting step is performed at a temperature of about 150° C. In one embodiment, the base is DIEA, the solvent is DMF or NMP, and the contacting step is performed at a temperature of about 150° C.

[0445] In one embodiment, the methods provided herein comprise preparing a compound of formula (j)

[0446]

[0447] wherein the method comprises making compound (ah)

[0448]

[0449] contacting with 3-bromopiperidine-2,6-dione in a solvent in the presence of a base under conditions suitable to obtain the compound of formula (j).

[0450] In one embodiment, the methods provided herein comprise preparing a compound of formula (ah)

[0451]

[0452] The method comprises deprotecting compound (ag) with a reducing agent under conditions suitable for obtaining a compound of formula (ah)

[0453]

[0454] In one embodiment, the reducing agent is H2. In one embodiment, PN' is Cbz, and the deprotection step is carried out in a solvent in the presence of a catalyst Pd / C, Pt / C or Pd(OH)2. In one embodiment, the solvent is MeOH or EtOAc.

[0455] In one embodiment, the methods provided herein comprise preparing a compound of formula (ag)

[0456]

[0457] wherein the method comprises making compound (af)

[0458]

[0459] With N-protected piperazine,

[0460]

[0461] contacting in a solvent in the presence of a base under conditions suitable for obtaining a compound of formula (ag), wherein P NFor the protecting group.

[0462] In one embodiment, P N is a Boc group. In one embodiment, the base is DIEA or TEA. In another embodiment, the solvent is DMF or NMP. In one such embodiment, the contacting step is performed at a temperature between about 60° C. and about 90° C. In one embodiment, the contacting step is performed in the presence of NaI or KI.

[0463] In one embodiment, the methods provided herein comprise preparing a compound of formula (af)

[0464]

[0465] wherein the method comprises making compound (ae)

[0466]

[0467] With Hal 2 -C(R 2 )(R 3 )COY (wherein Y is OH or Cl) under conditions suitable to obtain a compound of formula (af).

[0468] In some embodiments, where Y is OH, the contacting step is performed in a solvent in the presence of a coupling agent and a base. In one embodiment, the coupling agent is HATU, HBTU, EDC, or DCC, optionally in combination with HOBt. In some embodiments, the base is DIEA, TEA, or NMM. In one embodiment, the solvent is DCM, DMF, NMP, or a mixture thereof.

[0469] In other embodiments, wherein Y is Cl, the contacting step is performed in a solvent in the presence of a base. In some such embodiments, the base is TEA or DIEA. In other embodiments, the solvent is DMF or NMP. In some embodiments, the contacting step is performed at a temperature between about 0°C and about 25°C.

[0470] In some embodiments, the method additionally comprises preparing a compound of formula (a)

[0471]

[0472] The method comprises making a compound of formula (q)

[0473]

[0474] With compound

[0475]

[0476] contacting in a first solvent, followed by treatment with an acid in a second solvent under conditions suitable to yield a compound of formula (a), wherein L is -O(C 1-6 alkyl)-.

[0477] In some embodiments, the first solvent is DMF or DMA. In some embodiments, the acid is HCl. In some such embodiments, the second solvent is MeOH or EtOH. In some embodiments, the contacting with the acid is carried out at an elevated temperature. In some such embodiments, the temperature is between about 70°C and about 80°C.

[0478] In some embodiments, the method additionally comprises preparing a compound of formula (q)

[0479]

[0480] The method comprises making a compound of formula (o)

[0481]

[0482] With CN-C(R 5 )(R 6 )OH under conditions suitable to obtain the compound of formula (q) in the presence of a drying agent.

[0483] In some embodiments, the desiccant is MgSO 4 . In some embodiments, the contacting step is performed at an elevated temperature. In some such embodiments, the temperature is between about 50° C. and about 70° C.

[0484] In some embodiments, the method additionally comprises preparing a compound of formula (a)

[0485]

[0486] The method comprises making a compound of formula (p)

[0487]

[0488] With compound

[0489]

[0490] In a method suitable for obtaining a compound of formula (a) (wherein L is -O(C 1-6 alkyl)-), in a solvent, in the presence of a base, wherein R' is C 1-3 alkyl.

[0491] In some embodiments, the base is TEA. In other embodiments, the solvent is EtOAc. In some embodiments, the contacting step is performed at an elevated temperature. In some such embodiments, the temperature is between about 70°C and about 90°C.

[0492] In some embodiments, the method additionally comprises preparing a compound of formula (p)

[0493]

[0494] The method comprises making a compound of formula (o)

[0495]

[0496] With R'OOC-C(R 5 )(R 6 )Hal (wherein Hal is Br or Cl) in the presence of a base under conditions suitable to obtain a compound of formula (p).

[0497] In some embodiments, Hal is Br. In some embodiments, the base is DIEA or TEA. In some embodiments, the contacting step is performed at an elevated temperature. In some such embodiments, the temperature is between about 110°C and about 130°C.

[0498] In some embodiments, the method additionally comprises preparing a compound of formula (o)

[0499]

[0500] The method comprises reducing a compound of formula (n) with a reducing agent in a solvent under conditions suitable for obtaining a compound of formula (o)

[0501]

[0502] In some embodiments, the reducing agent is H2. In some such embodiments, the contacting step is performed in the presence of a catalyst. In some embodiments, the catalyst is Pd / C. In some such embodiments, the solvent is EtOH. In other embodiments, the reducing agent is Fe and NHCl. In some such embodiments, the solvent is EtOH and H2O. In some such embodiments, the contacting step is performed at an elevated temperature. In some embodiments, the temperature is about 80°C.

[0503] In some embodiments, the method additionally comprises preparing a compound of formula (n)

[0504]

[0505] The method comprises making a compound of formula (m)

[0506]

[0507] With compound

[0508]

[0509] contacting in a solvent in the presence of a base under conditions suitable to obtain a compound of formula (n) wherein A is N.

[0510] In some embodiments, the base is CsCO or KCO. In some embodiments, the base is KCO. In some embodiments, the solvent is acetonitrile, DMF, THF, or NMP. In some embodiments, the solvent is acetonitrile. In some embodiments, the contacting step is performed at an elevated temperature. In some such embodiments, the temperature is between about 50°C and about 70°C.

[0511] In some other embodiments, the method additionally comprises preparing a compound of formula (n)

[0512]

[0513] The method comprises making a compound of formula (1)

[0514]

[0515] With compound

[0516]

[0517] contacting under conditions suitable to obtain a compound of formula (n) wherein A is N, wherein LG 2 is Br, Cl or OH.

[0518] In some embodiments, LG 2 is Br or Cl, and the contacting step is performed in a solvent in the presence of a base. In some embodiments, the base is CsCO3 or K2CO3. In some embodiments, the base is CsCO3. In some embodiments, the solvent is acetonitrile, DMF, or NMP. In some embodiments, the solvent is acetonitrile. In some embodiments, the contacting step is performed at an elevated temperature. In some embodiments, the temperature is between about 50°C and 80°C. In some embodiments, Hal is Br, the base is CsCO3, the solvent is DMF, and the temperature is about 70°C. In other embodiments, Hal is Cl, the base is K2CO3, the solvent is acetonitrile, and the temperature is about 60°C. In some embodiments, LG 2In some embodiments, the contacting step is carried out at room temperature in the presence of PPh and DIAD or DEAD.

[0519] In some embodiments, the method additionally comprises preparing a compound of formula V-OH

[0520]

[0521] The method comprises deprotecting a compound of formula (s) under conditions suitable for obtaining a compound of formula V-OH

[0522]

[0523] where R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 Cycloalkyl, and P O It is a phenol protecting group.

[0524] In some embodiments, P O is acetyl, and the deprotection step is performed by treatment with a base in a solvent. In some such embodiments, the base is such as K2CO3. In some embodiments, the solvent is MeOH or EtOH. In other embodiments, P O In some embodiments, the reducing agent is H 2 and the contacting step is performed in the presence of a catalyst. In one embodiment, the catalyst is Pd / C. In some embodiments, the solvent is EtOH or MeOH.

[0525] In some embodiments, the method additionally comprises preparing a compound of formula (s)

[0526]

[0527] The method comprises making a compound of formula (r)

[0528]

[0529] With R A -Zn-Br (where R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 cycloalkyl) under conditions suitable to obtain a compound of formula (s), in a solvent, in the presence of a catalyst and a ligand.

[0530] In some embodiments, the catalyst and ligand are CPhosPdG3 and CPhos. In some embodiments, the solvent is toluene. In some embodiments, the contacting step is performed at low temperature. In some such embodiments, the temperature is between about 0°C and about 25°C.

[0531] In some embodiments, the method additionally comprises preparing a compound of formula (s)

[0532]

[0533] Where A is CH or CR A And P O is a phenol protecting group,

[0534] The method comprises making a compound of formula (az)

[0535]

[0536] With compound

[0537]

[0538] contacting in a solvent under conditions suitable for obtaining a compound of formula (s), followed by treatment with an acid in a solvent, wherein B is CH, CR B or N.

[0539] In one embodiment, P O In one embodiment, the solvent is DMF or DMA. In one embodiment, the acid is HCl. In one embodiment, the acid is in a solvent such as MeOH or EtOH. In one embodiment, the contacting step is carried out at a temperature between about 70° C. and about 80° C.

[0540] In one embodiment, provided herein is a method for preparing compound (az)

[0541]

[0542] wherein the method comprises making compound (ay)

[0543]

[0544] With CN-C(R 5 )(R 6 )OH in the presence of MgSO4 under conditions suitable to obtain the compound of formula (az).

[0545] In one embodiment, the contacting step is performed at a temperature between about 50°C and about 70°C.

[0546] In one embodiment, provided herein is a method for preparing compound (ay)

[0547]

[0548] wherein the method comprises making compound (ax)

[0549]

[0550] contacting with a reducing agent in a solvent in the presence of a Lewis acid under conditions suitable to obtain a compound of formula (ay).

[0551] In one embodiment, the reducing agent is iron. In one embodiment, the Lewis acid is ammonium chloride. In one embodiment, the solvent is a mixture of EtOH and water. In one embodiment, the contacting step is performed at a temperature of about 60°C.

[0552] In one embodiment, provided herein is a method for preparing compound (ax)

[0553]

[0554] wherein the method comprises making compound (aw)

[0555]

[0556] With R A -B(OH)2 is contacted in a solvent in the presence of a catalyst and a base under conditions suitable to obtain a compound of formula (ax).

[0557] In one embodiment, the catalyst is Pd(dppf)2Cl2. In one embodiment, the base is Cs2CO3. In one embodiment, the solvent is a mixture of toluene and water. In one embodiment, the contacting step is carried out at a temperature of about 100°C.

[0558] In one embodiment, provided herein is a method for preparing compound (aw)

[0559]

[0560] The method comprises making the compound

[0561]

[0562] The compound is contacted with an alkylating agent in a solvent containing a base under conditions suitable for obtaining the compound of formula (aw).

[0563] In one embodiment, the alkylating agent is bromomethylbenzene. In one embodiment, the solvent is acetonitrile. In one embodiment, the base is K2CO3. In one embodiment, the contacting step is performed at a temperature of about 80°C.

[0564] In some embodiments, the method additionally comprises preparing a compound of formula (u)

[0565]

[0566] The method comprises making a compound of formula (t)

[0567]

[0568] With R A -Zn-Br (where R A is substituted or unsubstituted C 1-6 Alkyl or substituted or unsubstituted C 3-6 cycloalkyl) in a solvent in the presence of a catalyst and a ligand under conditions suitable to obtain a compound of formula (u).

[0569] In some embodiments, the catalyst and ligand are CPhosPdG3 and CPhos. In some embodiments, the solvent is toluene. In some embodiments, the contacting step is performed at low temperature. In some such embodiments, the temperature is between about 0°C and about 25°C.

[0570] In some embodiments, the method additionally comprises preparing a compound of formula (x)

[0571]

[0572] The method comprises reducing a compound of formula (y) with a reducing agent in a solvent under conditions suitable for obtaining a compound of formula (x)

[0573]

[0574] Where L is -O(C 1-6 alkyl)- and R A is substituted or unsubstituted C 1-6 alkyl.

[0575] In some embodiments, the reducing agent is H2 in the presence of a catalyst. In some embodiments, the catalyst is Pd / C. In some embodiments, the solvent is MeOH or EtOH. In some embodiments, the contacting step is performed at a temperature between about 20°C and about 30°C.

[0576] In some embodiments, the method additionally comprises preparing a compound of formula (y)

[0577]

[0578] The method comprises treating a compound of formula (v)

[0579]

[0580] With R A BF3 - K + (where R A is substituted or unsubstituted C 1-6 alkyl) in a solvent, in the presence of a base, in the presence of a catalyst and a ligand under conditions suitable for obtaining a compound of formula (y).

[0581] In some embodiments, the catalyst and ligand are A Palladacycle Gen. 3 and butyldi-1-adamantylphosphine. In some embodiments, the base is Cs2CO3 or K2CO3. In some embodiments, the base is Cs2CO3. In some embodiments, the solvent is a toluene / water mixture. In some embodiments, the contacting step is performed at an elevated temperature. In some embodiments, the temperature is between about 90°C and about 110°C.

[0582] In some embodiments, the method additionally comprises preparing a compound of formula (x)

[0583]

[0584] The method comprises making a compound of formula (w)

[0585]

[0586] With a reducing agent in a suitable condition to obtain a compound of formula (x) (wherein R A is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 cycloalkyl) under the conditions of contact in a solvent, wherein L is -O(C 1-6 alkyl)-, and R A ' is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 cycloalkenyl, under conditions suitable to obtain a compound of formula (x).

[0587] In some embodiments, the reducing agent is H2 in the presence of a catalyst. In some embodiments, the catalyst is Pd / C. In some embodiments, the solvent is MeOH or EtOH. In some embodiments, the contacting step is performed at a temperature between about 20°C and about 30°C.

[0588] In some embodiments, the method additionally comprises preparing a compound of formula (w)

[0589]

[0590] The method comprises treating a compound of formula (v)

[0591]

[0592] With R A '[B(OR + )2]2(where R A ' is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkenyl, and R + The boron atom and the atom to which it is attached form a cyclic boronate ester, such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)) under conditions suitable for obtaining a compound of formula (w) in a solvent in the presence of a catalyst and a base.

[0593] In some embodiments, the catalyst is Pd(dppf)Cl 2 . In some embodiments, the base is K 3 PO 4 . In some embodiments, the solvent is a 1,4-dioxane / water mixture.

[0594] In some embodiments, the method additionally comprises preparing a compound of formula (v)

[0595]

[0596] The method comprises making a compound

[0597]

[0598] With compound

[0599]

[0600] contacting in a solvent in the presence of a base under conditions suitable to obtain a compound of formula (v) wherein Hal is Br.

[0601] In some embodiments, the base is DIEA or TEA. In some embodiments, the solvent is DMF or NMP. In some embodiments, the contacting step is performed at an elevated temperature. In some embodiments, the temperature is between about 50°C and about 70°C.

[0602] In some embodiments, the method additionally comprises preparing a compound of the formula

[0603]

[0604] The method comprises making a compound

[0605]

[0606] and Hal-L-Hal (wherein Hal is Br) in a solvent in the presence of a base under conditions suitable for obtaining a compound of the formula

[0607]

[0608] In some embodiments, the base is K2CO3 or CsCO3. In some embodiments, the solvent is acetonitrile or DMF. In some embodiments, the contacting step is performed at an elevated temperature. In some embodiments, the temperature is between about 80°C and about 100°C.

[0609] In some embodiments, the method additionally comprises preparing a compound of formula (v)

[0610]

[0611] The method comprises making a compound

[0612]

[0613] With compound

[0614]

[0615] contacting under conditions suitable to obtain a compound of formula (v), wherein LG 3 is OH, Br, Cl, OTs or OMs.

[0616] In some embodiments, LG 3 is Br, Cl, OTs or OMs, and the contacting step is carried out in a solvent in the presence of a base. In some embodiments, the base is CsCO3 or K2CO3. In some embodiments, the solvent is DMF, NMP or acetonitrile. In some embodiments, the contacting step is carried out at an elevated temperature. In some embodiments, the temperature is between about 40°C and about 70°C. In other embodiments, LG 3In some embodiments, the contacting step is carried out at room temperature in the presence of PPh and DIAD or DEAD.

[0617] In some embodiments, the method additionally comprises preparing a compound of formula (ad)

[0618]

[0619] The method comprises making a compound

[0620]

[0621] With V-(C 1-9 alkyl)-C(=O)H(wherein P N is an amine protecting group) in a solvent in the presence of a reducing agent under conditions suitable to obtain a compound of formula (ad).

[0622] In some embodiments, the reducing agent is sodium triacetoxyborohydride. In other embodiments, the solvent is MeOH.

[0623] In some embodiments, the method additionally comprises preparing a compound of formula V-(C 1-9 alkyl)-C(=O)H compound, the method comprising making a compound of formula (ac)

[0624] V-(C 2-9 alkyl)-OH

[0625] (ac)

[0626] With an oxidizing agent in a suitable condition to obtain the formula V-(C 1-9 alkyl)-C(═O)H in a solvent.

[0627] In some embodiments, the oxidizing agent is Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxolan-3(1H)-one). In other embodiments, the solvent is DCM. In some embodiments, the contacting step is performed at low temperature. In one embodiment, the temperature is about 0°C.

[0628] In some embodiments, the method additionally comprises preparing a compound of formula (ac)

[0629] V-(C 2-9 alkyl)-OH

[0630] (ac)

[0631] The method comprises deprotecting the compound of formula (ab) under conditions suitable for obtaining the compound of formula (ac)

[0632]

[0633] In some embodiments, the deprotection step is carried out by treating with an acid in a solvent. In one embodiment, the acid is TsOH. In another embodiment, the solvent is a DCM / EtOH mixture.

[0634] In some embodiments, the method additionally comprises preparing a compound of formula (ab)

[0635]

[0636] The method comprises making a compound of formula (aa)

[0637] V-OTf

[0638] (aa)

[0639] With THP-O(C 2-9 Alkyl)-zinc(II) is contacted in a solvent in the presence of a catalyst and a ligand under conditions suitable to obtain a compound of formula (ab).

[0640] In some embodiments, the catalyst and ligand are CPhosPdG3 and CPhos. In some embodiments, the solvent is toluene. In some embodiments, the contacting step is performed at low temperature. In some embodiments, the temperature is about 0°C.

[0641] In some embodiments, the method additionally comprises preparing a compound of formula (aa)

[0642] V-OTf

[0643] (aa)

[0644] The method comprises contacting V-OH with Tf2O in a solvent in the presence of a base under conditions suitable to obtain a compound of formula (aa).

[0645] In some embodiments, the base is DIEA or TEA. In other embodiments, the solvent is DCM.

[0646] In one embodiment, provided herein is a method for preparing compound (ao)

[0647]

[0648] wherein the method comprises making compound (ak)

[0649]

[0650] Among them, P O is an O-protecting group,

[0651] contacting with a reducing agent under conditions suitable for obtaining a compound of formula (ao) in the presence of a catalyst.

[0652] In one embodiment, contacting compound (ak) with a reducing agent in the presence of a catalyst is carried out under pressure at a temperature between about 20°C and about 30°C in a solvent.

[0653] In one embodiment, P O In one embodiment, the reducing agent is H2. In one embodiment, the catalyst is Pd / C or Pd(OH)2. In one embodiment, the solvent is MeOH or EtOAc. In one embodiment, the pressure is increased to about 15 psi.

[0654] In one embodiment, the methods provided herein comprise preparing a compound of formula (ak)

[0655]

[0656] wherein the method comprises making compound (aj)

[0657]

[0658] and

[0659]

[0660] Contacting is carried out under conditions appropriate to obtain a compound of formula (ak) wherein R is alkyl and Hal is Cl or Br.

[0661] In some embodiments, R is C 1-4 In one embodiment, R is methyl, ethyl, or tert-butyl. In some embodiments, the contacting step is carried out in a solvent in the presence of a base. In some embodiments, the base is TEA, DBU, or DIEA. In one embodiment, the solvent is THF, NMP, or DMF. In one embodiment, the contacting step is carried out at a temperature between about 20° C. and about 80° C. In one embodiment, the contacting step is carried out in the presence of NaI or KI.

[0662] In one embodiment, the methods provided herein comprise preparing a compound of formula (aj)

[0663]

[0664] wherein the method comprises making compound (ai)

[0665]

[0666] With alkylating agent

[0667]

[0668] contacting under conditions suitable to obtain a compound of formula (aj), wherein P o It is an O-protecting group.

[0669] In one embodiment, P O is benzyl, LG 4 is O, and Hal is Br or Cl. In one embodiment, the contacting step is carried out in a solvent in the presence of a base. In one embodiment, the contacting step is carried out in DMF in the presence of CsCO 3 or in acetonitrile in the presence of K 2 CO 3. In one embodiment, the contacting step is carried out at an elevated temperature. In one embodiment, the temperature is between about 40° C. and about 70° C.

[0670] In one embodiment, provided herein is a method for preparing compound (ao)

[0671]

[0672] wherein the method comprises making a compound (an)

[0673]

[0674] With LG 4 -L-Hal, where LG 4 is Br, Cl or OH, and Hal is Br or Cl,

[0675] The contacting is carried out in a solvent in the presence of a base under conditions suitable to obtain the compound of formula (ao).

[0676] In one embodiment, the base is DIEA, TEA, or NMM. In one embodiment, the solvent is DMF or NMP. In one embodiment, the contacting step is performed at a temperature between about 50°C and about 70°C.

[0677] In one embodiment, provided herein is a method for preparing compound (an)

[0678]

[0679] wherein the method comprises making compound (am)

[0680]

[0681] Among them, P N is a Boc group,

[0682] contacting with an acid in a solvent under conditions suitable to obtain a compound of formula (an).

[0683] In one embodiment, the acid is TFA or HCl. In one embodiment, the solvent is DCM, dioxane, MeOH or EtOH. In one embodiment, the acid and solvent are TFA and DCM or HCl and dioxane / DCM, MeOH or EtOAc.

[0684] In one embodiment, the methods provided herein comprise preparing a compound of formula (am)

[0685]

[0686] The method comprises the steps of:

[0687]

[0688] and

[0689]

[0690] contacting under conditions suitable to obtain a compound of formula (am), wherein P N is an N-protecting group, R is an alkyl group, and Hal is Cl or Br.

[0691] In one embodiment, P N In some embodiments, R is C 1-4 In one embodiment, R is methyl, ethyl, or tert-butyl. In some embodiments, the contacting step is carried out in a solvent in the presence of a base. In some embodiments, the base is TEA, DBU, or DIEA. In one embodiment, the solvent is THF, NMP, or DMF. In one embodiment, the contacting step is carried out at a temperature between about 20° C. and about 80° C. In one embodiment, the contacting step is carried out in the presence of NaI or KI.

[0692] In one embodiment, the methods provided herein comprise preparing a compound of formula (c)

[0693]

[0694] wherein the method comprises making compound (ao)

[0695]

[0696] and V-OH under conditions suitable for obtaining a compound of formula (c), wherein LG 4 is a leaving group, and R is an alkyl group.

[0697] In one embodiment, LG 4 Is -OH, and (ao) is contacted with V-OH under light-noble conditions, for example, at room temperature, in a solvent such as THF, in the presence of PPh3 and DIAD or DEAD. In one embodiment, the leaving group LG in compound (ao) is 4 is Br, Cl, OTs or OMs, and the reaction with V-OH is carried out in a solvent in the presence of a base. In one embodiment, the base is CsCO3 and the solvent is DMF. In one embodiment, the base is K2CO3 and the solvent is acetonitrile. In one embodiment, the reaction is carried out at an elevated temperature. In one embodiment, the reaction is carried out at a temperature between about 40°C and about 70°C.

[0698] In one embodiment, the methods provided herein comprise preparing a compound of formula (as)

[0699]

[0700] wherein the method comprises making compound (ao)

[0701]

[0702] With compound (ar)

[0703]

[0704] contacting under conditions suitable to obtain a compound of formula (as), wherein LG 4 Br, Cl or OH, LG 5 is OH, and A is CH or CR A or N.

[0705] In one embodiment, LG in compound (ao) 4 is OH, and the reaction is carried out in a solvent in the presence of a base. In one embodiment, the base is NaOtBu, CsCO3 or K2CO3. In one embodiment, the solvent is acetonitrile, DMF or NMP. In one embodiment, the reaction is carried out at a temperature between about 0°C and about 70°C.

[0706] In one embodiment, LG in compound (ao) 4 is OH, and the contacting of compound (ao) with compound (ar) is carried out under light-noble conditions, for example, at room temperature, in a solvent such as THF, in the presence of PPh3 and DIAD or DEAD, to obtain compound (as).

[0707] In one embodiment, in compound (ao), LG 4 is OH; in compound (ar), LG 5 is F or Cl, and A is N; and the contacting of compound (ao) with compound (ar) is carried out at a temperature between about 0° C. and about 70° C. in a solvent in the presence of a base to obtain compound (as). In one embodiment, the base is NaOtBu, CsCO 3 or K 2 CO 3. In one embodiment, the solvent is acetonitrile, DMF, THF or NMP.

[0708] In one embodiment, in compound (ao), LG 4 is OH; in compound (ar), LG 5 is F or Cl, and A is CH or CR A and contacting compound (ao) with compound (ar) is carried out at a temperature between about 0° C. and about 70° C. in a solvent in the presence of a base to obtain compound (as). In one embodiment, the base is NaOtBu, CsCO 3 or K 2 CO 3. In one embodiment, the solvent is acetonitrile, DMF, THF or NMP.

[0709] In one embodiment, the methods provided herein comprise preparing a compound of formula (as)

[0710]

[0711] wherein the method comprises making a compound (an)

[0712]

[0713] With compound (aq)

[0714]

[0715] The contacting is carried out under conditions suitable for obtaining a compound of formula (as) in a solvent in the presence of a base.

[0716] In one embodiment, the base is NaOtBu, CsCO3, or K2CO3. In one embodiment, the solvent is acetonitrile, DMF, THF, or NMP. In one embodiment, the contacting step is performed at a temperature between about 0°C and about 70°C.

[0717] In one embodiment, the methods provided herein comprise preparing a compound of formula (aq)

[0718]

[0719] wherein the method comprises subjecting the compound (ap) to

[0720]

[0721] Where A is CH, CR A or N;

[0722] With LG 6 -L-Hal in a solvent under conditions suitable to obtain a compound of formula (aq).

[0723] In one embodiment, LG 6 is Br or Cl, and Hal is Cl or Br, and the contacting step is carried out in the presence of a base. In some such embodiments, the base is NaOtBu, CsCO3, or K2CO3. In one embodiment, the solvent is acetonitrile, DMF, THF, or NMP. In one embodiment, the contacting step is carried out at a temperature between about 0°C and about 90°C.

[0724] In one embodiment, LG 6 In one embodiment, the solvent is THF. In one embodiment, the contacting step is carried out at room temperature.

[0725] In some embodiments, the methods provided herein comprise preparing a compound of formula (c)

[0726]

[0727] Where L is -O(C 1-6 alkyl)-,

[0728] The method comprises making a compound of formula (av)

[0729]

[0730] With compound

[0731]

[0732] contacting in a solvent in the presence of a base under conditions suitable for obtaining a compound of formula (c), wherein B is CH, CR B or N.

[0733] In one embodiment, the solvent is EtOAc. In one embodiment, the base is TEA. In one embodiment, the contacting step is performed at a temperature between about 60°C and about 90°C.

[0734] In some embodiments, the methods provided herein comprise preparing a compound of formula (av)

[0735]

[0736] The method comprises making a compound of formula (at)

[0737]

[0738] With R'OOC-C(R 5 )(R 6 )Hal (wherein Hal is Br or Cl, and R' is C 1-3 alkyl) in the presence of a base under conditions appropriate to obtain a compound of formula (av).

[0739] In one embodiment, the base is NaHCO3, DIEA, or TEA. In one embodiment, the contacting step is performed at a temperature between about 90°C and about 130°C.

[0740] In some embodiments, the methods provided herein comprise preparing a compound of formula (at)

[0741]

[0742] The method comprises making a compound of formula (as)

[0743]

[0744] contacting with a reducing agent under conditions suitable for obtaining the compound of formula (at), under pressure, in the presence of a catalyst, in a solvent.

[0745] In one embodiment, the reducing agent is H2 in MeOH or EtOH. In one embodiment, the catalyst is Pd / C. In one embodiment, the pressure is about 50 psi. In one embodiment, the contacting step is carried out at a temperature of about 80°C.

[0746] In some embodiments, the methods provided herein comprise preparing a compound of formula (c)

[0747]

[0748] Where L is -O(C 1-6 alkyl)-,

[0749] The method comprises making a compound of formula (au)

[0750]

[0751] With compound

[0752]

[0753] contacting in a solvent under conditions suitable for obtaining a compound of formula (c), followed by treatment with an acid in a solvent, wherein B is CH, CR B or N.

[0754] In one embodiment, the solvent is DMF or DMA. In one embodiment, the acid is HCl. In one embodiment, the acid is in a solvent such as MeOH or EtOH. In one embodiment, the contacting step is carried out at a temperature between about 70° C. and about 80° C.

[0755] In some embodiments, the methods provided herein comprise preparing a compound of formula (at)

[0756]

[0757] where R A is substituted or unsubstituted C 2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkyl, and L is -O(C 1-6 alkyl)-,

[0758] The method comprises making a compound of formula (as)

[0759]

[0760] contacting with a reducing agent in a solvent in the presence of a catalyst under conditions suitable for obtaining the compound of formula (at).

[0761] In one embodiment, the reducing agent is H2 in MeOH or EtOH.In one embodiment, the catalyst is Pd / C.In one embodiment, the contacting step is performed at a temperature between about 20°C and about 30°C.

[0762] In some embodiments, the methods provided herein comprise preparing a compound of formula (as)

[0763]

[0764] where R A is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 cycloalkenyl;

[0765] The method comprises making a compound of formula (as)

[0766]

[0767] where R A For Br,

[0768] With borate ester R A '[B(OR + )2]2,

[0769] In a method suitable for obtaining a compound of formula (as) (wherein R A is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 cycloalkenyl) under the conditions of, in a solvent, in the presence of a palladium catalyst and a base, wherein R A ' is substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C 5-6 Cycloalkenyl, and R + Together with the boron atom and the atom to which it is attached, it forms a cyclic borate ester.

[0770] In one embodiment, the cyclic boronate ester is 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane). In one embodiment, the catalyst is Pd(dppf)2Cl2. In one embodiment, the base is K3PO4. In one embodiment, the solvent is a 1,4-dioxane / water mixture.

[0771] In one embodiment, provided herein is a compound having the following formula (VL-Hal):

[0772]

[0773] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0774] In one embodiment, provided herein is a compound of formula (a), wherein

[0775] A is N, CH or CR A ;

[0776] B is N, CH or CR B ;

[0777] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0778] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0779] R C is halogen or CF3;

[0780] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0781] a is 0 to 3;

[0782] b is 0 to 2

[0783] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-; and

[0784] Hal is Cl, Br, OMs or OTs.

[0785] In one embodiment, provided herein is a compound having the following formula (a):

[0786]

[0787] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0788] In one embodiment, provided herein is a compound of formula (a), wherein

[0789] A is N, CH or CR A ;

[0790] B is N, CH or CR B ;

[0791] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0792] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0793] R C is halogen or CF3;

[0794] R 5 and R 6 C 1-3 Alkyl, or R 5 and R6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0795] a is 0 to 3;

[0796] b is 0 to 2

[0797] X is N;

[0798] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0799] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0800] m is 0 to 8; and

[0801] P N It is an amine protecting group.

[0802] In one embodiment, P N is tert-butoxycarbonyl or carboxybenzyl.

[0803] In one embodiment, provided herein is a compound having the following formula (a1):

[0804]

[0805] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein R x C 1-4 alkyl, and the remaining variables are as described elsewhere herein.

[0806] In one embodiment, there is provided herein a compound of formula (a1), wherein

[0807] A is N, CH or CR A ;

[0808] B is N, CH or CR B ;

[0809] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C3-6 Cycloalkyl;

[0810] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0811] R C is halogen or CF3;

[0812] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0813] a is 0 to 3;

[0814] b is 0 to 2

[0815] X is N;

[0816] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0817] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0818] m is 0 to 8; and

[0819] R x C 1-4 alkyl.

[0820] In one embodiment, provided herein is a compound having the following formula (b):

[0821]

[0822] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0823] In one embodiment, provided herein is a compound of formula (b), wherein

[0824] A is N, CH or CR A ;

[0825] B is N, CH or CR B ;

[0826] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0827] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0828] R C is halogen or CF3;

[0829] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0830] a is 0 to 3;

[0831] b is 0 to 2

[0832] X is N;

[0833] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0834] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group; and

[0835] m is 0 to 8.

[0836] In one embodiment, provided herein is a compound having the following formula (c):

[0837]

[0838] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0839] In one embodiment, provided herein is a compound of formula (c), wherein

[0840] A is N, CH or CR A ;

[0841] B is N, CH or CR B ;

[0842] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0843] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0844] R C is halogen or CF3;

[0845] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0846] a is 0 to 3;

[0847] b is 0 to 2

[0848] X is N;

[0849] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0850] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0851] m is 0 to 8;

[0852] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3The carbon to which it is connected forms a substituted or unsubstituted C 3-6 cycloalkyl; and

[0853] R is C 1-4 alkyl.

[0854] In one embodiment, provided herein is a compound having the following formula (d):

[0855]

[0856] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0857] In one embodiment, provided herein is a compound of formula (d), wherein

[0858] A is N, CH or CR A ;

[0859] B is N, CH or CR B ;

[0860] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0861] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0862] R C is halogen or CF3;

[0863] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0864] a is 0 to 3;

[0865] b is 0 to 2

[0866] X is N;

[0867] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0868] Each R 4 are independently substituted or unsubstituted C1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0869] m is 0 to 8; and

[0870] R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is connected forms a substituted or unsubstituted C 3-6 Cycloalkyl.

[0871] In one embodiment, provided herein is a compound having the following formula (t):

[0872]

[0873] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0874] In one embodiment, provided herein is a compound of formula (t), wherein

[0875] A is N, CH or CR A ;

[0876] B is N, CH or CR B ;

[0877] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0878] R C is halogen or CF3;

[0879] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0880] b is 0 to 2

[0881] X is N;

[0882] L is -O(C1-6 alkyl)- or -(C 1-9 alkyl)-;

[0883] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0884] m is 0 to 8; and

[0885] P N It is an amine protecting group.

[0886] In one embodiment, P N It is tert-butoxycarbonyl or carboxybenzyl.

[0887] In one embodiment, provided herein is a compound having the following formula (u):

[0888]

[0889] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0890] In one embodiment, provided herein is a compound of formula (u), wherein

[0891] A is N, CH or CR A ;

[0892] B is N, CH or CR B ;

[0893] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0894] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0895] R C is halogen or CF3;

[0896] R 5 and R 6 C 1-3 Alkyl, or R 5 and R6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0897] b is 0 to 2

[0898] X is N;

[0899] L is -O(C 1-6 alkyl)- or -(C 1-9 alkyl)-;

[0900] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0901] m is 0 to 8; and

[0902] P N It is an amine protecting group.

[0903] In one embodiment, P N It is tert-butoxycarbonyl or carboxybenzyl.

[0904] In one embodiment, provided herein is a compound having the following formula (ab):

[0905]

[0906] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0907] In one embodiment, provided herein is a compound of formula (ab), wherein

[0908] A is N, CH or CR A ;

[0909] B is N, CH or CR B ;

[0910] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0911] Each R B are independently selected from halogen and substituted or unsubstituted C1-6 alkyl;

[0912] R C is halogen or CF3;

[0913] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0914] a is 0 to 3; and

[0915] b is 0 to 2.

[0916] In one embodiment, provided herein are compounds having the following formula (ac):

[0917]

[0918] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0919] In one embodiment, provided herein is a compound of formula (ac), wherein

[0920] A is N, CH or CR A ;

[0921] B is N, CH or CR B ;

[0922] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0923] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0924] R C is halogen or CF3;

[0925] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0926] a is 0 to 3; and

[0927] b is 0 to 2.

[0928] In one embodiment, provided herein is a compound having the following formula (ad):

[0929]

[0930] or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein the variables are as described elsewhere herein.

[0931] In one embodiment, provided herein is a compound of formula (ad), wherein

[0932] A is N, CH or CR A ;

[0933] B is N, CH or CR B ;

[0934] Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl;

[0935] Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl;

[0936] R C is halogen or CF3;

[0937] R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group;

[0938] a is 0 to 3;

[0939] b is 0 to 2

[0940] X is N;

[0941] Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group;

[0942] m is 0 to 8; and

[0943] P N It is an amine protecting group.

[0944] In one embodiment, P N It is tert-butoxycarbonyl or carboxybenzyl.

[0945] How to use

[0946] In one embodiment, the compounds described herein have utility as a drug for treating, preventing, or ameliorating an animal or human disorder. The piperidinedione compounds described herein have utility as a drug for treating, preventing, or ameliorating an animal or human disorder. Thus, various uses of the piperidinedione compounds are provided herein, including the treatment or prevention of those diseases described below. In one embodiment, the methods provided herein comprise administering an effective amount of the compound to a subject in need thereof.

[0947] The methods provided herein comprise administering to a subject in need thereof an effective amount of one or more piperidinedione compounds.

[0948] 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.

[0949] 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 piperidinedione compound as described herein.

[0950] On the other hand, provided herein are compounds suitable for treating or preventing AR-mediated diseases in subjects, comprising administering to a subject in need thereof an effective amount of a piperidinedione compound as described herein. In some embodiments, provided herein are compounds suitable for treating AR-mediated diseases in subjects, comprising administering to a subject in need thereof an effective amount of a piperidinedione compound as described herein. In some embodiments, provided herein are compounds suitable for preventing AR-mediated diseases in subjects, comprising administering to a subject in need thereof an effective amount of a piperidinedione compound as described herein.

[0951] In some embodiments, the compound used in the methods herein is a piperidinedione compound as described herein. In some embodiments, the compound is a compound of formula (I). In some embodiments, the compound is a compound of formula (II). In some embodiments, the compound is a compound of formula (III). In some embodiments, the compound is a compound of formula (IV). In some embodiments, the compound is a compound of formula (V). In some embodiments, the compound is a compound of formula (VI). In some embodiments, the compound is a compound of formula (VII). In some embodiments, the compound is a compound of formula (VIII). In some embodiments, the compound is a compound of formula (IX). In some embodiments, the compound is a compound of formula (X). In some embodiments, the compound is a compound of formula (a). In some embodiments, the compound is a compound of formula (b). In some embodiments, the compound is a compound of formula (c). In some embodiments, the compound is a compound of formula (d). In some embodiments, the compound is a compound of formula (t). In some embodiments, the compound is a compound of formula (u). In some embodiments, the compound is a compound of formula (ab). In some embodiments, the compound is a compound of formula (ac). In some embodiments, the compound is a compound of formula (ad). In some embodiments, the compound is a compound from Table 1.

[0952] In some embodiments, the AR-mediated disease is a wild-type AR-mediated disease. In other embodiments, the AR-mediated disease is the result of AR amplification.

[0953] In certain embodiments, the disease mediated by AR is prostate cancer. In some such embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some such embodiments, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC). In another embodiment, the prostate cancer is non-metastatic CRPC (nmCRPC). In some embodiments, the prostate cancer is refractory to hormones. In some embodiments, the prostate cancer is resistant to the treatment of AR antagonists. For example, the prostate cancer is resistant to the treatment of enzalutamide, bicalutamide, abiraterone, ARN-509, ODM-201, EPI-001, EPI-506, AZD-3514, galeterone, ASC-J9, flutamide, hydroxyflutamide, nilutamide, cyproterone acetate, ketoconazole or spironolactone.

[0954] Provided herein are methods for reducing AR content, comprising administering an effective amount of a piperidinedione compound to a subject. Also provided herein are piperidinedione compounds suitable for methods of reducing AR content in cells in vivo, in vitro, or in vitro, comprising contacting the cells with an effective amount of a piperidinedione compound. In one embodiment, the cells are in the patient's body. In one embodiment, the cells are not in the patient's body. In one embodiment, provided herein are methods for reducing the content of wild-type AR in a tumor, comprising administering a therapeutically effective amount of a piperidinedione compound to reduce the content of wild-type AR in the tumor. In one embodiment, provided herein are methods for reducing the content of AR-full length (AR-FL) in a tumor, comprising administering a therapeutically effective amount of a piperidinedione compound to reduce the content of AR-full length (AR-FL) in the tumor. In some embodiments, AR content is reduced compared to AR content before the administration of the piperidinedione compound. In some embodiments, AR content is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% compared to AR content before the administration of the piperidinedione compound.

[0955] Also provided herein is a method for regulating the protein activity of AR in a patient in need thereof, the method comprising administering a certain amount of a piperidinedione compound to the patient. In some such embodiments, provided herein is a method for reducing the protein activity of AR in a patient in need thereof, the method comprising administering a certain amount of a piperidinedione compound to the patient. In some embodiments, the protein activity of AR is reduced compared to the protein activity of AR before the administration of the piperidinedione compound. In some embodiments, the protein activity of AR is reduced by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99% compared to the protein activity of AR before the administration of the piperidinedione compound.

[0956] In some embodiments of the methods described herein, the methods additionally comprise administering one or more second agents selected from the group consisting of AR antagonists (such as cyproterone acetate, spironolactone, bicalutamide, and enzalutamide), 5α-reductase inhibitors (such as finasteride and dutasteride), CYP17A1 inhibitors (such as abiraterone acetate), gonadotropin-releasing hormone (GnRH) analogs (such as leuprorelin and cetrorelix), and antigonadotropins (such as megestrol acetate and medroxyprogesterone acetate).

[0957] In some embodiments, the compounds provided herein can be used in any of the above-mentioned methods.

[0958] In some embodiments, the piperidinedione compounds provided herein can be used in any of the above-mentioned methods.

[0959] Pharmaceutical compositions and routes of administration

[0960] The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional formulations such as capsules, microcapsules, tablets, granules, powders, dragees, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0961] The piperidinedione compound can be administered orally, topically or parenterally to a subject in the form of conventional preparations, such as capsules, microcapsules, tablets, granules, powders, sugar-coated tablets, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable preparations 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 citric acid), glycerol, PEG-10 ... The compositions of the present invention may be prepared from a pharmaceutical composition comprising a piperidinedione compound, a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), a flavoring agent (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 piperidinedione compound in the pharmaceutical composition may be an amount that will achieve the desired effect; for example, a unit dose for oral and parenteral administration is about 0.005 mg / kg to about 10 mg / kg of subject body weight.

[0962] The dosage of the piperidinedione compound administered to a subject varies widely and can be judged by a health care practitioner. In general, the piperidinedione compound can be administered one to four times daily with a dosage of about 0.001mg / kg subject weight to about 10mg / kg subject weight, but the above dosage can be appropriately changed depending on the age, weight and condition of the subject and the type of administration. In one embodiment, the dosage is about 0.001mg / kg subject weight to about 5mg / kg subject weight, about 0.01mg / kg subject weight to about 5mg / kg subject weight, about 0.05mg / kg subject weight to about 1mg / kg subject weight, about 0.1mg / kg subject weight to about 0.75mg / kg subject weight or about 0.25mg / kg subject weight to about 0.5mg / kg subject weight. In one embodiment, a dosage is administered once a day. In any given case, the amount of piperidinedione compound administered will depend on such factors as the solubility of the active ingredient, the formulation used, and the route of administration.

[0963] In another embodiment, provided herein are methods for treating or preventing a disease or condition comprising administering to a subject in need thereof an amount of a piperidinedione compound of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0964] In another embodiment, provided herein are unit dose 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 a piperidinedione compound.

[0965] In a specific embodiment, provided herein are unit dose formulations comprising about 0.1 mg or 100 mg of a piperidinedione compound.

[0966] In another embodiment, provided herein are unit dose formulations comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a piperidinedione compound.

[0967] The piperidinedione compound can be administered once, twice, three times, four times or more daily. In a specific embodiment, a dose of 100 mg or less is administered as a single daily dose, and a dose exceeding 100 mg is administered twice daily in an amount equal to half the total daily dose.

[0968] The piperidinedione compound can be administered orally for convenience. In one embodiment, when administered orally, the piperidinedione compound is administered with food and water. In another embodiment, the piperidinedione compound is dispersed in water or fruit juice (e.g., apple juice or orange juice) or any other liquid and administered orally in the form of a solution or suspension.

[0969] The piperidinedione compound can also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracranially, intravaginally, transdermally, rectally, transmucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is at the discretion of the healthcare practitioner and may depend, in part, on the site of the condition.

[0970] In one embodiment, provided herein are capsules containing a piperidinedione compound without additional carriers, excipients, or vehicles.

[0971] In another embodiment, provided herein is a composition comprising an effective amount of a piperidinedione 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.

[0972] The composition may be in the form of tablets, chewable tablets, capsules, solutions, injections, sugar-coated tablets, suppositories and suspensions and the like. The composition may be formulated to contain a daily dose or a suitable fraction of a daily dose in a dosage unit, which may be a single tablet or capsule or a suitable volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt, such as a hydrochloride. In general, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing the piperidinedione compound with a suitable carrier or diluent and filling the capsule with an appropriate amount of the mixture. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch; powdered cellulose, especially crystalline and microcrystalline cellulose; sugars, such as fructose, mannitol and sucrose; cereal flours and similar edible powders.

[0973] Tablets can be prepared by direct compression, wet granulation or dry granulation. Their preparations are usually combined with diluents, binders, lubricants and disintegrants and the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride and powdered sugar). Powdered cellulose derivatives are also suitable. Typical tablet binders are materials such as: starch, gelatin and sugar, such as lactose, fructose, glucose and the like. Natural and synthetic gums are also suitable, including gum arabic, alginate, methylcellulose, polyvinyl pyrrolidine and the like. Polyethylene glycol, ethyl cellulose and wax can also serve as binders.

[0974] Lubricants may be necessary for tablet formulations to prevent tablets and punches from sticking in the mold. Lubricants may be selected from slippery solids such as talc, magnesium stearate and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are materials that swell when wetted to break the tablet and release the compound. They include starch, clay, cellulose, fucoidan and gum. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose and sodium lauryl sulfate can be used. Tablets may be coated with sugar or film-forming protective agents as flavorings and sealants to change the dissolution properties of the tablet. Compositions may also be formulated into chewable tablets, for example, by using substances such as mannitol in formulation.

[0975] When it is desired to administer the piperidinedione compound in the form of a suppository, a typical base can be used. Cocoa butter is a traditional suppository base, which can be modified by adding waxes to slightly raise its melting point. Water-miscible suppository bases containing, inter alia, polyethylene glycols of various molecular weights are widely used.

[0976] The effect of the piperidine dione compound can be delayed or prolonged by appropriate formulations. For example, slowly soluble aggregates of the piperidine dione compound can be prepared and incorporated into tablets or capsules or as slow-release implantable devices. This technology also includes making pills with several different dissolution rates and filling capsules with a mixture of pills. The tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral preparations can be made long-lasting by dissolving or suspending the piperidine dione compound in an oily or emulsifying vehicle that allows it to slowly disperse in the serum.

[0977] Example

[0978] The following examples are presented by way of illustration and not limitation. Compounds were named using the automatic name generation tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with the support of 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 products.

[0979] Salts of 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 after chromatographic purification with a solution of an acid (e.g., aqueous HCl).

[0980] Abbreviations used:

[0981]

[0982]

[0983] Compound synthesis

[0984] Example 1: 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide formate

[0985]

[0986] 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile To a solution of thiocarbonyl dichloride (75.9 g, 0.66 mol) in water (1000 mL) was slowly added portionwise 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile (95.0 g, 0.508 mol). The reaction mixture was stirred at 25 ° C for 4 hours. The reaction mixture was extracted with EtOAc (1000 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc / petroleum ether) to obtain 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (86.0 g, 73.9% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δppm 8.66 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H).

[0987] 2- (4- hydroxyanilino) -2- methyl - propionitrile. To a solution of 4-aminophenol (80.0 g, 0.733 mmol) in DCM (1600 mL) and acetone (400 mL) was added trimethylsilyl trifluoromethanesulfonate (8.15 g, 36.7 mmol) and trimethylsilylcarbonitrile (102 g, 1.03 mol). The reaction mixture was stirred at 25 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by recrystallization from MTBE (500 mL) and dried to give 2- (4- hydroxyanilino) -2- methyl - propionitrile (85.0 g, 65.8% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δppm 8.90 (s, 1H), 6.78-6.77 (m, 2H), 6.66-6.63 (m, 2H), 5.20 (s, 1H), 1.51 (s, 6H).

[0988] 5-[3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thione-imidazolidin-1-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile. To a solution of 2-(4-hydroxyanilino)-2-methyl-propionitrile (53.0 g, 0.301 mol) in DMA (500 mL) was added 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (72.4 g, 0.316 mol) at 28 ° C. The reaction mixture was stirred at 28 ° C for 2 hours. The reaction solution was mixed with MeOH (500 mL) and aqueous HCl (2M, 500 mL) and allowed to warm up to 70 ° C. After stirring for 2 hours, the reaction solution was cooled to 30 ° C, mixed with water (500 mL) and extracted with EtOAc (1000 mL × 2). The combined organic phases were washed with a saturated sodium chloride solution (500 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from EtOAc (100 mL) to give 5-[3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thione-imidazolidin-1-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile (41.5 g, 33.9% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 9.10 (s, 1H), 8.37 (d, J = 2.4Hz, 1H), 7.17 (dd, J = 2.0, 6.4Hz, 2H), 6.97 (dd, J = 2.0, 6.4Hz, 2H), 5.23 (s, 1H), 1.59 (s, 6H).

[0989] tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazine-1-carboxylate. 5-(3-(4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (2.00 g, 4.92 mmol), tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (1.44 g, 4.92 mmol), and cesium carbonate (2.40 g, 7.38 mmol) were combined in DMF (12 mL) and the mixture was heated to 45° C. in a screw-cap scintillation vial. After 48 hours, the solution was filtered, the solid was washed with additional MeOH / DCM, and the combined filtrate was concentrated under reduced pressure to give a partially solidified yellow oil. The solid was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound (0.971 g, 1.57 mmol, 31.9% yield) as an off-white solid. MS (ESI) m / z 619 [M+1] + .

[0990] 5-(4,4-dimethyl-5-oxo-3-(4-(2-(piperazin-1-yl)ethoxy)phenyl)-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile trihydrochloride. Tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazine-1-carboxylate (0.971 g, 1.57 mmol) was dissolved in DCM (4 mL) and a 4.0 M solution of HCl in dioxane (0.572 mL, 18.8 mmol) was added. After 90 minutes, the solution was concentrated under reduced pressure to give the title compound (1.07 g, 1.7 mmol, quantitative yield) as a yellow solid. MS (ESI) m / z 519 [M+1] + .

[0991] Methyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)acetate. 5-(4,4-Dimethyl-5-oxo-3-(4-(2-(piperazin-1-yl)ethoxy)phenyl)-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile trihydrochloride (0.400 g, 0.637 mmol) and TEA (0.444 mL, 3.19 mmol) were combined in THF (3 mL). After stirring for 2 minutes, methyl 2-bromoacetate (0.065 mL, 0.637 mmol) was added and the mixture was stirred at ambient temperature in a screw-cap flask. After 30 minutes, the solution was loaded onto a silica gel column for chromatography (0-100% EtOAc / hexanes, then 10% MeOH / EtOAc) to give the title compound (0.273 g, 0.462 mmol, 72.6% yield). MS (ESI) m / z 591 [M+1] + .

[0992] 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)acetic acid. Methyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)acetate (0.273 g, 0.462 mmol) was dissolved in THF (1 mL) and treated with a solution of hydrated lithium hydroxide (0.213 g, 5.08 mmol) in water (1.000 mL). The mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. To the resulting yellow oil was added water (3 mL) and 3.0 M aqueous HCl to reduce the pH to 4 to 5. The material was partitioned between 15% MeOH / DCM and water (75 mL). The aqueous phase was extracted with DCM, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (0.135 g, 0.234 mmol, 51.0% yield) as an off-white solid. MS (ESI) m / z 577 [M+1] + .

[0993] To a solution of 3-bromopiperidine-2,6-dione (120 g, 0.470 mol) in DMF (1 L) was added tert-butyl N-(3-aminophenyl)carbamate (81.4 g, 0.390 mol), and the mixture was stirred at 80 ° C for 12 hours, then slowly poured into water (2500 mL) and filtered. The solid was washed with EtOAc (200 mL) and dried to give tert-butyl N-[3-[(2,6-dioxo-3-piperidinyl)amino]phenyl]carbamate (56.0 g, crude product) as a blue solid. 1 H NMR(400MHz,DMSO-d6)δppm 10.78(s,1H),9.04(s,1H),6.96-6.92(m,1H),6.87(s,1H),6.67(d,J=8.0Hz,1H),6.31(dd,J=1.6Hz,8.0Hz,1H),5.7 9(s,1H),4.23-4.21(m,1H),2.74-2.62(m,1H),2.61-2.58(m,1H),2.10-2.08(m,1H),1.91-1.87(m,1H),1.47(s,9H).

[0994] 3-(3-aminoanilino)piperidine-2,6-dione. To a solution of tert-butyl N-[3-[(2,6-dioxo-3-piperidinyl)amino]phenyl]carbamate (55.6 g, 0.17 mol) in DCM (550 mL) was added TFA (385 g, 3.38 mol, 250 mL) at 0°C to 5°C. The reaction mixture was stirred at 25°C for 10 hours and then concentrated to a residue. MTBE (600 mL) was added to the residue to cause a blue solid to precipitate. 3-(3-aminoanilino)piperidine-2,6-dione trifluoroacetate (52.0 g, 89.6% yield) was collected by filtration. 1 H NMR(400MHz,DMSO-d6)δppm 10.83(s,1H),7.12(t,J=8.0Hz,1H),6.60(d,J=8.0Hz,1H),6.53(s,1H),6.50-6.43(m,1H),4.33(dd ,J=5.2Hz,11.6Hz,1H),2.76-2.73(m,1H),2.63-2.58(m,1H),2.13-2.07(m,1H),1.97-1.93(m,1H).

[0995] 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide formate. To a scintillation vial was added 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)acetic acid (0.135 g, 0.234 mmol), 3-((3-aminophenyl)amino)piperidine-2,6-dione (0.074 g, 0.234 mmol), and DIEA (0.123 mL, 0.702 mmol) in DMF (1 mL). Finally, HATU (0.089 g, 0.234 mmol) was added, and the solution was stirred at ambient temperature. After 30 minutes, the solution was diluted with DMSO (0.5 mL), and the mixture was purified by standard methods to give the title compound (0.050 g, 0.064 mmol, 27.5% yield). MS (ESI) m / z 778[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm10.78 (s, 1H), 9.36-9.44 (m, 1H), 9.24 (d, J = 1.22Hz, 1H), 8.82 (d, J = 1. 83Hz,1H),8.13(s,1H),7.28(m,J=8.68Hz,2H),7.12(m,J=8.56Hz,2H),6.96-7.03(m,2H),6.81(br d,J=8.07Hz,1H),6.52(s,1H),6.39(d,J=7.35Hz,1H),5.88(br d,J=8.68Hz,1H),4.25(dt,J=7.15,5.35Hz,1H),4.08-4.20(m,2H),3.37(br s,1H),3.24(br s,1H),2.95-3.19(m,3H),2.58-2.87(m,1H),2.54-2.81(m,10H),2.37-2.44(m,1H),2.33(br s,1H),2.04-2.14(m,1H),1.82-1.95(m,1H),1.46-1.54(m,7H),1.25(br d,J=1.47Hz,1H),0.04(br s,1H),-0.04(br d, J = 3.18 Hz, 1H).

[0996] Example 2: (2S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)propanamide hydrochloride

[0997]

[0998] 2-(3-chloro-4-hydroxy-anilino)-2-methyl-propionitrile.To a solution of 4-amino-2-chloro-phenol (45.0 g, 0.310 mol) in DCM (450 mL) and acetone (225 mL) at 10 ° C., trimethylsilyl trifluoromethanesulfonate (3.48 g, 16.0 mmol) and trimethylsilylcarbonitrile (43.5 g, 0.440 mol) were added. After addition, the reactant was stirred at 25 ° C. for 16 hours, then concentrated to a residue, which was purified by silica gel column chromatography (petroleum ether and EtOAc, 15: 1 to 7: 1) to give 2-(3-chloro-4-hydroxy-anilino)-2-methyl-propionitrile (41.5 g, 62.8% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δppm 9.52 (s, 1H), 6.89-6.84 (m, 2H), 6.76-6.73 (m, 1H), 5.52 (s, 1H), 1.54 (s, 6H).

[0999] 4-[3-(3-chloro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile. To a solution of 2-(3-chloro-4-hydroxy-anilino)-2-methyl-propionitrile (14.6 g, 69.0 mmol) in DMA (150 mL) at 20°C was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (19.0 g, 83.0 mmol). After stirring at 20°C for 2 hours, the reaction mixture was diluted with MeOH (150 mL) and aqueous HCl (2M, 150 mL) at 20°C and stirred at 70°C for 5 hours. The reaction mixture was cooled to 10°C and filtered. The filter cake was washed with water (200 mL) and dried to give 4-[3-(3-chloro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thione-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (20.0 g, 65.6% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δppm10.72(s,1H),8.38(d,J=8.4Hz,1H),8.27(d,J=1.6Hz,1H) ,8.07(dd,J=1.6Hz,8.0Hz,1H),7.39(d,J=2.4Hz,1H),7.15-7.10(m,2H),1.49(s,6H).

[1000] Tert-Butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)phenoxy)ethyl)piperazine-1-carboxylate. Tert-Butyl 4-(2-chloroethyl)piperazine-1-carboxylate (0.424 g, 1.70 mmol, 1.50 equiv) was dissolved in DMF (8.42 mL, 0.135 mol). Cesium carbonate (0.556 g, 1.70 mmol, 1.50 equiv) and 4-(3-(3-chloro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.500 g, 1.14 mmol, 1 equiv) were added and the reaction was warmed to 60° C. for 18 hours. The reaction was quenched with water and diluted with EtOAc, and the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH / DCM), and the corresponding fractions were combined and concentrated to give tert-butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioneimidazolidin-1-yl)phenoxy)ethyl)piperazine-1-carboxylate (0.792 g, 1.07 mmol, 95% yield) as a yellow oil. MS (ESI) m / z 652.2 [M] + .

[1001] 4-(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. Tert-Butyl 4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazine-1-carboxylate (0.701 g, 1.07 mmol, 1 equiv) was suspended in DCM (4.75 mL, 0.226 mol) and treated with a solution of HCl in dioxane (4.03 mL, 16.1 mmol, 15 equiv). The reaction was stirred at room temperature for 3 hours and then concentrated to give 4-(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.633 g, 1.08 mmol, 100% yield) as a white solid. MS (ESI) m / z 552.2 [M] + .

[1002] (S)-methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoate. (R)-methyl 2-chloropropanoate (0.033 mL, 0.31 mmol, 1.2 equiv) was added to a stirred mixture of 4-(3-(3-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.150 g, 0.255 mmol, 1 equiv), THF (2.179 mL, 0.117 mol), and TEA (0.142 mL, 1.02 mmol, 4 equiv). The reaction mixture was stirred at 60° C. for 18 hours and then heated to 80° C. for 36 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (0-80% EtOAc / hexane) to give (S)-methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoate (0.078 g, 0.122 mmol, 48.0% yield) as a yellow solid. MS (ESI) m / z 638.2 [M] + .

[1003] (S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoic acid. To (S)-methyl 2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoate (0.078 g, 0.12 mmol, 1 equiv) suspended in a 3:1 mixture (0.113 mol) of THF (0.811 mL) and water (0.270 mL) was added lithium hydroxide (0.031 g, 1.30 mmol, 10 equiv). The reactant was stirred at room temperature for 4 hours and then diluted with EtOAc and water. The pH value was reduced to about 3 by adding 6M HCl aqueous solution. The organic layer was extracted with EtOAc, dried over sodium sulfate, filtered and concentrated to give (S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoic acid (0.117 g, 0.127 mmol, 104% yield) as a beige solid. MS (ESI) m / z 624.2 [M] + .

[1004] (2S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)propanamide hydrochloride. (S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)propanoic acid (0.076 g, 0.12 mmol, 1 eq) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate (0.041 g, 0.12 mmol, 1 eq), HATU (0.051 g, 0.134 mmol, 1.1 eq), DIEA (0.085 mL, 0.49 mmol, 4 eq) and DMF (0.609 mL, 0.2 M), and the reaction was stirred at 25° C. for 2 h. The reaction was quenched with water and diluted with EtOAc, and the aqueous layer was extracted with EtOAc. The combined extracts were concentrated and the residue was purified by standard methods to give (2S)-2-(4-(2-(2-chloro-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)propanamide hydrochloride (0.022 g, 0.027 mmol, 22% yield). MS (ESI) m / z 825.2 [M] + ; 1 H NMR(400MHz,DMSO-d6)δppm10.79(s,1H),10.12(br s,1H),8.40(d,J=8.31Hz,1H),8.27(d,J=1.83Hz,1H),8.06(dd,J=1.59,8.19Hz,1H),7.54-7.57(m,1H),7.38(s,3H),6.96-7.06(m,2H),6.85(br d,J=7.83Hz,1H),6.45(dd,J=1.47,8.19Hz,1H),4.55(br s,2H),4.26(br dd,J=4.34,11.19Hz,1H),3.23-3.46(m,9H),2.69-2.80(m,1H),2.55-2.64(m,1H),2.54(s,2H),2.08-2.14(m,1H),1.90(br dq,J=4.46,12.08Hz,1H),1.52(s,6H),1.39(br s,3H).

[1005] Example 3: 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride

[1006]

[1007] tert-Butyl (2-fluoro-5-nitrophenyl) carbamate, tert-butyl N-tert-butoxycarbonyl-N-(2-fluoro-5-nitro-phenyl) carbamate. To a solution of 2-fluoro-5-nitroaniline (100.0 g, 640.6 mmol, 1.00 equiv) and Boc2O (279.6 g, 1.28 mol, 294 mL, 2.00 equiv) in THF (600 mL) was added 4-dimethylaminopyridine (7.83 g, 64.1 mmol, 0.10 equiv) in one portion. The mixture was stirred at 50 ° C under nitrogen for 12 hours. The mixture was cooled to 15 ° C and concentrated under reduced pressure to give a residue. The residue was diluted with water (1500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography (petroleum ether). A mixture of tert-butyl (2-fluoro-5-nitrophenyl)carbamate and tert-butyl N-tert-butoxycarbonyl-N-(2-fluoro-5-nitro-phenyl)carbamate was obtained as a colorless oil (200 g).

[1008] (5-amino-2-fluorophenyl) tert-butyl carbamate, N-(5-amino-2-fluoro-phenyl)-N-tert-butoxycarbonyl-tert-butyl carbamate. To a mixture of (2-fluoro-5-nitrophenyl) tert-butyl carbamate and N-tert-butoxycarbonyl-N-(2-fluoro-5-nitro-phenyl) tert-butyl carbamate (80.0 g, 224.5 mmol, 1.00 equivalent) in MeOH (800 mL) was added palladium / aluminum oxide (10.0 g, 224.5 mmol, 5% purity) under nitrogen. The suspension was vacuum degassed and purged with hydrogen several times. The mixture was stirred at 15 ° C under hydrogen (50 psi) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to give a residue. A mixture of tert-butyl (5-amino-2-fluorophenyl)carbamate and tert-butyl N-(5-amino-2-fluoro-phenyl)-N-tert-butoxycarbonyl-carbamate was obtained as a white solid (70 g). The mixture was used in the next step without further purification. MS (ESI) m / z 171.1 [M-55] + .

[1009] To a mixture of tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamate, tert-butyl N-tert-butoxycarbonyl-N-[5-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-phenyl]carbamate. To a mixture of tert-butyl (5-amino-2-fluorophenyl)carbamate and tert-butyl N-(5-amino-2-fluoro-phenyl)-N-tert-butoxycarbonyl-carbamate (30.00 g, 132.6 mmol, 1.00 equiv) and sodium bicarbonate (22.28 g, 265.2 mmol, 2.00 equiv) in DMF (250 mL) was added 3-bromopiperidine-2,6-dione (30.00 g, 156.2 mmol, 1.18 equiv) in one portion. The mixture was stirred at 50 ° C under nitrogen for 12 hours, then diluted with water (1000 mL) and extracted with EtOAc (300 mL×4). The combined organic layers were washed with brine (400 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (10-35% EtOAc / petroleum ether). A mixture of tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamate and tert-butyl N-tert-butoxycarbonyl-N-[5-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-phenyl]carbamate (43.00 g) was obtained as a light yellow solid. MS (ESI) m / z 282.1[M-55] + .

[1010] 3-(3-amino-4-fluorophenylamino)piperidine-2,6-dione. To a mixture of tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)carbamate and tert-butyl N-tert-butoxycarbonyl-N-[5-[(2,6-dioxo-3-piperidinyl)amino]-2-fluoro-phenyl]carbamate (30.00 g, 68.58 mmol, 1.00 equivalent) in DCM (300 mL) was added TFA (60.0 mL, 11.8 equivalents) at a time at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours and then at 20 ° C for 2 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure at 40 ° C to remove DCM. Subsequently, saturated sodium bicarbonate solution (500 mL) and solid sodium bicarbonate were added to the mixture to adjust the pH value to 7. The suspension was filtered and the filter cake was collected. The filter cake was washed with EtOAc (200×5) and dried under reduced pressure to give a gray solid. The compound 3-(3-amino-4-fluorophenylamino)piperidine-2,6-dione (10.02 g, 41.53 mmol, 60.6% yield) was obtained as a gray solid. MS (ESI) m / z 238.2 [M+1]+ ; 1 H NMR(400MHz,DMSO-d6)δppm 10.76(s,1H),6.69(dd,J=8.7,11.2Hz,1H),6.08(dd,J=2.7,7.9Hz,1H),5.84(td,J=3.1,8.7Hz,1H),5.40(d,J=7.3Hz,1H ), 4.81 (s, 2H), 4.16-4.07 (m, 1H), 2.76-2.65 (m, 1H), 2.61-2.53 (m, 1H), 2.13-2.04 (m, 1H), 1.83 (dq, J = 4.7, 12.0Hz, 1H).

[1011] 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1-carboxylate. A mixture of tert-butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (1.00 g, 2.00 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.616 g, 4.00 mmol, 2 equiv), potassium phosphate (2.12 g, 9.99 mmol, 5 equiv), (1,1'-bis(diphenylphosphino)ferrocene)-palladium(II) chloride (0.292 g, 0.399 mmol, 0.2 equiv) in dioxane (1 mL) and water (0.5 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 120 °C under a nitrogen atmosphere for 12 hours and then concentrated under reduced pressure at 40 °C. The residue was poured into ice water (50 mL). The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-33% EtOAc / petroleum ether) to give tert-butyl 4- (2- (4- ((1-methoxy-2-methyl-1-oxopropyl-2-yl) amino) -2-vinylphenoxy) ethyl) piperazine-1-carboxylate (0.500 g, 1.12 mmol, 55.9% yield) as a yellow oil. MS (ESI) m / z 448.1 [M + 1] + .

[1012] tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1-carboxylate (0.500 g, 1.12 mmol, 1 equiv) in MeOH (10 mL) was added Pd—C (10%, 0.200 g) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred at 40° C. under hydrogen (50 psi) for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.320 g, 0.712 mmol, 63.7% yield) as a yellow oil. MS (ESI) m / z 450.3 [M+1] + .

[1013] tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioximidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.319 g, 0.710 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.486 g, 2.130 mmol, 3 eq) in EtOAc (2 mL) was added TEA (0.359 g, 3.550 mmol, 5 eq). The mixture was stirred at 80° C. for 12 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (67% EtOAc / petroleum ether) to give tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioneimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 68.8% yield) as a yellow solid. MS (ESI) m / z 646.4 [M+1] + .

[1014] 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 1 equiv) in EtOAc (2 mL) was added HCl in dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 30 minutes and then concentrated under reduced pressure to obtain 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.300 g, crude product) as a yellow solid. MS (ESI) m / z 546.1 [M+1] + .

[1015] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)acetic acid hydrochloride. To a solution of 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (1.00 g, 1.72 mmol) in THF (10 mL) was added DIEA (1.20 mL, 6.87 mmol) followed by tert-butyl 2-bromoacetate (0.266 mL, 1.80 mmol). The gained mixture is stirred overnight at ambient temperature, then diluted with EtOAc (125mL), water (20mL) and salt solution (20mL).Separate solvent layer, and the organic extract merged is dried over anhydrous magnesium sulfate, filtered, and is concentrated into oily matter.Oily matter is dissolved in DCM (25mL), processed with TFA (2.65mL, 34.4mmol), and solution is stirred overnight at ambient temperature.Add 4.0M solution (5mL) of HCl in dioxane, and again at room temperature stir overnight.Subsequently, the reaction mixture is concentrated under reduced pressure, and the 4.0M solution (5mL) of HCl in dioxane is processed to residual oily matter.Gained precipitation is collected by filtration, and it is suspended in diethyl ether and wet-milled 3 hours. The material was collected by filtration, washed with hexanes, and dried in a vacuum oven at 45°C overnight to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)acetic acid hydrochloride (0.989 g, 1.54 mmol, 90.0% yield). MS (ESI) m / z 604.2 [M+1] + .

[1016] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride. 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)acetic acid hydrochloride (0.100 g, 0.156 mmol), 3-((3-amino-4-fluorophenyl)amino)piperidine-2,6-dione 2,2,2-trifluoroacetate (0.055 g, 0.156 mmol), DIEA (0.164 mL, 0.937 mmol) and DMF (1 mL) were combined and stirred for 5 minutes. HATU (0.065 g, 0.17 mmol) was added and the resulting mixture was stirred at ambient temperature. After 6 hours, the reaction mixture was filtered and purified by standard methods to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)acetamide hydrochloride (0.011 g, 0.013 mmol, 8.2% yield). MS (ESI) m / z 823.2 [M+1] + ; 1 HNMR(400MHz,DMSO-d6)δppm 10.67-10.89(m,1H),8.35-8.47(m,1H),8.24-8.35(m,1H),8.02-8.14( m,1H),7.10-7.28(m,4H),6.90-7.10(m,1H),6.38-6.55(m,1H),4.40-4. 55(m,3H),4.18-4.29(m,2H),3.49-3.81(m,5H),2.56-2.79(m,4H),2.0 1-2.15(m,1H),1.81-1.98(m,1H),1.40-1.57(m,6H),1.00-1.25(m,4H).

[1017] Example 4: 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

[1018]

[1019] N-(3-bromo-5-nitrophenyl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester. To a solution of 3-bromo-5-nitro-aniline (5.50 g, 25.3 mmol, 1.00 equiv) in pyridine (50 mL) was added Boc2O (27.66 g, 126.7 mmol, 5.00 equiv). The mixture was stirred at 25 ° C for 12 hours, then diluted with water (30 mL) and EtOAc (60 mL × 3). The combined organic extracts were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (3% EtOAc / petroleum ether) to obtain N-(3-bromo-5-nitro-phenyl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (8.00 g, 19.2 mmol, 76.0% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm 8.37 (t, J = 1.8 Hz, 1H), 8.20 (t, J = 1.8 Hz, 1H), 8.12 (t, J = 1.6 Hz, 1H), 1.40 (s, 18H).

[1020] To a mixture of N-(3-bromo-5-nitro-phenyl)-N-tert-butoxycarbonyl-tert-butyl carbamate (4.30 g, 10.31 mmol, 1.00 equivalent) in DMF (5 mL) was added zinc cyanide (2.42 g, 20.61 mmol, 2.00 equivalents), tetrakis[triphenylphosphine]palladium(0) (2.38 g, 2.06 mmol, 0.20 equivalents), and the mixture was stirred at 100 ° C under nitrogen for 10 hours. The reaction mixture was diluted with water (25 mL) and the product was extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (4% EtOAc / petroleum ether) to give tert-butyl (3-cyano-5-nitrophenyl)carbamate (1.10 g, 4.09 mmol, 30.0% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δppm10.24(s,1H),8.64(s,1H),8.31(s,1H),8.13(s,1H),1.50(s,9H).

[1021] tert-Butyl (3-amino-5-cyanophenyl)carbamate. To a mixture of tert-butyl N-(3-cyano-5-nitro-phenyl)carbamate (1.10 g, 4.2 mmol, 1.00 equiv) in EtOH (30 mL) and water (10 mL) was added ferric nitrate (1.40 g, 25.1 mmol, 6.00 equiv) and ammonium chloride (2.24 g, 41.8 mmol, 10.00 equiv) at 25 ° C. The mixture was heated to 80 ° C, stirred under nitrogen for 10 hours, and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (3-amino-5-cyanophenyl)carbamate (0.95 g, 4.07 mmol, 97.0% yield) as a dark brown oil. MS (ESI) m / z 178.1 [M-55] + .

[1022] 3,5-diaminobenzonitrile. To a solution of tert-butyl (3-amino-5-cyanophenyl)carbamate (0.200 g, 0.857 mmol, 1.00 equiv) in EtOAc (2 mL) was added a 4.0 M solution of HCl in 1,4-dioxane (2.14 mL, 10.00 equiv). The mixture was stirred at 25 ° C for 1 hour, then poured into a saturated aqueous sodium bicarbonate solution (50 mL), and the mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3,5-diaminobenzonitrile (0.100 g, 0.751 mmol, 88.0% yield) as a white solid. MS (ESI) m / z 134.2 [M + 1] + .

[1023] 3-amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile. To a solution of 3,5-diaminobenzonitrile (0.100 g, 0.75 mmol, 1.00 equiv) and 3-bromopiperidine-2,6-dione (0.288 g, 1.50 mmol, 2.00 equiv) in DMF (1 mL) was added sodium bicarbonate (0.094 g, 1.13 mmol, 1.50 equiv). The mixture was stirred at 50 ° C for 12 hours. The mixture was poured into ice water (20 mL) and the aqueous phase was extracted with EtOAc (20 mL×3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by preparative TLC (50% EtOAc / petroleum ether) to give 3-amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile (0.050 g, 0.204 mmol, 27.0% yield) as a white solid. MS (ESI) m / z 245.2 [M+1] + .

[1024] 2-(Difluoromethyl-fluoroalkyl)-4-isothiocyanato-benzonitrile. To a solution of thiocarbonyl dichloride (44.2 g, 385 mmol, 29.5 mL) in water (500 mL) was added 4-amino-2-(difluoromethyl-fluoroalkyl)benzonitrile (48.0 g, 256 mmol) at 15 ° C. After the addition, the reaction was stirred at 28 ° C. for 12 hours. The material was then extracted with DCM (3×300 mL). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (0-5% EtOAc / petroleum ether) to give 2-(difluoromethyl-fluoroalkyl)-4-isothiocyanato-benzonitrile (52.0 g, 88.4% yield) as a brown solid. 1 H NMR (400MHz, CDCl3) δppm 7.87 (d, J = 8.0Hz, 1H), 7.59 (s, 1H), 7.51-7.48 (m, 1H).

[1025] 2-(3-Fluoro-4-hydroxy-anilino)-2-methyl-propionitrile. To a solution of 4-amino-2-fluoro-phenol (25.0 g, 197 mmol) in DCM (250 mL) and acetone (125 mL) was added trimethylsilylcarbonitrile (27.3 g, 275 mmol, 34.57 mL) and trimethylsilyl trifluoromethanesulfonate (2.19 g, 9.83 mmol, 1.78 mL) at 0° C. to 5° C. After addition, the reaction was stirred at 20° C. for 16 hours, then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% EtOAc / petroleum) to give 2-(3-fluoro-4-hydroxy-anilino)-2-methyl-propionitrile (20.0 g, 53.4% ​​yield) as a white solid. 1 H NMR (400MHz, CDCl3) δppm 6.93 (t, J = 8.8 Hz, 1H), 6.82 (dd, J = 2.8 Hz, 12.0 Hz, 1H), 6.78-6.71 (m, 1H), 4.99 (s, 1H), 3.41 (s, 1H), 1.62 (s, 6H).

[1026] 4-[3-(3-fluoro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile. A solution of 2-(3-fluoro-4-hydroxy-anilino)-2-methyl-propionitrile (20.0 g, 103 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (31 g, 134 mmol) in DMA (300 mL) was stirred at 18 ° C for 3 hours, then diluted with MeOH (200 mL) and aqueous HCl (2M, 200 mL), and allowed to warm to 70 ° C. After 2 hours, the reaction mixture was cooled to room temperature (18 ° C), mixed with water (150 mL), and extracted with EtOAc (200 mL × 3). The organic phases were combined, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (11-16% EtOAc / petroleum ether) to give 4-[3-(3-fluoro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thione-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (19 g, 43.6% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δppm 8.00-7.96(m,2H),7.85-7.82(m,1H),7.16(t,J=8.8Hz,1H),7.09-7.06(m,1H),7.02-7.00(m,1H),5.84(s,1H),1.60(s,6H).

[1027] 4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-phenoxy]ethyl]piperazine-1-carboxylic acid tert-butyl ester. To a solution of 4-[3-(3-fluoro-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (11.4 g, 26.9 mmol) and cesium carbonate (13.1 g, 40.3 mmol) in DMF (330 mL) at 18° C. was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (10 g, 40.3 mmol). The reaction mixture was stirred at 60° C. for 10 hours, then diluted with water (500 mL) and extracted with EtOAc (300 mL×3). The combined organic phases were washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product (20 g) was purified by preparative HPLC to afford tert-butyl 4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thione-imidazolidin-1-yl]-2-fluoro-phenoxy]ethyl]piperazine-1-carboxylate (12.4 g, 72.6% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δppm 7.99-7.96(m,2H),7.85-7.82(m,1H),7.10-7.05(m,3H),4.24(t,J=5.6Hz,2H),3.46(t ,J=4.4Hz,4H),2.89(t,J=5.2Hz,2H),2.56(t,J=4.8Hz,4H),1.59(s,6H),1.47(s,9H).

[1028] 4-[3-[3-Fluoro-4-(2-piperazin-1-ylethoxy)phenyl]-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl 4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-2-fluoro-phenoxy]ethyl]piperazine-1-carboxylate (16.4 g, 25.8 mmol) in DCM (100 mL) was added TFA (26.5 g, 232 mmol, 17.2 mL) at 0° C. The reaction mixture was stirred at 20° C. for 10 hours and then concentrated in vacuo. The obtained oil is dissolved in acetonitrile (20mL), and the pH value is adjusted to pH 8-9 with saturated sodium bicarbonate aqueous solution, and the obtained solution is concentrated in vacuo. The aqueous phase is extracted with DCM (100mL×2). The combined organic phase is washed with water (100mL×2), dried over sodium sulfate, filtered and concentrated into a light yellow oil. The residue is freeze-dried to obtain 4-[3-[3-fluoro-4-(2-piperazine-1-ylethoxy)phenyl]-4,4-dimethyl-5-oxo-2-thioxo-imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (12.1g, 87.5% yield) as a light yellow solid. 1 H NMR (400MHz, CDCl3) δppm 7.99-7.96(m,2H),7.84-7.82(m,1H),7.10-7.04(m,3H),4.24(t,J=5.6Hz,2H),2.94-2.86(m,6H),2.59(s,4H),1.59(s,6H).

[1029] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)acetate. 4-(3-(3-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.250 g, 0.467 mmol) was combined with THF (4 mL) containing methyl 2-bromoacetate (0.047 mL, 0.47 mmol). The solution was stirred at ambient temperature for 30 minutes in a screw-capped vial. The reaction mixture was diluted with DCM, and the organic layer was washed with water and brine. The organic extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography (0-100% EtOAc / hexanes followed by 5% MeOH / EtOAc (500 mL)) to afford the title compound (0.230 g, 0.379 mmol, 81.0% yield). MS (ESI) m / z 608 [M+1] + .

[1030] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)acetic acid. A solution of methyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)acetate (0.230 g, 0.379 mmol) in THF (2 mL) was treated with a solution of aqueous lithium hydroxide (0.159 g, 3.79 mmol) in water (2.00 mL). After 30 minutes, the pH value was adjusted to 5 with a 2.0M HCl aqueous solution, and the mixture was diluted with DCM (100mL) and water (30mL). The organic phase was separated, and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.183g, 0.308mmol, 81% yield) as a white solid. MS (ESI) m / z 594[M+1] + .

[1031] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a solution of 3-amino-5-((2,6-dioxopiperidin-3-yl)amino)benzonitrile (0.040 g, 0.16 mmol, 1.0 equiv) and 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)acetic acid (0.097 g, 0.16 mmol, 1.0 equiv) in DMF (1 mL) were added HATU (0.093 g, 0.24 mmol, 1.5 equiv) and DIEA (0.064 g, 0.49 mmol, 3.0 equiv), and the mixture was stirred under nitrogen at 25° C. for 1 hour and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by standard methods to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-fluorophenoxy)ethyl)piperazin-1-yl)-N-(3-cyano-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.050 g, 0.060 mmol, 37.0% yield). MS (ESI) m / z 820.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm 10.82(s,1H),10.51(br s,1H),8.40(d,J=8.2Hz,1H),8.27(d,J=1.6Hz,1H),8.07(d,J=8.2Hz,1H),7.45-7.35(m,2H),7.29-7.20(m,3H),6.82(s,1H),4.57(br s,2H),4.40(br dd,J=4.8,11.8Hz,1H),4.19-3.76(m,7H),3.60(br s,5H),3.40(br s,2H),2.81-2.69(m,1H),2.64-2.54(m,1H),2.14-2.03(m,1H),2.00-1.86(m,1H),1.52(s,6H).

[1032] Example 5: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetamide hydrochloride

[1033]

[1034] 6- chloro-5-vinylpyridine -3- amine.A mixture of 5- bromo- 6- chloropyridine -3- amine (0.750g, 3.62mmol, 1 equivalent), tributyltin alkylethylene (1.52mL, 5.19mmol, 1.43 equivalents), tetrakis triphenylphosphine palladium (0) (0.209g, 0.181mmol, 5mol%) and lithium chloride (0.476g, 11.2mmol, 3.10 equivalents) in dioxane (19.0mL, 0.190 mole) was heated under reflux for 24 hours, then cooled to room temperature, diluted with water, and extracted with DCM. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (0-15% MeOH / DCM) to obtain 6- chloro- 5- vinylpyridine -3- amine (0.804g, 3.20mmol, 89.0% yield) as a yellow solid. MS (ESI) m / z 155.0 [M+1] + .

[1035] 6- chloro- 5- ethylpyridine -3- amine hydrochloride.The solution of 6- chloro- 5- vinylpyridine -3- amine (0.194g, 1.25mmol, 1 equivalent) in EtOH (12.5mL, 0.1 mole) is purged with nitrogen, and processed with 10% Pd / C (0.099g, 0.094mmol, 7.5mol%).Suspension is purged with hydrogen, and stirred at room temperature for 30 minutes under a hydrogen atmosphere.Reactant mixture is filtered through diatomite and concentrated to obtain light yellow oil, which is suspended in DCM (5.17mL, 0.226 mole) and processed with a solution of HCl in dioxane (4.38mL, 17.53mmol, 15 equivalents), and stirred at room temperature for 6 hours. The reaction was concentrated to give 6-chloro-5-ethylpyridin-3-amine hydrochloride (0.226 g, 1.171 mmol, 93.7% yield) as a light yellow solid. MS (ESI) m / z 157.0 [M+1] + .

[1036] 2-((6-chloro-5-ethylpyridin-3-yl)amino)-2-methylpropionitrile. To 6-chloro-5-ethylpyridin-3-amine hydrochloride (0.226 g, 1.17 mmol, 1 equivalent), TEA (0.280 mL, 1.17 mmol, 1 equivalent) was added acetone cyanohydrin (0.307 mL, 3.36 mmol, 2.87 equivalents) and magnesium sulfate (0.324 g, 2.69 mmol, 2.3 equivalents), and the mixture was stirred at 80 ° C for 18 hours. The reaction mixture was quenched with saturated sodium chloride aqueous solution, and the aqueous phase was washed with EtOAc. The combined organic extracts were washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-80% EtOAc / hexanes) to give 2-((6-chloro-5-ethylpyridin-3-yl)amino)-2-methylpropionitrile (0.232 g, 1.04 mmol, 30.9% yield) as a yellow residue. MS (ESI) m / z 224.2 [M+1] + .

[1037] 4-(3-(6-chloro-5-ethylpyridin-3-yl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of 2-((6-chloro-5-ethylpyridin-3-yl)amino)-2-methylpropionitrile (0.232 g, 1.04 mmol, 1 eq) in DMA (2.19 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.284 g, 1.24 mmol, 1.19 eq) at 25°C, and the reaction mixture was stirred at room temperature for 18 hours, then at 70°C for 4 hours. MeOH (2.188 mL, 0.474 mol) and 3M aqueous HCl (1.46 mL, 4.38 mmol, 4.22 eq) were added to the reaction solution, and the mixture was heated to 70°C again. After 18 hours, the reactant was quenched with water and diluted with EtOAc, the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-10% MeOH / DCM). The corresponding fractions were combined and concentrated to give 4- (3- (6- chloro-5-ethylpyridin-3-yl) -4,4- dimethyl -5- oxo -2-thioketo imidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile (0.117 g, 0.258 mmol, 24.91% yield) as an orange solid. MS (ESI) m / z 453.2 [M+1] + .

[1038] Tert-Butyl 4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate. Tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.028 g, 0.12 mmol, 1 eq) and 4-(3-(6-chloro-5-ethylpyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.056 g, 0.12 mmol, 1 eq) were dissolved in THF (2.86 mL, 0.043 mol). To the 1.0M solution (0.618mL, 0.62mmol, 5 equivalents) of potassium tert-butoxide in THF, and keep 36 hours after making the reactant warming to 60 DEG C, so that the product part is deprotected.The reactant is cooled to 25 DEG C, and Boc o (0.034mL, 0.15mmol, 1.2 equivalents) is added. After 4 hours, the reactant is quenched with water, diluted with DCM, and extracted with DCM aqueous phase. The organic extract is dried over sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (0-4% MeOH / DCM) crude material. The corresponding fractions were combined and concentrated to give tert-butyl 4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate (0.033 g, 0.051 mmol, 41.3% yield) as a light yellow solid. MS (ESI) m / z 647.2 [M+1] + .

[1039]

[0146] 4-(3-(5-ethyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. A suspension of tert-butyl 4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazine-1-carboxylate (0.033 g, 0.051 mmol, 1 eq) in DCM (0.226 mL, 0.226 mol) was treated with a solution of HCl in dioxane (0.191 mL, 0.765 mmol, 15 eq) and stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give 4-(3-(5-ethyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.030 g, 0.051 mmol, 101% yield) as a beige solid. MS (ESI) m / z 547.2 [M+1] + .

[1040] Tert-butyl 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioneoimidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetate. To a stirred mixture of 4-(3-(5-ethyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.030 g, 0.051 mmol, 1 eq), THF (0.440 mL, 0.117 mole), and TEA (0.029 mL, 0.206 mmol, 4 eq) was added tert-butyl 2-bromoacetate (9.97 μl, 0.062 mmol, 1.2 eq). The reaction mixture was stirred at 60° C. for 18 hours. The reaction was then concentrated under reduced pressure and purified by silica gel column chromatography (0-4% MeOH / DCM) to give tert-butyl 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioneylimidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetate (0.014.2 g, 0.021 mmol, 41.8% yield) as a light yellow solid. MS (ESI) m / z 661.4 [M+1] + .

[1041] 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetic acid hydrochloride. A suspension of tert-butyl 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetate (0.014 g, 0.021 mmol, 1 equiv) in DCM (0.500 mL) was treated with a solution of hydrochloric acid in dioxane (0.081 mL, 0.322 mmol, 15 equiv) and stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetic acid hydrochloride (0.014 g, 0.022 mmol, 102% yield) as a beige solid. MS (ESI) m / z 605.2 [M+1] + .

[1042] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetamide hydrochloride. 2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetic acid hydrochloride (14 mg, 0.023 mmol, 1 eq) was combined with 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione trifluoroacetate (8.51 mg, 0.023 mmol, 1 eq), HATU (9.68 mg, 0.025 mmol, 1.1 eq), DIEA (0.016 mL, 0.093 mmol, 4 eq) and DMF (0.116 mL) and the reaction was stirred at 25° C. for 2 h. The reaction mixture was quenched with water, diluted with EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-((5-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-3-ethylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)acetamide hydrochloride (5 mg, 5.47 μmol, 23.6% yield). MS (ESI) m / z 840.2 [M+1] + ; 1 H NMR (500MHz, acetonitrile-d3) δppm 9.12 (br s,1H),8.7-8.8(m,1H),8.1-8.2(m,3H),7.9-8.0(m,2H),7.50(d,1H,J=2.5Hz),7.03(s,1H),6.95(s,1H),6.49(s,1H),5.04(br d,1H,J=6.6Hz),4.54(t,2H,J=5.5Hz),4.24(ddd,1H,J=5.2,6.7,12.1Hz),3.06(s,2H),2.86(br t,2H,J=5.7Hz),2.77(ddd,2H,J=5.4,12.6,17.3Hz),2.7-2.7(m,4H),2.67(q,4H,J=7.3Hz),2.60(br s,4H),1.57(s,6H),1.25(t,3H,J=7.6Hz).

[1043] Example 6: 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioneimidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)acetamide

[1044]

[1045] 2-(1,1-difluoroethyl)-4-nitrophenol. A solution of 1-(2-hydroxy-5-nitrophenyl)ethanone (1.27 g, 7.00 mmol) in DCM (18 mL) was cooled to 0° C. and bis(2-methoxyethyl)aminosulfur trifluoride ( To the 4-thiazolinyl esters (1.24g, 1.79mmol) of 4-nitro-1-oxo-2-oxo-4-oxo-6-piperidin-2-yl)-2-nitro-1-oxo-2-oxo-4 ... 1 HNMR (400MHz, CDCl3) δppm 8.33 (d, J = 2.57Hz, 1H), 8.24 (dd, J = 8.99, 2.63Hz, 1H), 7.06 (d, J = 9.05Hz, 1H), 6.51-6.92 (br s, 1H), 2.08 (t, J = 18.9Hz, 3H).

[1046] tert-Butyl 4-(2-(2-(1,1-difluoroethyl)-4-nitrophenoxy)ethyl)piperazine-1-carboxylate. To a solution of 2-(1,1-difluoroethyl)-4-nitrophenol (1.20 g, 5.91 mmol) and tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (2.08 g, 7.09 mmol) in anhydrous DMF (12 mL) was added cesium carbonate (3.85 g, 11.81 mmol), and the mixture was stirred at 65 ° C for 4 hours under a nitrogen atmosphere. The mixture was cooled to ambient temperature, poured into ice water (60 mL), and mixed. The mixture was extracted with EtOAc, and the combined extracts were washed with water, brine, and dried over magnesium sulfate and activated carbon. The solution was filtered through a plug of silica gel, eluting with EtOAc, concentrated, and the residue dried in vacuo to give tert-butyl 4-(2-(2-(1,1-difluoroethyl)-4-nitrophenoxy)ethyl)piperazine-1-carboxylate (2.33 g, 95% yield) as a light tan solid. MS (ESI) m / z 416.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm 8.44(d,J=2.81Hz,1H),8.30(dd,J=9.11,2.75Hz,1H),7.03(d,J=9.17Hz,1H),4.26(t,J=5.56Hz,2H ),3.40-3.47(m,4H),2.88(t,J=5.56Hz,2H),2.49-2.58(m,4H),2.00(t,J=18.8Hz,3H),1.46(s,9H).

[1047] tert-Butyl 4-(2-(4-amino-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-(2-(1,1-difluoroethyl)-4-nitrophenoxy)ethyl)piperazine-1-carboxylate (2.30 g, 5.54 mmol) in MeOH (20 mL) was added 10% Pd / C and 50 wt% water (1.18 g, 0.554 mmol), and the mixture was purged with H gas. The reaction mixture was stirred under an H atmosphere (balloon) at ambient temperature for 3 hours. The mixture was purged with nitrogen, filtered through a packing of celite, and concentrated. The remaining slurry was dissolved in diethyl ether, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (25-100% EtOAc / hexanes) to give tert-butyl 4-(2-(4-amino-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (1.85 g, 87.0% yield) as a light gold syrup. MS (ESI) m / z 386.2 [M+1] + ; 1H NMR (400MHz, CDCl3) δppm 6.87 (d, J = 2.81Hz, 1H), 6.78 (d, J = 8.68Hz, 1H), 6.68 (d, J = 8.61Hz, 1H), 4.05 (t, J = 5.69Hz, 2H), 3.51 (br s,2H),3.38-3.46(m,4H),2.78(t,J=5.69Hz,2H),2.44-2.58(m,4H),1.99(t,J=18.8Hz,3H),1.46(s,9H).

[1048] Tert-Butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate. A solution of tert-butyl 4-(2-(4-amino-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (1.59 g, 4.13 mmol) in acetone (15 mL) was cooled to 0°C, and trimethylsilyl cyanide (0.774 mL, 6.19 mmol) was added, followed by trimethylsilyl trifluoromethanesulfonate (0.037 mL, 0.21 mmol). The mixture was stirred for 7 hours, during which time the reaction mixture reached ambient temperature after approximately 2 hours. The mixture was concentrated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and EtOAc and mixed. The organic layer was removed, and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over magnesium sulfate and activated carbon, and filtered through a plug of silica gel eluting with EtOAc. The solution was concentrated, and the residue was dried under vacuum to give tert-butyl 4-(2-(4-((2-cyanopropyl-2-yl)amino)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (1.77 g, 95.0% yield) as a slightly pink solid. MS (ESI) m / z 453.4 [M+1] + . 1 HNMR(400MHz,CDCl3)δppm 7.02-7.19(m,2H),6.89(d,J=8.68Hz,1H),4.11(t,J=5.56Hz,2H),3.35-3.52(m,4H),2.8 2(t,J=5.62Hz,2H),2.44-2.60(m,4H),2.01(t,J=18.8Hz,3H),1.64(s,6H),1.46(s,9H).

[1049] 4-(3-(3-(1,1-difluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thionetomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. To a solution of tert-butyl 4-(2-(4-((2-cyanopropan-2-yl)amino)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-carboxylate (0.200 g, 0.442 mmol) in DMF (1.0 mL) was added 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.121 g, 0.530 mmol), and the mixture was stirred at 60° C. for 3 hours. Additional 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.020 g) was added, and the mixture was heated at 60° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and diluted with MeOH (3 mL). 2.0 M HCl aqueous solution (1.11 mL, 2.21 mmol) was added and the mixture was stirred at 60 ° C for 23 hours. The mixture was concentrated and the remaining slurry was dissolved in isopropanol (3 mL) containing 5.0 M HCl aqueous solution and stirred at ambient temperature for 90 minutes. The mixture was concentrated and the residue was partitioned between EtOAc and water and cooled to 0 ° C. The mixture was treated with 1.0 M sodium hydroxide aqueous solution to a pH value of 9-10, the organic layer was removed, and the aqueous layer was extracted with EtOAc. The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (20-100% EtOAc / hexanes, then 5-50% MeOH / DCM) to afford 4-(3-(3-(1,1-difluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.112 g, 44.0% yield) as a white solid. MS (ESI) m / z 582.2 [M+1] + .

[1050] tert-Butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate. To a solution of 5-(3-(3-(1,1-difluoroethyl)-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile (0.140 g, 0.240 mmol) and DIEA (0.092 mL, 0.529 mmol) in anhydrous THF (2 mL) was added tert-butyl 2-bromoacetate (0.039 mL, 0.264 mmol), and the mixture was stirred at ambient temperature for 6 hours. The mixture is diluted with EtOAc (4mL), added into water (10mL), and mixed. The organic layer is removed and the aqueous layer is extracted with EtOAc. The organic stream is combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel column chromatography (0-10% MeOH / DCM containing 10% ammonium hydroxide solution) to give tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazine-1-yl)acetate (0.085g, 51.0% yield) as a colorless foam. MS (ESI) m / z 697.2[M+1] + .

[1051] 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid trifluoroacetate. To a solution of tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetate (0.083 g, 0.12 mmol) in DCM (1 mL) was added TFA (2 mL) and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residual glass was sonicated in diethyl ether to give a granular solid. The solid was collected, washed with diethyl ether and dried in vacuo to give 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid trifluoroacetate (0.083 g, 92.0% yield) as a white solid. MS (ESI) m / z 641.2 [M+1] + .

[1052] (N-3-nitro-5,6-difluorophenyl) iminodicarbonate bis-tert-butyl ester. 2,3-Difluoro-5-nitroaniline (1.0 g, 5.74 mmol) was placed in a vial containing Boc2O (3.33 mL, 14.36 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.351 g, 2.87 mmol), TEA (1.60 mL, 11.49 mmol) and THF (50.0 mL). The reaction mixture was stirred at 25 ° C for 18 hours. Volatile organic matter was removed under reduced pressure to obtain a dark orange oil. The oil was dissolved in EtOAc and purified by silica gel column chromatography (0-100% EtOAc / hexane). Fractions containing the desired product were combined and the volatile organics were removed under reduced pressure to give bis-tert-butyl (N-3-nitro-5,6-difluorophenyl)imidodicarbonate (1.29 g, 3.45 mmol, 60.0% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 8.53 (ddd, J=2.81, 6.72, 9.78Hz, 1H), 8.42 (td, J=2.34, 5.84Hz, 1H), 1.34-1.46 (m, 18H); MS (ESI) m / z 397.0 [M+Na] + .

[1053] (5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)iminodicarbonate bis-tert-butyl ester. (N-3-nitro-5,6-difluorophenyl)iminodicarbonate bis-tert-butyl ester (0.200 g, 0.534 mmol), 3-bromopiperidine-2,6-dione (0.513 g, 2.67 mmol), zinc (0.175 g, 2.67 mmol) and iron (II) chloride tetrahydrate (0.032 g, 0.16 mmol) were combined in NMP (1.5 mL). After degassing with argon for a few minutes and treating with trimethylsilyl chloride (0.171 mL, 1.34 mmol), the reaction mixture was sealed and stirred at 90 ° C overnight, and then diluted with EtOAc (100 mL) and water (15 mL). The two-phase mixture was filtered through celite. The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate solution (50 mL), followed by washing with brine (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to a dark green oil. The oil was dissolved in EtOAc and purified by silica gel column chromatography (0-80% EtOAc / hexane). The stream containing the desired product was combined and concentrated under reduced pressure to give (5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)iminodicarbonate bis-tert-butyl ester (0.075 g, 0.16 mmol, 30.8% yield) as a yellow oil. MS (ESI) m / z 300.0 [M-(Boc+tert-butyl)] + .

[1054] 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6-dione dihydrochloride. A solution of bis-tert-butyl (5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)imidodicarbonate (0.075 g, 0.165 mmol) in DCM (1.0 mL) was treated with a 4.0 M solution of HCl in dioxane (1.0 mL, 4.00 mmol). The reaction mixture was stirred at 25 °C for 18 hours. The volatile organics were removed under reduced pressure to give 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6-dione dihydrochloride (0.074 g, 0.23 mmol, 137% yield) as a light orange solid. MS (ESI) m / z 256.0 [M+1] + .

[1055] 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)acetamide. To a solution of 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionoimidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)acetic acid trifluoroacetate (0.113 g, 0.150 mmol) and 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6-dione dihydrochloride (0.054 g, 0.165 mmol) in anhydrous DMF (1.0 mL) were added HATU (0.068 g, 0.180 mmol) and DIEA (0.131 mL, 0.749 mmol) sequentially, and the mixture was stirred at ambient temperature for 16 hours. Additional 3-((3-amino-4,5-difluorophenyl)amino)piperidine-2,6-dione dihydrochloride (0.025 g), HATU (0.035 g) and DIEA (0.070 mL) were added and the mixture was stirred for an additional 3 hours. The reaction mixture was slowly poured into ice water (10 mL) with stirring, and the resulting suspension was filtered. The collected solid was washed with water and diethyl ether and dissolved in DMSO (2 mL) containing 25% formic acid solution. The solution was filtered (45 μm nylon membrane) and purified by standard methods to give 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-(1,1-difluoroethyl)phenoxy)ethyl)piperazin-1-yl)-N-(5-((2,6-dioxopiperidin-3-yl)amino)-2,3-difluorophenyl)acetamide (0.010 g, 8.0% yield). MS (ESI) m / z 878.0 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm 10.82(br s,1H),9.81(br s,1H),9.26(br s,1H),8.83(br s,1H),7.17-7.65(m,4H),6.98(br s,1H),6.22(br s,1H),4.48(br s,2H),4.28(br s,1H),3.08-3.16(m,4H),2.67-2.77(m,4H),2.02-2.16(m,5H),1.90(br s,3H),1.55(br s,9H).

[1056] Example 7: 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

[1057]

[1058] 1-(Benzyloxy)-2-bromo-4-nitrobenzene. To a mixture of 2-bromo-4-nitrophenol (30.00 g, 137.61 mmol, 1 equivalent) and potassium carbonate (57.06 g, 412.8 mmol, 3 equivalents) in acetonitrile (300 mL) was added (bromomethyl)benzene (25.89 g, 151.4 mmol, 17.98 mL, 1.1 equivalents) under nitrogen. The reaction mixture was stirred at 80 ° C for 2 hours, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (5-20% EtOAc / petroleum ether) to give the product, obtaining 1-(benzyloxy)-2-bromo-4-nitrobenzene (35.80 g, 116.2 mmol, 84.4% yield) as a yellow solid. MS (ESI) m / z 332.0 [M + Na] + ; 1 H NMR(400MHz,DMSO-d6)δppm 8.44(d,J=2.7Hz,1H),8.27(dd,J=2.8,9.2Hz,1H),7.52-7.46(m,2H),7.45-7.40(m,3H),7.38-7.34(m,1H),5.37(s,2H).

[1059] 1-(Benzyloxy)-4-nitro-2-vinylbenzene. To a mixture of 1-(benzyloxy)-2-bromo-4-nitrobenzene (20.00 g, 64.91 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (19.99 g, 129.82 mmol, 22.02 mL, 2.0 equivalents) and potassium phosphate (41.33 g, 194.72 mmol, 3 equivalents) in dioxane (300 mL) and water (150 mL) was added [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (4.75 g, 6.49 mmol, 0.1 equivalents) at room temperature (25 ° C). The reaction mixture was degassed and then heated to 100 ° C under nitrogen for 12 hours, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-1% EtOAc / petroleum ether) to give the product. 1-(benzyloxy)-4-nitro-2-vinylbenzene (12.50 g, 48.97 mmol, 75.4% yield) was obtained as a yellow solid. MS (ESI) m / z 278.1 [M+Na] + .

[1060] 4-amino-2-ethylphenol. To a solution of 1-(benzyloxy)-4-nitro-2-vinylbenzene (12.50 g, 48.97 mmol, 1 equivalent) in MeOH (50 mL) and THF (50 mL) was added Pd / C (2.00 g, 10% purity) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen. The mixture was stirred at 50 ° C under hydrogen (50 psi) for 12 hours, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-2% EtOAc / petroleum ether) to give the product, and 4-amino-2-ethylphenol (6.40 g, 46.65 mmol, 95.3% yield) was obtained as a brown solid. MS (ESI) m / z 170.2 [M+Na] + ; 1 H NMR(400MHz,DMSO-d6)δppm 8.13 (s, 1H), 6.46 (d, J = 8.3Hz, 1H), 6.34 (d, J = 2.6Hz, 1H), 6.23 (dd, J = 2.8, 8.3Hz, 1H), 4.28 (s, 1H), 2.41 (q, J = 7.5Hz, 2H), 1.07 (t, J = 7.5Hz, 3H).

[1061] 5-isothiocyanate-3-(trifluoromethyl)picolinonitrile. To a solution of 5-amino-3-(trifluoromethyl)picolinonitrile (20.00g, 106.88mmol, 1 equivalent) in toluene (200mL) was added thiocarbonyl dichloride (24.58g, 213.76mmol, 16.39mL, 2 equivalents). The reaction mixture was stirred at 110 ° C for 12 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc / petroleum ether) to obtain the product 5-isothiocyanate-3-(trifluoromethyl)picolinonitrile (18.90g, 82.47mmol, 77.2% yield) obtained as a yellow liquid. MS (ESI) m / z 230.1 [M + 1] + .

[1062] 2-((3-ethyl-4-hydroxyphenyl)amino)-2-methylpropionitrile. To a solution of 2-hydroxy-2-methylpropionitrile (18.64 g, 219.00 mmol, 20 mL, 4.69 equiv) in 4-amino-2-ethylphenol (6.400 g, 46.65 mmol, 1 equiv) was added magnesium sulfate (14.04 g, 116.62 mmol, 2.5 equiv). The reaction mixture was stirred at 60 ° C for 12 hours, then poured into EtOAc-water (v / v=1 / 1, 100 mL) and stirred for 15 minutes. The organic phase was separated and the aqueous phase was extracted with EtOAc (100 mL×2). The combined organic extracts were washed with brine (200 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 2-((3-ethyl-4-hydroxyphenyl)amino)-2-methylpropionitrile (12.00 g, crude product) was obtained as a brown solid. MS (ESI) m / z 205.1 [M+1] + .

[1063] 5-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. A solution of 2-((3-ethyl-4-hydroxyphenyl)amino)-2-methylpropionitrile (9.50 g, 46.51 mmol, 1 eq) and 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (8.53 g, 37.21 mmol, 0.8 eq) in DMF (100 mL) was stirred at 20 ° C for 1 hour. Subsequently, 4.0 M HCl solution / MeOH (100 mL, 2.15 eq) was added. The resulting mixture was stirred at 70 ° C for 12 hours and then concentrated in vacuo to remove MeOH. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The combined organic extracts were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-30% EtOAc / petroleum ether) to give the product, and 5- (3- (3-ethyl-4-hydroxyphenyl) -4,4-dimethyl-5-oxo-2-thioneimidazolidin-1-yl) -3- (trifluoromethyl) picolinonitrile (13.30 g, 30.61 mmol, 65.8% yield) was obtained as a brown solid. MS (ESI) m / z 457.2 [M + Na] + .

[1064] Tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate. By 5- (3- (3-ethyl -4- hydroxyphenyl) -4,4- dimethyl -5- oxo -2- thione imidazolidin-1-yl) -3- (trifluoromethyl) picolinonitrile (0.800g, 1.84mmol), 4- (2- bromoethyl) -2,2- dimethylpiperazine -1- carboxylic acid tert-butyl ester (0.887g, 2.76mmol), sodium iodide (0.276g, 1.84mmol) and cesium carbonate (0.900g, 2.76mmol) are combined in DMF (7.366mL) and heated to 60 ℃ and kept for 1.5 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc (150mL) and water (50mL). After separation, the organic layer is washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude material is purified by silica gel column chromatography (0-50% EtOAc / hexane). The fractions were combined and concentrated under reduced pressure to give tert-butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate (1.45 g, 2.15 mmol, 117% yield) as an oil. MS (ESI) m / z 675.4 [M+1] + .

[1065] tert-Butyl 4-(2-bromoethyl)-2,2-dimethylpiperazine-1-carboxylate. tert-Butyl 2,2-dimethylpiperazine-1-carboxylate (3.60 g, 16.8 mmol) and potassium phosphate (10.70 g, 50.4 mmol) were combined in THF (168 mL). To this mixture was added 1,2-dibromoethane (21.7 mL, 252 mmol). The reaction mixture was stirred at 60 ° C for 48 hours, filtered, and concentrated under reduced pressure to an oil, which was dissolved in minimal DCM and purified by silica gel column chromatography (0-70% EtOAc / hexanes). The fractions containing the product were combined and concentrated to give tert-butyl 4-(2-bromoethyl)-2,2-dimethylpiperazine-1-carboxylate (2.93 g, 9.12 mmol, 54.3% yield) as an oil, which was dried under vacuum overnight. MS(ESI)m / z 321.2,323.2[M+1,M+3] + .

[1066] 5-(3-(4-(2-(3,3-dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile hydrochloride. Tert-Butyl 4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazine-1-carboxylate (1.456 g, 2.158 mmol) was dissolved in DCM (40 mL) and treated with a 4.0 M solution of HCl in dioxane (10.8 mL, 43.2 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to an oil, which was then triturated in diethyl ether at ambient temperature overnight. The resulting solid, 5-(3-(4-(2-(3,3-dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile hydrochloride (1.24 g, 2.02 mmol, 94.0% yield), was collected by filtration and dried in a vacuum oven for 1.5 hours. MS (ESI) m / z 575.2 [M+1] + .

[1067] Tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetate. 5-(3-(4-(2-(3,3-dimethylpiperazin-1-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile hydrochloride (1.24 g, 2.02 mmol) was dissolved in THF (15 mL) and treated with DIEA (1.77 mL, 10.11 mmol) followed by tert-butyl 2-bromoacetate (0.314 mL, 2.12 mmol). The reaction mixture was stirred at 50 ° C overnight. To this mixture, sodium iodide (0.303 g, 2.02 mmol, 1 equivalent), DMF (1 mL) and 0.75 equivalents of DIEA and tert-butyl 2-bromoacetate were added and heated to 50 ° C again and kept overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 2- (4- (2- (4- (3- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -5,5-dimethyl-4-oxo-2-thione imidazolidin-1-yl) -2-ethylphenoxy) ethyl) -2,2-dimethylpiperazine-1-yl) tert-butyl acetate (1.32 g, 1.92 mmol, 95.0% yield) as an oil, which was used without further purification. MS (ESI) m / z 689.3 [M+1] + .

[1068] 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetic acid trihydrochloride. A solution of tert-butyl 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetate (1.32 g, 1.92 mmol) in DCM (10 mL) was treated with a 4.0 M solution of HCl in dioxane (15.6 mL, 62.3 mmol). After 6 hours, the temperature was raised to 45°C to 50°C and maintained for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetic acid trihydrochloride (1.37 g, 1.84 mmol, 96.0% yield) as a brown solid. MS (ESI) m / z 633 [M+1] + .

[1069] 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

[0266] 2-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)acetic acid trihydrochloride (0.125 g, 0.168 mmol, 1 eq) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate (0.056 g, 0.17 mmol, 1 eq), HATU (0.070 g, 0.18 mmol, 1.1 eq), DIEA (0.177 mL, 1.01 mmol, 6 eq) and DMF (0.842 mL, 0.2 M) and the reaction was stirred at 25°C for 1 hour. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic extracts were concentrated under reduced pressure. The residue was purified by standard methods to give 2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)-2,2-dimethylpiperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.063 g, 0.076 mmol, 45.1% yield). MS (ESI) m / z 834.4[M+1] + ; 1H NMR(400MHz,DMSO-d6)δppm10.80(s,1H),10.14(br s,1H),9.25(d,1H,J=1.7Hz),8.82(d,1H,J=2.1Hz),7.1-7.2(m,3H),7.04(t,1H,J=8.1Hz),7.01(br s,1H),6.83(br d,1H,J=8.3Hz),6.45(dd,1H,J=1.8,8.0Hz),4.42(br s,2H),4.27(br dd,1H,J=4.8,11.4Hz),3.3-3.5(m,6H),3.2-3.3(m,4H),2.6-2.8(m,5H),2. 10(td,1H,J=4.1,8.5Hz),1.91(dq,1H,J=4.8,12.1Hz),1.52(s,6H),1.41(br s,3H),1.35(br s,3H),1.18(t,3H,J=7.5Hz).

[1070] Example 8: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(7-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octan-4-yl)acetamide hydrochloride

[1071]

[1072] 2-bromo-1-(2-bromoethoxy)-4-nitrobenzene. To a solution of 2-bromo-4-nitrophenol (10 g, 45.9 mmol) in DMF (115 mL) was added cesium carbonate (29.9 g, 92 mmol), followed by 1,2-dibromoethane (39.5 mL, 460 mmol), and the mixture was stirred at 70 ° C overnight. The reactant was diluted with EtOAc (400 mL), water (75 mL) and brine (75 mL). The layers were separated, and the organic layer was washed with brine (3 × 100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. The resulting oil was purified by silica gel column chromatography (0-30% EtOAc / hexane) to give the title compound (9.20 g, 28.3 mmol, 61.7% yield). MS (ESI) m / z 325.9 [M + 1] + .

[1073] tert-Butyl 7-(2-(2-bromo-4-nitrophenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate. To a solution of 2-bromo-1-(2-bromoethoxy)-4-nitrobenzene (6.20 g, 19.08 mmol) in DMF (47.7 mL) was added DIEA (6.66 mL, 38.2 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (4.86 g, 22.90 mmol), and the mixture was stirred at 60 ° C for 5 hours. The reaction mixture was then cooled to ambient temperature and diluted with EtOAc (400 mL), water (75 mL), and brine (75 mL). The layers were separated and the organic layer was washed with brine (3 x 100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (8.29 g, 18.18 mmol, 95.0% yield), which was used without further purification. MS (ESI) m / z 456.2 [M+1] + .

[1074] Tert-Butyl 7-(2-(4-nitro-2-vinylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate Tert-Butyl 7-(2-(2-bromo-4-nitrophenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (8.71 g, 19.1 mmol), potassium trifluoro(vinyl)borate (7.67 g, 57.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.12 g, 3.82 mmol), and cesium carbonate (18.66 g, 57.3 mmol) were combined in a 4:1 mixture of THF (100 mL) and water (25 mL) and heated at 70° C. under nitrogen for 6 hours and then allowed to cool to ambient temperature overnight. The reaction mixture was diluted with EtOAc (500 mL), water (100 mL), and brine (100 mL). The solvent layer was separated, and the organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to an oil. The crude material was purified using silica gel chromatography [0-70% EtOAc (containing 10% 7N ammonia in MeOH) / hexanes] to provide the title compound in an assumed theoretical yield. MS (ESI) m / z 404.2 [M+1] + .

[1075] tert-Butyl 7-(2-(4-amino-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate. A solution of tert-butyl 7-(2-(4-nitro-2-vinylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (7.92g, 19.63mmol) in MeOH (196mL) was purged with nitrogen and treated with moist 10% Pd / C (2.09g, 1.96mmol). The reaction mixture was stirred overnight at ambient temperature under a hydrogen atmosphere. Additional moist 10% palladium (2g) and stirring at room temperature under a hydrogen atmosphere for 12 hours were required to achieve complete conversion. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 7-(2-(4-amino-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (6.52 g, 17.36 mmol, 88% yield). MS (ESI) m / z 376.2 [M+1] + .

[1076] 4-(3-(4-(2-(4,7-diazaspiro[2.5]octan-7-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thionetomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. Tert-Butyl 7-(2-(4-((2-cyanopropan-2-yl)amino)-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octane-4-carboxylate (3.50 g, 7.91 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (1.80 g, 7.91 mmol) were combined in DMA (26.4 mL) and mixed at ambient temperature. The reaction mixture was treated with MeOH (10 mL) and 3N HCl aqueous solution (10 mL) and stirred at 70 ° C for 6 hours, then diluted with EtOAc (400 mL) and water (50 mL) and saturated sodium bicarbonate aqueous solution (50 mL). The solvent layer was separated, and the pH value of the aqueous layer was detected to ensure its alkalinity. The organic layer was washed with brine (2×75 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to an oil. This oil was dissolved in DCM (30 mL) and a 4N solution of HCl in dioxane (29.6 mL, 119 mmol) was added. The mixture was stirred at ambient temperature for 1 hour and concentrated to dryness under reduced pressure. The substance was wet-ground with diethyl ether at ambient temperature overnight. The resulting solid was collected by filtration and dried under reduced pressure to give the title compound (3.193 g, 5.25 mmol, 66.5% yield). MS (ESI) m / z 572.2[M+1] + .

[1077] 5-Chlorobenzene-1,3-diamine. A solution of 1,3-dibromo-5-chlorobenzene (30.00 g, 111 mmol, 1 equivalent), diphenylmethaneimine (44.7 mL, 266 mmol, 2.4 equivalents), tris(dibenzylideneacetone)dipalladium(0) (2.03 g, 2.22 mmol, 2 mol%), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (4.15 g, 6.66 mmol, 6 mol%), and sodium tert-butoxide (27.7 g, 289 mmol, 2.6 equivalents) in toluene (556 mL, 0.067 M) was heated to 80°C for 18 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is dissolved in THF (444mL, 0.049 mole), treated with 1.0N HCl aqueous solution (388mL, 388mmol, 3.5 equivalents), and stirred for 5 minutes. The reaction mixture is diluted with a 3: 1 mixture of EtOAc and hexane, and the water layer is washed with a 3: 1 mixture of EtOAc and hexane. The pH value of the water layer is adjusted to 11 with a 1.0N NaOH aqueous solution, and extracted with DCM. The organic extract is dried over sodium sulfate, filtered and concentrated to give 5-chlorobenzene-1,3-diamine (13.48g, 95mmol, 85.0% yield) as a beige solid. MS (ESI) m / z 143.0[M+1] + .

[1078] 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione. 5-Chlorobenzene-1,3-diamine (13.48 g, 95 mmol, 1 equivalent), 3-bromopiperidine-2,6-dione (18.15 g, 95 mmol, 1 equivalent) and sodium bicarbonate (9.53 g, 113 mmol, 1.2 equivalents) were combined in DMF (95 mL, 1 mole) and heated at 50 ° C for 3 days. The reaction mixture was partitioned between EtOAc and brine. The organic layer was washed twice with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc / hexane, then 20% MeOH / EtOAc) to give 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione (2.38 g, 9.37 mmol, 9.9% yield) as a bluish-green solid. MS (ESI) m / z 254.0 [M+1] + .

[1079] 2-Chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione (3.74 g, 14.74 mmol, 1 eq), 2-chloroacetic acid (1.06 mL, 17.69 mmol, 1.2 eq), HATU (8.41 g, 22.11 mmol, 1.5 eq), and DIEA (7.72 mL, 44.2 mmol, 3 eq) were combined in DMF (42.1 mL, 0.350 mol) and stirred at room temperature. After 10 minutes, the reaction mixture was partitioned between EtOAc and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel column chromatography (50-100% EtOAc / hexanes) to give a green oil, which was triturated in DCM and hexanes. After removal of the solvent under reduced pressure and further drying in vacuo, 2-chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (3.25 g, 9.84 mmol, 66.7% yield) was isolated as a light green solid. MS (ESI) m / z 330.0 [M] + ; 1 H NMR(400MHz,DMSO-d6)δppm 10.80(s,1H),10.19(s,1H),6.92(t,1H,J=1.7Hz),6.82(t,1H,J=1.8Hz),6.47(t,1H,J=1.9Hz),6.32(d,1H,J=8.1 Hz), 4.3-4.4 (m, 1H), 4.22 (s, 2H), 2.7-2.8 (m, 1H), 2.5-2.6 (m, 1H), 2.0-2.1 (m, 1H), 1.90 (dq, 1H, J = 4.7, 12.4Hz).

[1080] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(7-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octan-4-yl)acetamide hydrochloride.

[0266] 2-Chloro-N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.285 g, 0.863 mmol, 1.5 equiv) was added to a stirred mixture of 4-(3-(4-(2-(4,7-diazaspiro[2.5]octan-7-yl)ethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thionetomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.350 g, 0.576 mmol, 1 equiv), sodium iodide (0.129 g, 0.863 mmol, 1.5 equiv), DMF (4.80 mL, 0.12 mole), and DIEA (0.402 mL, 2.302 mmol, 4 equiv). The reaction mixture was stirred at 60° C. for 20 minutes. The solution was then cooled to room temperature, filtered, concentrated under reduced pressure, and the crude material was purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(7-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)-4,7-diazaspiro[2.5]octan-4-yl)acetamide hydrochloride (0.122 g, 0.141 mmol, 24.5% yield). MS (ESI) m / z 865.3 [M+1]. + ; 1H NMR(400MHz,DMSO-d6)δppm 10.79(s,1H),10.58(br s,1H),9.49(s,1H),8.39(d,1H,J=8.3Hz),8.29(d,1H,J=1.7Hz),8.08(dd,1H,J=1.6,8.2Hz),7.1-7.2(m,3H), 6.9-7.0(m,2H),6.45(t,1H,J=1.8Hz),4.4-4.6(m,2H),4.32(dd,1H,J=4.8,11.7Hz),3.3-3.5(m,6H),3.11(br d,1H,J=12.8Hz),2.92(br d,1H,J=12.1Hz),2.5-2.8(m,4H),2.5-2.5(m,2H),2.0-2.1(m,1H),1.90(dq,1H,J=4.9,12.3Hz),1.50(s,6H),1.17(t,3H,J=7.5Hz),1.02(br s,1H),0.87(br s,2H),0.6-0.7(m,1H).

[1081] Example 9: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanamide hydrochloride

[1082]

[1083] 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1-carboxylate.

[0266] A mixture of tert-butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (1.00 g, 2.00 mmol, 1 equiv) (prepared as described herein), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.62 g, 4.00 mmol, 2 equiv), potassium phosphate (2.12 g, 9.99 mmol, 5 equiv), (1,1'-bis(diphenylphosphino)ferrocene)-palladium(II) dichloride (0.29 g, 0.40 mmol, 0.2 equiv) in dioxane (1 mL) and water (0.5 mL) was degassed and purged with nitrogen three times. The mixture was stirred at 120 °C under nitrogen for 12 hours and then concentrated under reduced pressure at 40 °C. The residue was poured into ice water (50 mL). The aqueous phase was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20%-33% EtOAc / petroleum ether) to give tert-butyl 4-(2-(4-((1-methoxy-2-methyl-1-oxopropyl-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1-carboxylate (0.50 g, 1.12 mmol, 55.9% yield) as a yellow oil. MS (ESI) m / z 448.1[M+1] + .

[1084] tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)-2-vinylphenoxy)ethyl)piperazine-1-carboxylate (0.500 g, 1.120 mmol, 1 equiv) in MeOH (10 mL) was added Pd—C (10%, 0.2 g) under nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred at 40° C. under hydrogen (50 psi) for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.320 g, 0.712 mmol, 63.7% yield) as a yellow oil. MS (ESI) m / z 450.3 [M+1] + .

[1085] tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(2-(2-ethyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.319 g, 0.71 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.486 g, 2.13 mmol, 3 eq) in EtOAc (2 mL) was added TEA (0.359 g, 3.55 mmol, 5 eq). The mixture was stirred at 80° C. for 12 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (66.7% EtOAc / petroleum ether). tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 68.8% yield) was obtained as a yellow solid. MS (ESI) m / z 646.4 [M+1] + .

[1086] 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazine-1-carboxylate (0.315 g, 0.488 mmol, 1 equivalent) in EtOAc (2 mL) was added HCl / dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 30 minutes and then concentrated under reduced pressure. The crude material was used without further purification to give 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.300 g, crude product) as a yellow solid. MS (ESI) m / z 546.1 [M+1] + .

[1087] tert-Butyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoate. To a stirred mixture of 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.200 g, 0.34 mmol, 1 equiv), THF (2.94 mL, 0.12 mole), and TEA (0.192 mL, 1.37 mmol, 4 equiv) was added tert-butyl 2-bromo-2-methylpropanoate (0.077 mL, 0.41 mmol, 1.2 equiv). The reaction mixture was stirred at 85 ° C for 4 days. To the reaction was added another 4.8 equivalents of tert-butyl 2-bromo-2-methylpropanoate, and the reaction was stirred at 85 ° C for another 4 days. The reaction was concentrated and purified by silica gel column chromatography (20-100% EtOAc / hexanes, then 0-5% MeOH / DCM) to give tert-butyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoate (0.026 g, 0.038 mmol, 11.0% yield) as a beige solid mixed with some hydantoin product. MS (ESI) m / z 688.2[M+1] + .

[1088] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoic acid trihydrochloride. A suspension of tert-butyl 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoate (0.026 g, 0.038 mmol, 1 eq) in DCM (0.170 mL, 0.226 M) was treated with a solution of HCl in dioxane (142 μL, 0.567 mmol, 15 eq) and stirred at room temperature for 4 days. The reaction was concentrated to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoic acid trihydrochloride (0.028 g, 0.038 mmol, 100% yield) as a brown solid. MS (ESI) m / z 632.2 [M+1] + .

[1089] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanamide hydrochloride. A mixture of 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanoic acid trihydrochloride (0.028 g, 0.038 mmol, 1 eq) was combined with 3-((3-amino-5-chlorophenyl)amino)piperidine-2,6-dione (0.011 g, 0.038 mmol, 1 eq), HATU (0.016 g, 0.042 mmol, 1.1 eq), DIEA (0.040 mL, 0.23 mmol, 6 eq) and DMF (0.189 mL, 0.2 mole) was stirred at 25° C. for 4 days. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic extracts were concentrated. The material was purified by standard methods to give N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-2-methylpropanamide hydrochloride (0.002 g, 0.002 mmol, 5.2% yield). MS (ESI) m / z 867.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.80(s,1H),10.40(br s,1H),9.48(br s,1H),8.39(d,1H,J=8.2Hz),8.29(d,1H,J=1.6Hz),8.07(dd,1H,J=1.8,8.3Hz),7.1-7.2(m,4H),6.86(s,1H),6.46(s,1H),4.48(br s,2H),4.35(br dd,1H,J=4.7,11.7Hz),3.6-3.6(m,4H),3.2-3.3(m,4H),2.9-3.0(m,2H),2.7-2.8(m,1H),2.67(q,2H,J=7.5Hz),2.62( td,1H,J=4.0,13.6Hz),2.07(tt,1H,J=3.9,8.1Hz),1.90(dq,1H,J=4.0,11.9Hz),1.50(s,6H),1.2-1.2(m,6H),1.17(br t,3H,J=7.5Hz).

[1090] Example 10: 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)cyclopropanecarboxamide hydrochloride

[1091]

[1092] Ethyl 1-(4-benzylpiperazin-1-yl)cyclopropanecarboxylate. To a stirred mixture of N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (0.886 g, 3.30 mmol, 1.09 equiv), EtOH (6.66 mL, 0.453 mol) and DIEA (5.30 mL, 30.3 mmol, 10.05 equiv) was added ethyl 1-aminocyclopropanecarboxylate hydrochloride (0.500 g, 3.02 mmol, 1 equiv). The reaction mixture was stirred at 78 °C for 18 hours then concentrated under reduced pressure. The crude material was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (5-10% EtOAc / hexanes) to give ethyl 1-(4-benzylpiperazin-1-yl)cyclopropanecarboxylate (0.409 g, 1.42 mmol, 47.0% yield) as a yellow oil. MS (ESI) m / z 289.2 [M+1] + .

[1093] 1- (piperazine -1- base) cyclopropanecarboxylic acid ethyl ester hydrochloride. To a solution of 1- (4-benzylpiperazine -1- base) cyclopropanecarboxylic acid ethyl ester (0.200g, 0.694mmol, 1 equivalent) in anhydrous DCM (1.692mL, 0.410 mole) cooled to 0 ° C, 1-chloroethyl chloroformate (0.110mL, 1.02mmol, 1.465 equivalents) was slowly added to maintain the temperature below 0 ° C. The mixture was stirred at 18 ° C for 1 hour. The reactant was concentrated to dryness, and the residue was dissolved in EtOH (1.69mL, 0.410M). The resulting solution was stirred at 78 ° C for 18 hours. The reaction mixture was concentrated to dryness. The residue was then stirred in a 5:1 mixture of EtOH and MTBE, and the precipitate was collected by filtration to give ethyl 1-(piperazin-1-yl)cyclopropanecarboxylate hydrochloride (0.107 g, 0.456 mmol, 65.7% yield) as a beige solid. MS (ESI) m / z 199.2 [M+1] + .

[1094] 2-((3-bromo-4-hydroxyphenyl)amino)-2-methylpropionitrile. To a solution of 4-amino-2-bromophenol (5.00 g, 26.6 mmol) in DCM (177 mL) and acetone (89 mL) was added trimethylsilyl cyanide (4.66 mL, 37.2 mmol) and trimethylsilyl trifluoromethanesulfonate (0.241 mL, 1.33 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated to remove the solvent. The crude material was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give 2-((3-bromo-4-hydroxyphenyl)amino)-2-methylpropionitrile (4.56 g, 17.87 mmol, 67.2% yield) as a brown solid. MS (ESI) m / z 256.2[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm 9.55-9.66 (m, 1H), 7.05 (d, J = 2.69Hz, 1H), 6.83-6.87 (m, 1H), 6.77-6.81 (m, 1H), 5.51 (s, 1H), 1.55 (s, 6H).

[1095] 4-(3-(3-bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thionetomidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. 2-((3-bromo-4-hydroxyphenyl)amino)-2-methylpropionitrile (1.00 g, 3.92 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.894 g, 3.92 mmol) were combined in DMA (13.07 mL) and stirred at room temperature overnight. MeOH (5 mL) and 3.0 N aqueous HCl (5 mL) were added, and the reaction was heated at 70 ° C. After 2 hours, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to afford 4-(3-(3-bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (1.23 g, 2.423 mmol, 62.0% yield) as a white solid. MS (ESI) m / z 484.0 [M+1] + .

[1096] Acetate 2-bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)phenyl ester. A solution of 4-(3-(3-bromo-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.75 g, 1.55 mmol) treated with DIEA (0.541 mL, 3.10 mmol) and acetyl chloride (0.132 mL, 1.86 mmol) in DCM (7.74 mL) was stirred at room temperature. After 12 hours, the reactant was diluted with EtOAc (100 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate solution (2×100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated to give a colorless oil, which was purified by silica gel column chromatography (20-50% EtOAc / hexanes) to give the title compound (0.766 g, 1.455 mmol, 94% yield). MS (ESI) m / z 526.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δppm 7.97 (s, 1H), 7.94 (s, 1H), 7.82 (dd, J = 2.1, 8.2Hz, 1H), 7.58 (d, J = 2.3Hz, 1H), 7.36-7.27 (m, 2H), 2.40 (s, 3H), 1.61 (s, 6H).

[1097] 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenyl acetate. 2-Bromo-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenyl acetate (2 g, 3.80 mmol), [(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.311 g, 0.380 mmol) and 2-(2-dicyclohexylphosphinophenyl)-N-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)phenyl acetate were combined in a schlenk flask and purged with argon. 1 ,N 1 ,N 3 ,N 3 -tetramethyl-benzene-1,3-diamine (0.166g, 0.38mmol) was added toluene (15.20mL). The reaction mixture was placed in an ice bath for 5 minutes and then treated with a 0.5M solution (6.08mL, 3.04mmol, 0.8 equivalent) of ethylzinc bromide (II) in THF. After 30 minutes, another 0.5 equivalent of ethylzinc bromide (II) solution (3.80mL, 1.90mmol) was used at 0 ° C for 30 minutes, quenched by adding 2.0M HCl aqueous solution (2.470mL, 4.94mmol), and the mixture was diluted with EtOAc (350mL). The organic layer was washed twice with saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a brown solid. The crude material was purified by silica gel column chromatography (0-45% EtOAc / hexanes) to give 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenyl acetate (0.986 g, 2.07 mmol, 55.0% yield). MS (ESI) m / z 476 [M+1] + .

[1098] 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. A suspension of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenyl acetate (0.876 g, 1.84 mmol) and potassium carbonate (0.255 g, 1.84 mmol) in MeOH (20 mL) was stirred at ambient temperature. After 40 minutes, the solution was diluted with EtOAc (200 mL) and distributed through water (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.766 g, 1.76 mmol, 96.0% yield). MS (ESI) m / z 434[M+1] + .

[1099] 4-(3-(4-(2-bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile. In a preheated flask, 1,2-dibromoethane (2.99 mL, 34.6 mmol, 20.0 equiv), cesium carbonate (1.97 g, 6.06 mmol, 3.5 equiv), and 4-(3-(3-ethyl-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.750 g, 1.73 mmol, 1 equiv) were dissolved in DMF (20.36 mL, 0.085 M), and the reaction was stirred at 60 °C under nitrogen for 18 hours. The reactant is quenched with water and the mixture is diluted with EtOAc. The aqueous phase is extracted with EtOAc, and the combined organic extracts are washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue is purified by silica gel column chromatography (0-100% EtOAc / hexane). The stream is concentrated to a residue, which is wet-ground with DCM and hexane to give 4- (3- (4- (2- bromoethoxy) -3- ethylphenyl) -4,4- dimethyl -5- oxo -2- thioneto imidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile (0.296 g, 0.548 mmol, 31.7% yield) as a beige solid. MS (ESI) m / z 540.0 [M] + .

[1100] 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropanecarboxylic acid ethyl ester. To a solution of 1-(piperazin-1-yl)cyclopropanecarboxylic acid ethyl ester hydrochloride (0.107 g, 0.456 mmol, 1 eq) in DMF (4.56 mL, 0.1 mol) was added 4-(3-(4-(2-bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (0.296 g, 0.547 mmol, 1.2 eq) and DIEA (0.279 mL, 1.596 mmol, 3.5 eq). The vessel was sealed and the mixture was heated to 60° C. with stirring for 18 hours. The reactants were concentrated and purified by silica gel column chromatography (0-10% MeOH / DCM) to give ethyl 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropanecarboxylate (0.090 g, 0.137 mmol, 30.0% yield) as an orange oil. MS (ESI) m / z 658.2 [M+1] + .

[1101] (S)-2-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperidin-1-yl)propanoic acid tetrahydrochloride. To ethyl 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropanecarboxylate (0.090 g, 0.137 mmol) was slowly added 6 M aqueous HCl (1.140 mL, 6.84 mmol) at 0°C. The reaction was gradually warmed to 100°C and stirred for 18 hours. The reaction mixture was concentrated to give 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropanecarboxylic acid tetrahydrochloride (0.108 g, 0.139 mmol, 102% yield) as a light yellow solid. MS (ESI) m / z 630.2 [M+1] + .

[1102] 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)cyclopropanecarboxamide hydrochloride. 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropanecarboxylic acid tetrahydrochloride (0.108 g, 0.139 mmol, 1 eq) was combined with 3-((3-aminophenyl)amino)piperidine-2,6-dione trifluoroacetate (0.046 g, 0.139 mmol, 1 eq), HATU (0.058 g, 0.153 mmol, 1.1 eq), DIEA (0.170 mL, 0.975 mmol, 7 eq) in DMF (0.696 mL, 0.2 mole) and the reaction was stirred at 25° C. for 15 min. The reaction was quenched with water and the mixture was diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic extracts were concentrated. The crude material was purified by standard methods to give 1-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)cyclopropanecarboxamide hydrochloride (0.027 g, 0.032 mmol, 22.7% yield). MS (ESI) m / z 831.6 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.78(s,1H),10.49(br s,1H),9.48(s,1H),8.39(d,1H,J=8.3Hz),8.29(d,1H,J=1.7Hz),8.07(dd,1H,J=1.7,8.3Hz),7.1-7.2(m,4H),7.02(t,1H,J= 8.0Hz), 6.79 (dd, 1H, J = 1.0, 8.1Hz), 6.43 (dd, 1H, J = 1.7, 8.1Hz), 4.49 (t, 2H, J = 4.4Hz), 4.30 (dd, 1H, J = 4.8, 11.3Hz), 3.58 (br s,2H),3.44(t,4H,J=10.6Hz),2.97(br d,2H,J=12.2Hz),2.7-2.9(m,3H),2.66(q,2H,J=7.4Hz),2.59(td,1H,J=4.3,17.2Hz),2.1-2.1(m,1H ), 1.89 (dq, 1H, J = 4.5, 12.2Hz), 1.50 (s, 6H), 1.17 (t, 3H, J = 7.5Hz), 1.1-1.2 (m, 2H), 1.0-1.1 (m, 2H).

[1103] Example 11: N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-1-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropane-1-carboxamide hydrochloride

[1104]

[1105] 5-(3-(4-(2-Bromoethoxy)-3-ethylphenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-3-(trifluoromethyl)picolinonitrile. In a preheated flask, 1,2-dibromoethane (2.39 mL, 27.6 mmol, 20 equiv), cesium carbonate (1.57 g, 4.83 mmol, 3.5 equiv) and 5-[3-(3-ethyl-4-hydroxy-phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile (0.600 g, 1.38 mmol, 1 equiv) were dissolved in DMF (16.2 mL, 0.085 mol) and the reaction was stirred at 60 °C under nitrogen for 18 hours. The reactant is quenched with water and diluted with EtOAc, and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (0-100% EtOAc / hexane). The stream is concentrated, and the residue is wet-ground in DCM and hexane to give 5- [3- [4- (2- bromoethoxy) -3- ethyl -phenyl] -4,4- dimethyl -5- oxo -2- thionyl -imidazolidin-1-yl] -3- (trifluoromethyl) pyridine -2- carbonitrile (0.324 g, 0.60 mmol, 43.3% yield) as a light pink solid. MS (ESI) m / z 539.8 [M] + .

[1106] Ethyl 1-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropane-1-carboxylate. To a solution of ethyl 1-piperazin-1-ylcyclopropanecarboxylate hydrochloride (0.181 g, 0.69 mmol, 1.15 equiv) in DMF (6.00 mL, 0.100 mol) was added 5-[3-[4-(2-bromoethoxy)-3-ethyl-phenyl]-4,4-dimethyl-5-oxo-2-thione-imidazolidin-1-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile (0.324 g, 0.60 mmol, 1 equiv) and DIEA (0.36 mL, 2.09 mmol, 3.5 equiv). The reaction was sealed and heated to 60° C. with stirring for 18 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give ethyl 1-[4-[2-[4-[3-[6-cyano-5-(trifluoromethyl)-3-pyridinyl]-5,5-dimethyl-4-oxo-2-thione-imidazolidin-1-yl]-2-ethyl-phenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylate (0.036 g, 0.05 mmol, 9.1% yield) as a pale yellow semisolid. MS (ESI) m / z 496.0 [M+1] + .

[1107] 1-(4-(2-(4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropane-1-carboxylic acid trihydrochloride. To ethyl 1-[4-[2-[4-[3-[6-Cyano-5-(trifluoromethyl)-3-pyridin-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl]-2-ethyl-phenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylate (0.036 g, 0.05 mmol, 1 equiv) was slowly added 6.0 N aqueous HCl (0.46 mL, 2.73 mmol, 50 equiv) at 0°C. The reaction mixture was gradually warmed to 100° C. and stirred for 18 hours, then concentrated to give 1-[4-[2-[4-[3-[6-cyano-5-(trifluoromethyl)-3-pyridinyl]-5,5-dimethyl-4-oxo-2-thione-imidazolidin-1-yl]-2-ethyl-phenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylic acid trihydrochloride (0.040 g, 0.05 mmol, 99.9% yield) as a light yellow solid. MS (ESI) m / z 629.8 [M+1] + .

[1108] N-(3-chloro-5-((2,6-dioxopiperidin-3-yl)amino)phenyl)-1-(4-(2-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)cyclopropane-1-carboxamide hydrochloride. 1-[4-[2-[4-[3-[6-Cyano-5-(trifluoromethyl)-3-pyridinyl]-5,5-dimethyl-4-oxo-2-thione-imidazolidin-1-yl]-2-ethyl-phenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxylic acid trihydrochloride (0.040 g, 0.050 mmol, 1 eq) was combined with 3-(3-amino-5-chloro-anilino)piperidine-2,6-dione (13.8 mg, 0.050 mmol, 1 eq), HATU (22.8 mg, 0.060 mmol, 1.1 eq), DIEA (0.05 mL, 0.270 mmol, 5 eq) and DMF (0.273 mL, 0.200 M) and the reaction was stirred at 25 °C for 18 h. The reaction was quenched with water and diluted with EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and purified by standard methods to give N-[3-chloro-5-[(2,6-dioxo-3-piperidinyl)amino]phenyl]-1-[4-[2-[4-[3-[6-cyano-5-(trifluoromethyl)-3-pyridinyl]-5,5-dimethyl-4-oxo-2-thiono-imidazolidin-1-yl]-2-ethyl-phenoxy]ethyl]piperazin-1-yl]cyclopropanecarboxamide hydrochloride (0.005 g, 5.8 × 10 -2 mmol, 10.6% yield). MS (ESI) m / z 866.7 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.81(s,1H),10.53(s,1H),10.45(br s,1H),9.22(d,1H,J=1.8Hz),8.76(d,1H,J=2.1Hz),7.2-7.3(m,3H),7.02(s,1H),6.98(s,1H),6.57(t,1H,J=1.8Hz),6.36(br s,1H),4.4-4.5(m,2H),4.34(br dd,1H,J=4.8,11.9Hz),3.69(br d,2H,J=10.8Hz),3.58(br dd,2H,J=4.4,7.7Hz),3.22(q,2H,J=9.8Hz),2.5-2.8(m,7H),2.4-2.5(m,2 H), 2.0-2.1 (m, 1H), 1.8-2.0 (m, 6H), 1.5-1.6 (m, 1H), 1.18 (t, 3H, J = 7.5Hz).

[1109] Example 12: 2-(4-(2-(2-chloro-4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thione-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

[1110]

[1111] To a solution of tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (10.00 g, 48.02 mmol, 1 eq) and 3-bromopiperidine-2,6-dione (9.22 g, 48.02 mmol, 1 eq) in DMF (100 mL) was added sodium bicarbonate (4.03 g, 48.02 mmol, 1 eq). The reaction mixture was stirred at 50 °C for 10 h and then filtered. The filtrate was purified by preparative reverse phase HPLC (25%-55% acetonitrile / water + 0.225% formic acid, 30 min) to afford tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (6.04 g, 18.91 mmol, 39.4% yield) as a green solid. 1H NMR(400MHz,DMSO-d6)δppm 10.76(s,1H),9.02(s,1H),6.92(t,J=8.0Hz,1H),6.85(s,1H),6.65(d,J=8.4Hz,1H),6.29(d, J=7.6Hz,1H),5.78(d,J=7.2Hz,1H),2.76-2.59(m,2H),2.11-2.07(m,1H),1.92-1.82(m,1H).

[1112] 3-((3-Aminophenyl)amino)piperidine-2,6-dione. To a solution of tert-butyl (3-((2,6-dioxopiperidin-3-yl)amino)phenyl)carbamate (6.04 g, 18.91 mmol, 1 eq) in DCM (50 mL) was added a 4.0 M solution of HCl in dioxane (28.37 mL, 6 eq), and the reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to dryness. 3-((3-Aminophenyl)amino)piperidine-2,6-dione hydrochloride (4.50 g, 17.60 mmol, 93.1% yield) was isolated as a light green solid and used in the next step without purification. 1 H NMR(400MHz,DMSO-d6)δppm 10.81(s,1H),10.12(s,3H),7.16(t,J=8.0Hz,1H),6.70-6.68(m,1H),6.64-6.63(m,1H),6.55-6.53( m,1H),4.36-4.32(m,1H),2.79-2.70(m,1H),2.67-2.56(m,1H),2.11-2.05(m,1H),1.95-1.86(m,1H).

[1113] Tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate. To a solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (1.05 g, 4.30 mmol, 1.1 equiv), HATU (1.78 g, 4.69 mmol, 1.2 equiv), and DIEA (1.26 g, 9.78 mmol, 2.5 equiv) in DMF (10 mL) at 0°C was added 3-(3-aminoanilino)piperidine-2,6-dione hydrochloride (1.00 g, 3.91 mmol, 1 equiv). The mixture was stirred at 15°C for 10 hours. Water (60 mL) was added to the mixture, and the resulting suspension was extracted with EtOAc (40 mL x 2). The combined organic extracts were washed with brine (50 mL x 5), dried, filtered and concentrated to give tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (1.37 g, 3.08 mmol, 78.6% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 10.78(s,1H),9.84(br,1H),7.01(t,J=8.0Hz,1H),6.95(s,1H),6.82(d,J=7.6Hz,1H),6.42(d,J=8.0Hz,1H),5.92(d,J=7.2Hz,1H ),4.28-4.22(m,1H),3.63-3.33(m,10H),2.72-2.70(m,1H),2.62-2.56(m,1H),2.13-2.07(m,1H),1.95-1.84(m,1H),1.40(s,9H).

[1114] N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(piperazin-1-yl)acetamide. To a solution of tert-butyl 4-(2-((3-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (1.35 g, 3.03 mmol, 1 eq) in DCM (10 mL) was added a 4.0 M solution of HCl in dioxane (3.79 mL, 5 eq). The reaction was stirred at 15 °C for 12 h. EtOAc (20 mL) was added to the suspension, and the resulting suspension was filtered. The filter cake was washed with EtOAc (20 mL) and dried under reduced pressure to give N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(piperazin-1-yl)acetamide hydrochloride (1.26 g, crude product) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δppm 10.82(s,1H),10.67(s,1H),10.01(br,1H),7.05(t,J=8.0Hz,1H),7.01(s,1H),6.89(d,J=7.6Hz,1H),6.50(d,J=7.6Hz,1H),4.2 9-4.26(m,3H),3.73-3.57(m,4H),3.44-3.35(m,4H),2.77-2.69(m,1H),2.61-2.57(m,1H),2.11-2.09(m,1H),1.98-1.89(m,1H).

[1115] 1-((3-chloro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile. To a mixture of 4-amino-2-chlorophenol (0.300 g, 2.09 mmol, 1 eq) and cyclobutanone (0.293 g, 4.18 mmol, 2 eq) in DCM (3 mL) was added trimethylsilylcarbonitrile (0.249 g, 2.51 mmol, 1.20 eq) dropwise. The mixture was stirred at 25 ° C for 10 hours. At the end of the dropwise addition of saturated aqueous sodium bicarbonate solution (0.5 mL), the mixture was concentrated to a residue that was purified by column chromatography (0-50% EtOAc / petroleum ether) to give 1-((3-chloro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile (0.320 g, 1.44 mmol, 68.8% yield) as a red solid. MS (ESI) m / z 223.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm 9.34 (s, 1H), 6.84 (d, J = 8.7Hz, 1H), 6.55 (d, J = 2.8Hz, 1H), 6.47-6.40 (m, 1H), 6.27 (s, 1H), 2.72-2.61 (m, 2H), 2.29 (br d,J=10.5Hz,2H),2.12-2.00(m,2H).

[1116] 4-(5-(3-chloro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile. To a mixture of 1-((3-chloro-4-hydroxyphenyl)amino)cyclobutanecarbonitrile (0.210 g, 0.943 mmol, 1 eq) and 4-amino-2-(trifluoromethyl)benzonitrile (0.176 g, 0.943 mmol, 1 eq) in DMA (3 mL) was added thiocarbonyl dichloride (0.108 g, 0.943 mmol, 1 eq) dropwise. The mixture was stirred at 60 ° C for 12 hours, then diluted with MeOH (0.6 mL) and aqueous HCl (2 M, 0.4 mL) and stirred at 15 ° C for 2 hours. The mixture was poured into water (10 mL), and the aqueous phase was extracted with EtOAc (15 mL × 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the crude product. The substance was purified by preparative TLC followed by flash silica gel chromatography (0-50% EtOAc / petroleum ether) to afford 4-(5-(3-chloro-4-hydroxyphenyl)-8-oxo-6-thionyl-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (0.208 g, 0.460 mmol, 48.8% yield) as a brown solid. MS (ESI) m / z 451.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δppm10.76(s,1H),8.37(d,J=8.3Hz,1H),8.22(d,J=1.8Hz,1H),8.09-7.97(m,1H),7.42(d,J=2 .4Hz,1H),7.23-7.18(m,1H),7.15(s,1H),2.64-2.55(m,2H),2.47-2.37(m,2H),1.95-1.89(m,1H),1.60-1.49(m,1H).

[1117] 4-(5-(4-(2-bromoethoxy)-3-chlorophenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile. To a mixture of 4-(5-(3-chloro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (0.200 g, 0.44 mmol, 1 eq) in acetonitrile (7 mL) was added potassium carbonate (0.245 g, 1.77 mmol, 4 eq) and 1,2-dibromoethane (0.416 g, 2.21 mmol, 5 eq). The mixture was stirred at 80 °C for 12 h, then concentrated and poured into water (10 mL). The aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The substance was purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to give 4-(5-(4-(2-bromoethoxy)-3-chlorophenyl)-8-oxo-6-thionyl-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (0.170 g, 0.285 mmol, 64.4% yield) as a light yellow oil. MS (ESI) m / z 558.1 559.1 [M+1, M+2] + ; 1 H NMR (400MHz, CDCl3) δppm 8.01-7.95(m,2H),7.84(dd,J=1.9,8.2Hz,1H),7.39(d,J=2.5Hz,1H),7.21(dd,J=2.5,8.7Hz,1H),7.10(d,J=8.8Hz,1H), 4.44(t,J=6.3Hz,2H), 3.75(t,J=6.3Hz,2H), 2.74-2.64(m,2H), 2.61-2.50(m,2H), 2.33-2.17(m,1H), 1.74-1.67(m,1H).

[1118] 2-(4-(2-(2-chloro-4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thione-5,7-diazaspiro[3.4]oct-5-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride.

[0266] To a solution of 4-(5-(4-(2-bromoethoxy)-3-chlorophenyl)-8-oxo-6-thione-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile (0.161 g, 0.288 mmol, 1.1 equiv) and N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)-2-(piperazin-1-yl)acetamide hydrochloride (0.100 g, 0.262 mmol, 1.00 equiv) in DMF (1 mL) was added DIEA (0.169 g, 1.310 mmol, 5 equiv). The mixture was stirred at 60 °C for 12 h then treated with potassium iodide (0.087 g, 0.524 mmol, 2 equiv) and stirred at 80 °C for 8 h. The material was purified by standard methods to give 2-(4-(2-(2-chloro-4-(7-(4-cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thione-5,7-diazaspiro[3.4]octan-5-yl)phenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.046 g, 0.052 mmol, 20.0% yield). MS (ESI) m / z 823.4 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm 10.80(s,1H),10.46-10.03(m,1H),8.39(d,J=8.3Hz,1H),8.22(d,J=1.5Hz,1H) ,8.10-7.97(m,1H),7.60(s,1H),7.43(s,2H),7.03(s,1H),6.97(s,1H),6.84(br d,J=7.9Hz,1H),6.50-6.38(m,1H),4.60(br s,2H),4.31-4.22(m,1H),3.93(br s,13H),2.82-2.68(m,1H),2.62(br s,2H),2.43(br d,J=10.3Hz,3H),2.15-2.05(m,1H),2.02-1.83(m,2H),1.61-1.50(m,1H).

[1119] Example 13: 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

[1120]

[1121] tert-Butyl 4-(2-(2-bromo-4-nitrophenoxy)ethyl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (5.71 g, 22.94 mmol, 1 eq) and 2-bromo-4-nitrophenol (5.00 g, 22.94 mmol, 1 eq) in acetonitrile (50 mL) was added potassium carbonate (15.85 g, 114.68 mmol, 5 eq). The mixture was stirred at 60 ° C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (30 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (15 mL × 1). The combined organic phases were washed with water (20 mL × 3) and brine (10 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Tert-butyl 4-(2-(2-bromo-4-nitrophenoxy)ethyl)piperazine-1-carboxylate (8.22 g, 19.10 mmol, 83.3% yield) was obtained as a yellow solid and used without further purification. MS (ESI) m / z 432.0 [M+3] + .

[1122] tert-Butyl 4-(2-(4-amino-2-bromophenoxy)ethyl)piperazine-1-carboxylate. To tert-butyl 4-(2-(2-bromo-4-nitrophenoxy)ethyl)piperazine-1-carboxylate (6.00 g, 13.94 mmol, 1 eq) in MeOH (60 mL) was added zinc (4.56 g, 69.72 mmol, 5 eq) and ammonium chloride (14.92 g, 278.88 mmol, 20 eq). The mixture was stirred at 50° C. for 48 hours, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by semi-preparative reverse phase HPLC (5%-35% acetonitrile + 0.225% formic acid / water). The collected fractions were concentrated to remove most of the acetonitrile and treated with saturated aqueous sodium bicarbonate to adjust the pH to 7. The aqueous phase was extracted with EtOAc (200 mL×3). The combined organic phases were washed with brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 4-(2-(4-amino-2-bromophenoxy)ethyl)piperazine-1-carboxylic acid tert-butyl ester (3.02 g, 7.55 mmol, 54.2% yield) was obtained as a yellow solid. MS (ESI) m / z 400.1 [M+1] + ; 1 HNMR(400MHz,DMSO-d6)δppm 6.83(d,J=8.8Hz,1H),6.79(d,J=2.8Hz,1H),6.51(dd,J=2.4,8.8Hz,1H),4.90(br s,2H),3.97(t,J=5.6Hz,2H),3.29(br s,4H),2.67(t,J=5.6Hz,2H),2.47-2.41(m,4H),1.39(s,9H)

[1123] tert-Butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate. To tert-butyl 4-(2-(4-amino-2-bromophenoxy)ethyl)piperazine-1-carboxylate (1.90 g, 4.13 mmol, 1 eq) in DIEA (15 mL) was added methyl 2-bromo-2-methylpropanoate (2.24 g, 12.39 mmol, 3 eq). The mixture was stirred at 120° C. for 12 hours. The mixture was concentrated under reduced pressure and diluted with water (20 mL). The aqueous phase was extracted with EtOAc (20 mL×2). The combined organic phases were washed with brine (10 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (30-60% EtOAc / petroleum ether). Tert-butyl 4-(2-(2-bromo-4-((l-methoxy-2-methyl-l-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-l-carboxylate was obtained as a yellow solid (1.90 g, 3.80 mmol, 92.0% yield). 1 H NMR(400MHz,DMSO-d6)δppm 6.89(d,J=8.8Hz,1H),6.75-6.66(m,1H),6.36(dd,J=2.8,8.8Hz,1H),5. 83-5.78(m,1H),5.81(s,1H),3.99(t,J=5.6Hz,2H),3.59(s,3H),3.29(br s,4H),2.72-2.65(m,2H),2.46-2.39(m,4H),1.41-1.37(m,15H).

[1124] Tert-butyl 4-(2-(2-cyclopropyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(2-(2-bromo-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.300 g, 0.599 mmol, 1 eq) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.201 g, 1.200 mmol, 2 eq) in dioxane (5 mL) and water (0.5 mL) was added potassium phosphate (0.636 g, 3.000 mmol, 5 eq) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.088 g, 0.120 mmol, 0.2 eq) under nitrogen. The mixture was stirred at 120° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc / petroleum ether) followed by semi-preparative reverse phase HPLC (10%-40% acetonitrile + 0.225% formic acid / water, 10 minutes). The collected fractions were then concentrated to remove most of the acetonitrile and lyophilized. tert-Butyl 4-(2-(2-cyclopropyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.108 g, 0.234 mmol, 39.0% yield) was obtained as a yellow oil. MS (ESI) m / z 462.2 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)δppm 8.15(s,1H),6.68(d,J=8.8Hz,1H),6.16(dd,J=2.8,8.6Hz,1H),5.95(d,J=2.8Hz,1H),5.37(br s,1H),3.96(t,J=5.6Hz,2H),3.57(s,3H),3.38(br s,4H),2.69(t,J=5.6Hz,2H),2.47-2.40(m,4H),2.12-2.00(m,1H),1.45-1. 31(m,15H),0.90-0.75(m,1H),0.79(s,1H),0.50-0.36(m,1H),0.50(s,1H).

[1125] tert-Butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)piperazine-1-carboxylate. To a mixture of tert-butyl 4-(2-(2-cyclopropyl-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)phenoxy)ethyl)piperazine-1-carboxylate (0.108 g, 0.234 mmol, 1 eq) and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (0.160 g, 0.702 mmol, 3 eq) in EtOAc (1 mL) was added TEA (0.118 g, 1.170 mmol, 5 eq). The mixture was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (66.7% EtOAc / petroleum ether). Tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionetomidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)piperazine-1-carboxylate (0.090 g, 0.137 mmol, 58.5% yield) was obtained as a yellow solid. MS (ESI) m / z 658.1 [M+1] + .

[1126] 4-(3-(3-cyclopropyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride. To a solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioketoimidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)piperazine-1-carboxylate (0.09 g, 0.1374 mmol, 1 equivalent) in EtOAc (2 mL) was added a solution of HCl in dioxane (4 M, 5 mL). The mixture was stirred at 25° C. for 30 minutes. The mixture was concentrated under reduced pressure. 4-(3-(3-cyclopropyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thionemidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.10 g, crude product) was obtained as a yellow oil and used without further purification. MS (ESI) m / z 558.1 [M+1] + .

[1127] 2-Chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide. To a mixture of 2-chloroacetic acid (1.39 g, 14.66 mmol, 1.1 eq), HATU (5.57 g, 14.66 mmol, 1.1 eq) and DMF (40 mL) stirred at 15 ° C for 2 hours was added 3-((3-aminophenyl)amino)piperidine-2,6-dione hydrobromide (4.00 g, 13.33 mmol, 1 eq) and DIEA (5.17 g, 39.98 mmol, 6.96 mL, 3 eq). The reaction mixture was stirred at 15 ° C for 1 hour, diluted with brine (150 mL) and EtOAc (150 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL × 2). The combined organic extracts were concentrated and the resulting suspension was filtered. The filtrate was purified by reverse phase semi-preparative HPLC (10-40% acetonitrile / water + 0.05% HCl, 26 min) to afford 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (2.60 g, 8.79 mmol, 66.0% yield) as a grey solid. 1 H NMR (400MHz, DMSO-d6) δppm10.81(s,1H),10.17(s,1H),7.06-7.02(m,2H),6.86(d,J=8.0Hz,1H),6.48(dd,J=8.0,1.6Hz,1H),4 .36-4.26(m,1H),4.22(s,2H),2.77-2.68(m,1H),2.59(dt,J=17.6,4.0Hz,1H),2.12-2.05(m,1H),1.91(qd,J=12.4,4.8Hz,1H).

[1128] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a mixture of 4-(3-(3-cyclopropyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.100 g, 0.168 mmol, 1 eq) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.060 g, 0.202 mmol, 1.2 eq) in DMF (2 mL) was added DIEA (0.109 g, 0.842 mmol, 5 eq). The mixture was stirred at 50° C. for 10 h. The mixture was filtered and the filtrate was purified by standard methods to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-cyclopropylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.079 g, 0.095 mmol, 56.5% yield). MS (ESI) m / z 817.2 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δppm 10.80(s,1H),10.38(br s,1H),8.39(d,J=8.4Hz,1H),8.27(d,J=1.6Hz,1H),8.06(dd,J=1.6,8.2Hz,1H),7.19-7.11(m,2H),7.07-7.00(m,1H),6.97(s,1H),6.86(br s,2H),6.46(br d,J=8.0Hz,1H),4.53(br s,2H),4.25(br dd,J=4.8,11.2Hz,1H),4.09(br s,4H),3.83(brs,8H),2.79-2.68(m,1H),2.64-2.51(m,2H),2.29-2.17(m,1H),2.10(td,J=4. 4,8.5Hz,1H),1.91(dq,J=4.8,12.4Hz,1H),1.47(s,6H),1.00-0.88(m,2H),0.66-0.54(m,2H).

[1129] Example 14: 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride

[1130]

[1131] 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thionemidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride. To a mixture of 4-(3-(3-ethyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4,4-dimethyl-5-oxo-2-thioketoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (0.150 g, 0.258 mmol, 1 eq) and 2-chloro-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide (0.091 g, 0.309 mmol, 1.2 eq) in DMF (2 mL) (prepared as described herein) was added DIEA (0.167 g, 1.29 mmol, 5 eq). The mixture was stirred at 50 °C for 10 h then filtered. The filtrate was purified by standard methods to give 2-(4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxidomidazolidin-1-yl)-2-ethylphenoxy)ethyl)piperazin-1-yl)-N-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)acetamide hydrochloride (0.106 g, 0.131 mmol, 50.8% yield). MS (ESI) m / z 805.2 [M+1] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.80(s,1H),10.48(br s,1H),8.39(d,J=8.4Hz,1H),8.29(d,J=1.2Hz,1H),8.08(d,J=8.4Hz,1H),7.24-7.11(m ,3H),7.09-7.01(m,1H),7.09-7.01(m,1H),6.98(s,1H),6.87(d,J=8.0Hz,1H),6.47(br d,J=7.6Hz,1H),4.52(br s,2H),4.26(br dd,J=4.8,11.4Hz,1H),4.16(br s,4H),3.70(br s,8H),2.80-2.66(m,3H),2.66-2.52(m,2H),2.10(td,J=4.0,8.8Hz,1H),1.91 (dq,J=4.0,12.0Hz,1H),1.53-1.47(m,1H),1.50(s,5H),1.17(t,J=7.6Hz,3H).

[1132] Example 1...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopomer or stereoisomer thereof, wherein R N is H; Each R 1 independently selected from halogen, CN and C 1-3 alkyl; R 2 and R 3 Each independently selected from H and C 1-3 Alkyl, or R 2 and R 3 The carbon to which it is attached forms a substituted or unsubstituted C 3-6 Cycloalkyl; Each R 4 are independently substituted or unsubstituted C 1-3 Alkyl, or two R 4 The group and the same carbon atom or adjacent carbon atom to which it is attached together form a substituted or unsubstituted C 3-6 Cycloalkyl, or two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms a substituted or unsubstituted 4- to 7-membered heterocyclic group; X is N; L is -O(C 1-6 Alkyl)- or -(C 1-9 alkyl)-; n is 0 to 4; m is 0 to 8; V in A is N, CH or CR A ; B is N, CH or CR B ; Each R A are independently selected from halogen, substituted or unsubstituted C 1-6 Alkyl and substituted or unsubstituted C 3-6 Cycloalkyl; Each R B are independently selected from halogen and substituted or unsubstituted C 1-6 alkyl; R C is halogen or CF3; R 5 and R 6 C 1-3 Alkyl, or R 5 and R 6 Together with the carbon atom to which it is attached, it forms a substituted or unsubstituted C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic group; a is 0 to 3; and b is 0 to 2.

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

3. The compound as claimed in claim 1, wherein each R 1 Independently selected from Cl, F, Br, CN, -CH3, -CH2CH3 and isopropyl.

4. The compound of claim 1, wherein each R 1 Independently selected from Cl, F, CN and -CH3. The compound as claimed in claim 1 , wherein n is 0. The compound according to claim 1 , wherein n is 1 or 2.

7. The compound of claim 1, wherein R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or wherein R 2 and R 3 The carbon to which it is attached forms a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl.

8. The compound of claim 1, wherein R 2 and R 3 are each independently selected from H and methyl, or wherein R 2 and R 3 The carbon to which it is attached forms an unsubstituted cyclopropyl group.

9. The compound of claim 1, wherein R 2 and R 3 Both are H or methyl, or R 2 and R 3 The carbon to which it is attached forms an unsubstituted cyclopropyl group.

10. The compound of claim 1, wherein each R 4 are independently selected from substituted or unsubstituted methyl and ethyl, or two of them 4 The groups, together with the same carbon atom to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl group.

11. The compound of claim 1, wherein each R 4 are independently selected from substituted or unsubstituted methyl, or two R 4 The group together with the same carbon atom to which it is attached forms an unsubstituted cyclopropyl group.

12. The compound of claim 1, wherein each R 4 are independently selected from methyl, CF3 and CH2OH, or two of them 4 The group together with the same carbon atom to which it is attached forms an unsubstituted cyclopropyl group.

13. The compound of claim 1, wherein m is 0, 1, 2, 3 or 4.

14. The compound of claim 1, wherein m is 0, 1 or 2.

15. The compound of claim 1, wherein two R 4 The group, together with the non-adjacent carbon atoms to which it is attached, forms an unsubstituted 4- to 7-membered heterocyclic group.

16. The compound according to claim 1, wherein L is O(CH2)(CH2)-, -O(CH2)(CH(CH3))-, -O(CH2)(C(CH3)2)-, -O(CH(CH3))(CH2)-, -O(C(CH3)2)(CH2)-, -O(CH(CH3))(CH(CH3))-, -O(CH(CH3))(C(CH3)2)-, -O(C(CH3)2)(CH(CH3))-, -(CH2)-, -(CH2)(CH2)-, -(CH2)(CH2)(CH2)-, -(C(CH3)2)(C(CH3)2)-, -(CH(CH3))-, -(C(CH3)2)-, -(CH(CH3))(CH(CH3))-, -(CH(CH3))(C(CH3)2)-, -(C(CH3)2)(CH(CH3))-, -(C(CH3)2)(C(CH3)2)-, -(CH3)(CH3)(CH(CH3))-, -(CH2)(CH(CH3))(CH2)-, -(CH(CH3))(CH2)(CH2)-, -(CH2)(CH2)(C(CH2)2)-, -(CH2)(C(CH2)2)(CH2)-, -(C(CH2)2)(CH2)(CH2)-, -(CH2)(CH(CH3))(CH(CH3))-, -(CH(CH3))(CH(CH3))(CH(CH3))-, -(CH(CH3))(CH(CH3))(CH2)-, -(CH(CH3))(CH2)(CH(CH3))-, -(CH2)(CH(CH3))(C(CH3)2)-, -(CH(CH3))(CH2)(C(CH2)2)-, -(C(CH3)2)(CH2)(C(CH3)2)-, -(CH2)(C(CH3)2)(C(CH3)2)-, -(CH2)(C(CH3)2)(CH(CH3))-, -(CH(CH3)(C(CH3)2)(CH2)-, -(C(CH3)2)(CH2)(CH(CH3))-, -(C(CH3)2)(CH(CH3))(CH2)-, -(C(CH3)2)(C(CH3)2)(CH2)-, -(CH(CH3))(CH(CH3))(C(CH3)2)-, -(CH(CH3))(C(CH3)2)(C(CH3)2)-, -(C(CH3)2)(CH(CH3))(C(CH3)2)-, -(CH(CH3))(C(CH3)2)(CH(CH3))-, -(C(CH3)2)(C(CH3)2)(CH(CH3))--(C(CH3)2)(CH(CH3))(CH(CH3))- and -(C(CH3)2)(C(CH3)2)(C(CH3)2)-。, 17. A compound as described in claim 1, wherein L is -O(CH2)(CH2)-, -O(CH2)(CH(CH3))-, -O(CH2)(C(CH3)2)-, -O(CH(CH3))(CH2)-, -O(C(CH3)2)(CH2)-, -(CH2)-, -(CH2)(CH2)-, or -(CH2)(CH2)(CH2)-.

18. The compound of claim 1, wherein L is -O(CH2)(CH2)-, -O(CH2)(CH(CH3))-, -O(CH(CH3))(CH2)-, or -(CH2)(CH2)(CH2)-.

19. The compound of claim 1, wherein A is CH.

20. The compound of claim 1, wherein B is CH.

21. The compound of claim 1, wherein B is N.

22. The compound of claim 1, wherein a is 0, 1 or 2.

23. The compound of claim 19, wherein each R A Independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2, CH(CH3)CH(CH3)2, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2OH, CH(CH3)OH, CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl.

24. The compound of claim 1, wherein each R A Independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, cyclopropyl, cyclobutyl and cyclopentyl.

25. The compound of claim 1, wherein each R A Independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, cyclopropyl, cyclobutyl and cyclopentyl.

26. The compound of claim 1, wherein each R A Independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, cyclopropyl and cyclobutyl.

27. The compound of claim 1, wherein b is 0 or 1.

28. The compound of claim 1, wherein R B It is methyl.

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

30. The compound of claim 1, wherein R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl or tetrahydropyranyl group.

31. The compound of claim 1, wherein R 5 and R 6 is methyl, or R 5 and R 6 Together with the carbon atom to which it is attached it forms a cyclobutyl, cyclopentyl, cyclohexyl or tetrahydrofuranyl group.

32. A compound as shown in Table 1.

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

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

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

36. The method of claim 34 or 35, wherein the androgen-mediated disease is prostate cancer.

37. The method of claim 36, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

38. A compound as claimed in any one of claims 1 to 32 for use in a method of treating an androgen receptor mediated disease.

39. The pharmaceutical composition of claim 33, for use in a method of treating an androgen receptor mediated disease.

40. A compound for use according to claim 38 or a pharmaceutical composition for use according to claim 39, wherein the androgen-mediated disease is prostate cancer.

41. The compound or pharmaceutical composition for use according to claim 40, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

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