Novel heterobifunctional protein degraders and use thereof

Abstract

A compound defined by chemical formula 1, a stereoisomer thereof, a tautomer thereof, and a pharmaceutically acceptable salt of the compound, the stereoisomer and the tautomer are provided. The compound of the present invention can reduce the amount of EP300 in a cell. In chemical formula 1, m, R1 to R3, Q1, Q2, E1, E2, X, L, Z, A and B are the same as those defined in the present specification. [Chemical formula 1]

Description

Novel heterobifunctional protein degraders and their uses

[0001] The present invention relates to novel heterobifunctional compounds capable of inhibiting the activity of specific body proteins. Furthermore, the present invention relates to small organic compounds that induce the degradation of these specific proteins.

[0002] Histone acetyltransferases (HATs) catalyze the acetylation of the ε-amino group of the target lysine side chain within the substrate histone protein, while histone deacetylases (HDACs) catalyze the removal of the acetyl group from the acetylated lysine residue. Histone acetyltransferases are broadly divided into four protein families, one of which, the type 3 lysine acetyltransferase (KAT3) protein family, includes two proteins: EP300 (also called p300) and CREB binding protein (CBP). The HAT domains of EP300 and CBP are very similar, sharing over 90% sequence identity, and these two acetyltransferases are responsible for most of the acetylation of intracellular histone H3 lysine 18 and lysine 27, which are histone modifications associated with active promoters and enhancers in the genome.

[0003] EP300 and CBP are involved in numerous cellular processes, including cell growth, proliferation, and differentiation. Mutations in EP300 and CBP have been observed in many human diseases, with a frequency of up to 30% in cancer. Mutations are even more frequent within the HAT domain, suggesting that there is pressure in cancer to selectively alter the acetyltransferase activity of EP300 or CBP.

[0004] In addition to its acetyltransferase function, EP300 activates transcription by acting as a scaffold for transcription factors or as a bridge between transcription factors and the fundamental components of transcription. High expression of EP300 has been observed in various cancers, which correlates with poor survival rates and malignant phenotypes. Therefore, inhibiting the activity of EP300 or CBP holds promise as a cancer therapeutic. Specifically, selective inhibition of EP300 over CBP can result in the death of cancer cells in cancers with CBP loss, but can also spare normal cells, where CBP can substitute for EP300. Therefore, treatments that selectively inhibit EP300 over CBP can have a selective apoptotic effect on cancer cells, thereby reducing side effects.

[0005] However, there have been many difficulties in finding small organic compound inhibitors with strong inhibitory potency against the acetyltransferase activity of EP300 (Cole, Nat. Chem. Biol. Vol. 4 (2008), pp. 590-597), and designing inhibitors with high specificity for EP300 is not easy due to the sequence homology between CBP and EP300. On the other hand, EP300 HAT inhibitors derived from natural compounds have moderate potency but lack specificity. Therefore, the demand in this field for small organic compounds with excellent potency and specificity that can inhibit the activity of EP300 or reduce the amount of EP300 is not yet sufficiently met.

[0006] The technical task of the present invention is to provide a novel compound capable of inhibiting the activity of EP300. More specifically, the technical task of the present invention is to provide a compound capable of reducing the intracellular amount of EP300. Even more specifically, the technical task of the present invention is to provide a heterologous bifunctional compound with a degradation-inducing activity that is selective for EP300 among CBP and EP300. Furthermore, the technical task of the present invention is to provide a novel drug capable of inhibiting the activity of EP300.

[0007] In one aspect of the present invention, a compound defined by chemical formula 1 or a tautomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

[0008] [Chemical Formula 1]

[0009]

[0010] In chemical formula 1, m is an integer from 0 to 5,

[0011] R 1 In each case, halogen, C 1~3 Alkyl, C 3~6 Cycloalkyl, CN and CF3 are substituents selected independently from each other in m order;

[0012] Q 1 Silver CR 4 R 5 , CR 6 , Geminal C 3~5 Cycloalkylene, geminal haloC 3~5 Cycloalkylene, C 3~5 Cycloalkylene, haloC 3~5 Cycloalkylene, or C≡C, where R 4 , R 5 Wow R 6 are H and C respectively 1~5 Alkyl, C 3~5 Cycloalkyl and haloC 3~5 A functional group independently selected from the group consisting of cycloalkyl;

[0013] Q 2 is CR 7 R 8 , CR 9 , Geminal C 3~5 Cycloalkylene or C 3~5 Cycloalkylene, where R 7 , R 8 and R 9 are H and C respectively 2~5 Alkyl and C 3~5 A functional group independently selected from the group consisting of cycloalkyl, provided that Q 1 This CR 6 When Q 2 Go CR 9 It should be, Q 2 Go CR 9 Q on the other side 1 This CR 6 It must be,

[0014] Q 1 and Q 2 In between The sign is Q 1 and Q 2 Each CR 6 and CR 9 When Q 1 and Q 2 Indicates that it is directly connected by a double bond, otherwise Q 1 and Q 2 It indicates that they are directly connected by a single bond;

[0015] R 2 is a substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl;

[0016] R 3 , X and Is

[0017] a) R 3 This X and with one substituted or unsubstituted C 8~14 Forming a fused bicyclic heteroarylene together, or

[0018] b) X is CH or N, and R 3 This H, C 1~3 Alkyl, C 1~2 alkyleneNHR 10 , NH2, NHR 10 or NR 10 R 11 and, is any one ring selected from the group consisting of substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene, wherein R 10 and R 11 C are chosen independently from each other 1~3 It is alkyl;

[0019] is selected from substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene;

[0020] E 1 and E 2 are each independently hydrogen or halogen.

[0021] L is a linker, Z is an E3 ligase binding functional group,

[0022] The above substitution C 6~10 Aryl, substituted 5-6 membered heteroaryl, substituted C 8~14 Fused bicyclic heteroarylene, substituted phenylene or substituted 5-6 membered heteroarylene is a fused bicyclic heteroarylene in which at least one ring hydrogen is C 1~6 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0023] In another aspect of the present invention, a pharmaceutical composition for treating or preventing cancer is provided, comprising a therapeutically effective amount of the compound described above, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0024] In another aspect of the present invention, a method for treating or preventing cancer is provided. The method comprises administering a therapeutically effective amount of a compound of the present invention, such as a compound defined by Formula 1, or a pharmaceutical composition comprising such a compound of the present invention, to a subject in need of treatment or prevention.

[0025] The compound of the present invention can reduce the intracellular amount of EP300. The compound of the present invention exhibits antitumor activity.

[0026] Hereinafter, embodiments of the present invention will be described in detail. Prior to this, it should be noted that the terms and words used in this specification and claims should not be construed as limited to their conventional or dictionary meanings. Based on the principle that the inventor can appropriately define the concept of a term to best explain his or her invention, they should be interpreted in a way that aligns with the technical spirit of the present invention.

[0027] Therefore, the embodiments described in this specification are merely examples presented for the purpose of helping to understand the present invention and do not represent all of the technical ideas of the present invention. Therefore, it should be understood that there may be various equivalents and modified examples that can replace them at the time of filing this application.

[0028] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. While preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. The numerical range indicated using the term "to" herein includes the ranges that include the values ​​described before and after the term "to" as the lower and upper limits, respectively.

[0029] Definition of Terms

[0030] In this specification, the prefix "C x~y " or "C x ~C y "(where x and y are natural numbers) is used in front of a functional group to indicate the number of carbon atoms that the functional group has in its backbone. For example, C 1~4 An alkyl group has 1 to 4 carbon atoms, C 1~3 An alkyl group refers to an alkyl group having 1 to 3 carbon atoms. For example, C1~C4 alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, and tert-butoxy. For example, C3~C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups. For example, C1~4 alkylene groups include methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, and tert-butylene.

[0031] In addition, in the present specification, when the number of elements forming the ring is indicated in front of a ring functional group or compound (including both carbon rings and heterocycles), the ring is a ring formed of the corresponding number of elements, i.e., carbon and / or heteroatoms. For example, a six-membered ring heteroaryl refers to a heteroaryl group that contains one or more heteroatoms and is formed together with carbon, and the number of elements forming the ring is 6.

[0032] Unless otherwise specified herein, when a functional group is linked to another part of a compound by a bond, the linkage may be via any atom of that functional group, provided that it is a suitable atom. For example, when referring to a propyl group, both prop-1-yl and prop-2-yl are included.

[0033] In this specification, "C 1~6 The term "alkyl" refers to a group whose chemical formula is C when n is a natural number from 1 to 6. n H 2n+1 It refers to a saturated hydrocarbon group of 1-valent. C1~6 Alkyl groups include all linear or branched saturated hydrocarbons having 1 to 6 carbon atoms, such as n-propyl, i-propyl, 2-methyl-pentyl, sec-butyl, tert-butyl, etc.

[0034] In this specification, "C m~n The term "alkylene" refers to a group whose chemical formula is C when the number of carbon atoms is a natural number from m to n. m H 2m From C n H 2n It refers to a divalent saturated hydrocarbon atom group that reaches .

[0035] The term "cycloalkyl" as used herein refers to a monovalent saturated hydrocarbon atom group containing one or more carbon rings. A monocyclic cycloalkyl containing only one carbon ring has a chemical formula of C n H 2n-1 is a single ring C 3~6 Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0036] The term "cycloalkylene" as used herein refers to a divalent saturated hydrocarbon group forming one or more rings, wherein one hydrogen atom is replaced in the aforementioned cycloalkyl, and the functional group is linked to the remainder of the molecule containing the cycloalkylene at the position of the replaced hydrogen. The cycloalkylene is linked to the remainder of the molecule containing the cycloalkylene by two covalent bonds, and these two bonds may be borne by two different ring carbon atoms of the cycloalkylene, or a single carbon atom may bear both bonds. The term "geminal cycloalkylene" as used herein refers to the latter case, that is, the case where both covalent bonds are formed through the same cycloalkylene carbon atom.

[0037] As used herein, the term "bicyclic" refers to a carbon ring compound or heterocyclic compound composed of two rings, which is formed by sharing one or more ring atoms between the two constituent rings. In a bicyclic compound, the atom shared between the two rings is called a bridgehead atom. Bicyclic compounds are divided into three types depending on the number of bridgehead atoms and whether or not there is a direct connection between the bridgehead atoms. A fused bicyclic compound has two bridgehead atoms, which are directly connected to each other by a bond. Examples of fused bicyclic compounds include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, and quinoline. A ring compound with only one bridgehead atom is a spirocyclic compound. A bridged ring compound has two bridgehead carbon atoms, which are not directly adjacent, but have one or more ring atoms between them. Examples of bridged ring compounds include norbornane, 7-oxabicyclo[2.2.1]heptane, and adamantane.

[0038] In this specification, fused bicyclic compounds can be expressed by specifying the number of ring atoms in each of the two rings that make up the compound. For example, thienopyridine, benzofuran, indole, etc. can be referred to as five- or six-membered fused bicyclic compounds. Similarly, naphthalene, chromane, tetrahydroquinoline, quinoline, quinoxaline, pteridine, etc. can be referred to as six- or six-membered fused bicyclic compounds.

[0039] The term "aryl" in this specification refers to an aromatic C6~C 14 It refers to a monovalent hydrocarbon functional group that can have one to three aromatic rings as a functional group. For example, aryl has C6, C 10 , C 13 and C 14Aromatic hydrocarbon ring atoms are included, such as phenyl, naphthyl, anthracenyl, and fluorenyl.

[0040] The term "heteroaryl" as used herein refers to a monovalent aromatic ring composed of an unsaturated ring group containing one or more rings, wherein the ring atoms include, in addition to carbon atoms, one or more heteroatoms selected from nitrogen, oxygen, and sulfur. The ring system of the heteroaryl may be a single ring, a double ring, or a triple ring in the form of a fused ring. The term heteroaryl excludes rings containing a direct linkage between oxygen and sulfur atoms, such as -OO-, -OS-, or -SS- among the ring constituent atoms. Some examples of heteroaryl include pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazolyl, quinazolinyl, 2-furyl, 3-furyl, benzofuryl, 2-thienyl, oxazolyl, isothiazolyl, and thiadiazolyl. Heteroaryl can also be defined by specifying the heteroatom. For example, heteroaryl in which the heteroatom is nitrogen includes pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, etc., but excludes furyl, thienyl, etc.

[0041] Fused bicyclic heteroaryl groups include six- and five-membered fused bicyclic heteroaryl groups such as benzimidazolyl, benzofuranyl, benzothiophenyl, isoindolyl, indazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrazinyl, triazolopyrimidinyl, triazolopyrimidinyl, purinyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzothiadiazolyl, etc., and six- and six-membered fused bicyclic heteroaryl compounds such as benzopyridinyl, benzopyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, Examples include quinoxalinyl, naphthyridinyl, quinolizinyl, and cinnolinyl.

[0042] The term "arylene" as used herein refers to a divalent unsaturated hydrocarbon atom group formed by removing one more ring hydrogen from the aforementioned aryl ring and linking it to another part of the compound. "Phenylene" refers to a case where the aryl ring is a phenyl ring.

[0043] The term "heteroarylene" as used herein refers to a divalent unsaturated atomic group in the form of a heteroaryl ring as described above, wherein one more ring hydrogen is removed to connect to another part of the compound.

[0044] The term "heterocycloalkyl" as used herein refers to a monovalent saturated atomic group in which at least one or more of the carbon atoms forming the ring in the cycloalkyl is independently replaced in each instance by a heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heterocycloalkyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolyl, piperazinyl, morpholinyl, and thiazolidinyl.

[0045] The term "heterocyclyl" in this specification refers to a monovalent atomic group including the aforementioned heterocycloalkyl and heteroaryl, and even a ring in which some of the ring bonds of the heterocycloalkyl are replaced by unsaturated bonds.

[0046] The term "spiroheterocycloalkyl" in this specification refers to a monovalent saturated heterobicyclic atomic group that is both a heterocycloalkyl as described above and a spirobicyclic ring having one bridge carbon atom.

[0047] The term "heterocyclylene" as used herein refers to a divalent atomic group in which one more hydrogen is replaced from the aforementioned heterocyclyl and is connected to the remainder of the molecule containing the heterocyclylene at the position of the replaced hydrogen.

[0048] The term "spiroheterocycloalkylene" as used herein refers to a divalent atomic group in which one more hydrogen is replaced from the aforementioned spiroheterocycloalkyl, thereby connecting the group to the remainder of the molecule containing the spiroheterocycloalkylene at the position of the replaced hydrogen.

[0049] The term "halogen" as used herein, when referring to a substituent in a chemical structure, refers to an atom selected from fluorine, chlorine, bromine, and iodine. In the present specification, halogen may also be used in the form of the prefix "halo" to mean that one or more of the hydrogens of a hydrocarbon or heterosubstituted hydrocarbon is replaced by a halogen. For example, "haloC 3~5 "Cycloalkylene" refers to a functional group in which at least one hydrogen atom in a cycloalkylene functional group having 3 to 5 carbon atoms is independently replaced with a halogen.

[0050] In this specification, the term "substituted" or "substituted" in front of a functional group refers to a structure in which at least one of the hydrogens of the functional group is replaced with a designated functional group other than hydrogen, unless otherwise stated in the specification, provided that the substituted functional group maintains its normal valence and yields a chemically stable functional group. In typical cases, the substituent is a halogen, CN, OH, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~14 Heteroaryl, C 1~6 Choose between alkoxy and CF3.

[0051] In this specification, a specific atom of a substituent forming part of a compound is " " indicates that the substituent is directly chemically bonded to the rest of the compound through that atom.

[0052] In the present specification, "---" or " between adjacent ring atoms of a carbon ring or heterocycle represented by a chemical structural formula "When there is a dotted line like this, it indicates that it is an optional element that may or may not have a covalent bond between the two adjacent ring atoms. For example, A notation like "---" implies that this structural formula encompasses benzene and 1,3-cyclohexadiene. However, "---" or " "The maximum possible number of covalent bonds between two adjacent ring atoms implied or implied by a single dotted line mark such as "is not necessarily one, but is determined by the number specified therein, e.g., the number designated as no bond, single bond or double bond, if otherwise specified for the chemical structure in this specification.

[0053] As used herein, the term "pharmaceutically acceptable salt" for a compound refers to a salt that does not impair the desired biological activity of the compound and does not cause inappropriate toxicity, irritation, or allergic reactions when used in contact with human or animal tissues. Pharmaceutically acceptable salts are well known in the art. For example, reference may be made to prior literature, such as the paper by Berge et al., J. Pharmaceutical Sciences (1977), Vol. 66, pp. 1-19. Some examples of pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, and hydrosulfide, and base addition salts such as alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium (N + (C 1~4 There are alkyl)4), and examples of alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.

[0054] As used herein, the term "subject in need of treatment" or "subject" refers to a human being diagnosed by a physician with a proliferative disease, such as cancer, or a mammal diagnosed by a veterinarian with a proliferative disease, such as cancer. The term "subject in need of treatment" or "subject" further includes a human being or mammal who has suffered from such a proliferative disease but whose symptoms have improved, as well as a human being or mammal suspected of having or will have such a proliferative disease, such as a human being or mammal exhibiting one or more symptoms associated with the proliferative disease. Here, the term "proliferative disease" refers to a disease whose symptoms or progression can be alleviated by the compound of the present invention.

[0055] As used herein, "treatment" refers to any treatment or action that alleviates, to some extent, the symptoms, markers, and / or any negative effects of a disease, condition, or condition in a subject with a current condition. Depending on the specific embodiment, such treatment may be administered to a subject who is only showing early signs of the condition, in order to reduce the risk of progression to the disease, condition, and / or condition.

[0056] As used herein, "prevention" refers to any method that completely or partially delays or prevents the onset of one or more symptoms or signs of a relevant disease, condition, and / or condition. Prevention may be applied to subjects who do not exhibit signs of the disease, condition, and / or condition.

[0057] Those skilled in the art will appreciate that some of the compounds of the present invention may exist in more than one tautomeric form. Since a single chemical structural formula can only represent one tautomeric form, it is well understood that when a compound is referred to by a single structural formula for convenience, the structural formula also encompasses the tautomeric variations of the compound. Depending on the compound, one tautomer may exist primarily in one form, a mixture of multiple tautomers may exist at room temperature, or only one tautomer may be isolated. Examples of tautomers include those between the pyridone and hydroxypyridine forms, and those between the keto and enol forms.

[0058] compound

[0059] In one aspect of the present invention, a compound defined by chemical formula 1, a tautomer thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof are provided.

[0060]

[0061] In chemical formula 1, m is an integer from 0 to 5,

[0062] R 1 In each case, halogen, C 1~3 Alkyl, C 3~6 Cycloalkyl, CN and CF3 are substituents that are independently selected from each other in order,

[0063] Q 1 Silver CR 4 R 5 , CR 6 , Geminal C 3~5 Cycloalkylene, geminal haloC 3~5 Cycloalkylene, C 3~5 Cycloalkylene, haloC 3~5 Cycloalkylene, or C≡C, where R 4 , R 5 Wow R 6 are H and C respectively1~5 Alkyl, C 3~5 Cycloalkyl and haloC 3~5 A functional group independently selected from the group consisting of cycloalkyl,

[0064] Q 2 is CR 7 R 8 , CR 9 , Geminal C 3~5 Cycloalkylene or C 3~5 Cycloalkylene, and in this case R 7 , R 8 and R 9 are H and C respectively 2~5 Alkyl and C 3~5 A functional group independently selected from the group consisting of cycloalkyl, provided that Q 1 This CR 6 When Q 2 Go CR 9 It should be, Q 2 Go CR 9 Q on the other side 1 This CR 6 It must be,

[0065] Q 1 and Q 2 In between The sign is Q 1 and Q 2 Each CR 6 and CR 9 When Q 1 and Q 2 Indicates that it is directly connected by a double bond, otherwise Q 1 and Q 2 It indicates that they are directly connected by a single bond,

[0066] R 2 is a substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl,

[0067] R 3 , X and Is

[0068] a) R 3 This X and with one substituted or unsubstituted C 8~14 Forming a fused bicyclic heteroarylene together or

[0069] b) X is CH or N, and R 3 This H, C 1~3 Alkyl, C 1~2 alkyleneNHR 10 , NH2, NHR 10 or NR 10 R 11 and, is any one ring selected from the group consisting of substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene, wherein R 10 and R 11 C are chosen independently from each other 1~3 It is alkyl,

[0070] is R 3 C substituted or unsubstituted with X 8~14 When not forming a fused bicyclic heteroarylene, it is any one ring selected from the group consisting of substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene.

[0071] is selected from substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene.

[0072] E 1 and E 2 are each independently hydrogen or halogen.

[0073] L is a linker and Z is an E3 ligase binding functional group.

[0074] The above substitution C 6~10 Aryl, substituted 5-6 membered heteroaryl, substituted C 8~14 Fused bicyclic heteroarylene, substituted phenylene or substituted 5-6 membered heteroarylene is a fused bicyclic heteroarylene in which at least one ring hydrogen is C 1~6A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0075] In the compound of the present invention, the portions excluding L and Z are portions that target EP300 and are functional groups having affinity for EP300.

[0076] In the compound of the present invention, Z can be used as a functional group that has the property of binding to E3 ligase, and is not particularly limited.

[0077] In one embodiment, the compound of the present invention is wherein the E3 ligase is von Hippel-Lindau tumor suppressor (VHL) or cereblon (CRBN).

[0078] In one specific embodiment of the compound of the present invention, the E3 ligase is cereblon, and Z is thalidomide or a thalidomide derivative.

[0079] In a more specific embodiment, the linker L of the compound of the present invention has a structure represented by chemical formula 2.

[0080]

[0081] L in chemical formula 2 1 Silver NHC 1~3 A functional group independently selected from the group consisting of alkylene, 5-6 membered heterocyclylene, substituted 5-6 membered heterocyclylene and 8-12 membered spiroheterocycloalkylene, L 1 This NHC 1~3 When it is alkylene, NHC 1~3 C of alkylene 1~3 L on alkylene carbon 2 are connected, and at this time, the substituted 5-6 membered heterocyclylene has at least one ring hydrogen as C 1~2 These are functional groups each independently substituted with an alkyl group.

[0082] L in chemical formula 2 2is C 1~3 Alkylene or substituted C 1~3 Alkylene, wherein the above-mentioned substituted C 1~3 Alkylene is a group in which one or more hydrogens are C 1~3 A functional group substituted with a substituent independently selected from the group consisting of alkyl and oxo.

[0083] L in chemical formula 2 3 NHC, which is connected to Z 1~3 A functional group independently selected from the group consisting of alkylene, 5-6 membered heterocyclylene, 8-12 membered spiroheterocycloalkylene and substituted 5-6 membered heterocyclylene, wherein the substituted 5-6 membered heterocyclylene has at least one ring hydrogen atom of C 1~2 These are functional groups independently substituted with alkyl.

[0084] In another specific embodiment of the compound of the present invention, the E3 ligase binding moiety Z of the compound of the present invention has a structure represented by Chemical Formula 3.

[0085]

[0086] In the chemical formula 3 above is any one selected from the group consisting of substituted or unsubstituted phenylene, substituted or unsubstituted fused bicyclic heteroarylene, and 2,3-dihydro-3-methyl-2-oxo-1H-benzo[d]imidazolylene, wherein the substituted phenylene or the substituted fused bicyclic heteroarylene has at least one ring hydrogen atom as C 1~6 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

[0087] Q in chemical formula 3 3 is NH, CONH or a chemical bond.

[0088] Q in chemical formula 3 4 is CH or N.

[0089] In chemical formula 3 Is It indicates that L is chemically bonded to A.

[0090] In another specific embodiment of the present invention, the compound of the present invention is a compound having a structure represented by chemical formula 4.

[0091]

[0092] Q in chemical formula 4 3 is NH, CONH or a chemical bond.

[0093] Q in chemical formula 4 4 is CH or N.

[0094] In chemical formula 4, m is an integer from 0 to 4, and each Q 5 are halogens that are selected independently of each other.

[0095] J in chemical formula 4 1 is CN or CF3.

[0096] J 2 J 4 Wow n is

[0097] a) If n is 0, then J 2 Ga CH, J 3 and J 4 is N, or J 2 is S, and J 3 This C, J 4 is CH or,

[0098] n) If n is 1, J 2 Wow J 4 is CH, and J 3 This is C.

[0099] In chemical formula 4 class Is this And, go This or that,

[0100] this And, go , and here ★ is or The ring of -C(G 2 )(G 3 ) points to the location connected to, and ■ or It refers to the position where the ring is connected to the carbonyl group or phenyl group of chemical formula 4.

[0101] G in chemical formula 4 1 and G 2 are each independently hydrogen or methyl, or G 1 and G 2 Together they form an oxo substituent.

[0102] In another specific embodiment of the present invention, the compound of the present invention is a compound having a structure represented by chemical formula 5.

[0103]

[0104] Q in chemical formula 5 3 is NH, CONH or a chemical bond, and J 1 is CN, halogen or CF3.

[0105] In chemical formula 5 Is And, at this time * is indicates the position where it is connected to the carbonyl group, and ** It points to the position where it is connected to the 1H-pyrazolyl group.

[0106] G in chemical formula 5 1 and G 2 are each independently hydrogen or methyl, or G 1 and G 2 Together they form an oxo substituent, G 3 and G 4 are each independently hydrogen or methyl.

[0107] In chemical formula 5 Is And, at this time † is ‡ indicates the position where the piperazine group is connected to the piperazine group. Go Q3 It points to the position connected to m. m is a natural number from 1 to 4, and each Q 5 are independently selected halogens, and Q 6 is hydrogen or methyl.

[0108] In a most specific embodiment of the compound of the present invention, the compound of the present invention is the following compound, a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable salt thereof:

[0109] 2-((4-cyanophenylethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0110] 2-((4-cyanophenethyl)amino)-N-(5-(1-(2-(((R)-5-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)amino)-3-methylpentyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0111] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0112] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0113] N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0114] N-(5-(1-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0115] N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide,

[0116] 4-(2-((2-(6-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0117] 3-(4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione,

[0118] 4-(4-((1-(2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide,

[0119] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl))phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide,

[0120] 4-(4-((1-(2-(4-(3-(2-((4-cyanophenethyl)amino)-2-phenylacetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide,

[0121] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl))phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide,

[0122] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0123] N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0124] N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide,

[0125] 4-(2-((2-(6-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0126] 3-((3-fluoro-4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione,

[0127] 2-((3-(4-cyanophenyl)prop-2-yn-1-yl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6)-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0128] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-)indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0129] N-(5-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0130] 4-(2-((2-(6-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-)yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0131] 3-(1-methyl-6-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione,

[0132] 2-((4-cyanophenethyl)amino)-N-(5-(1-(2-(((3R)-5-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)-3-methylpentyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0133] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0134] 4-(2-((2-(6-(1-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0135] 3-(4-(4-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)a

[0136] (cetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)piperidine-2,6-dione,

[0137] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0138] N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0139] N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0140] 4-(2-((2-(6-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl )amino)ethyl)benzonitrile,

[0141] 3-(4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)piperidine-2,6-dione,

[0142] N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0143] 4-(2-((2-(6-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0144] 3-(4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3,5-difluorophenyl)piperidine-2,6-dione,

[0145] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0146] N-(5-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0147] 4-(2-((2-(6-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0148] 3-((3-fluoro-4-(4-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione,

[0149] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0150] N-(5-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0151] 4-(2-((2-(6-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0152] 3-((4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione,

[0153] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0154] N-(5-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0155] 4-(2-((2-(6-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile,

[0156] 3-((3-fluoro-4-(4-(2-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)propan-2-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione,

[0157] 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0158] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0159] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0160] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0161] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0162] 4-(4-((1-(2-(4-(6-((R)-2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide,

[0163] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0164] (2R)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0165] (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0166] (2R)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0167] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-((R)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide,

[0168] (2R)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0169] (2S)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0170] (2R)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide,

[0171] (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide,

[0172] (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide,

[0173] (2R)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide,

[0174] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-((R)-2-((4-fluorophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide,

[0175] (2R)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide,

[0176] (2R)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide,

[0177] (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide,

[0178] (2R)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide,

[0179] N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-((R)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide,

[0180] (2R)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide,

[0181] 2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0182] (2S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0183] (2S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0184] (2S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide,

[0185] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0186] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0187] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0188] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0189] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0190] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0191] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0192] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0193] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0194] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0195] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0196] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0197] 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(9-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide,

[0198] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(9-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0199] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0200] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0201] N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0202] N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide,

[0203] 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide,

[0204] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide or

[0205] (2R)-N-(5-(1-(2-(4-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide.

[0206] The compound of the present invention can reduce the intracellular amount of EP300. The compound of the present invention can reduce the intracellular activity of EP300.

[0207] In one embodiment of the present invention, the compound of the present invention selectively reduces the amount of intracellular EP300 over CBP.

[0208] Synthesis of the compound of the present invention

[0209] The compounds of formula I of the present invention can be synthesized by synthetic routes including methods similar to those well known in the chemical art. Starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, WI), or can be prepared using methods well known to those skilled in the art (e.g., methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, NY (eds. 1967-1999) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including appendix (also available through the Beilstein online database)).

[0210] pharmaceutical composition

[0211] In another aspect, the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and further comprising a pharmaceutically acceptable excipient. A pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient can be used to reduce the intracellular amount of EP300 in the body. For example, this pharmaceutical composition can be used to treat cancer.

[0212] In the pharmaceutical composition of the present invention, the aforementioned compounds may be present as pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts may be formed with addition salts of metals or amines, such as alkali metal bases, alkaline earth metal bases, or organic amines. Pharmaceutically acceptable salts of the compounds may also be prepared using pharmaceutically acceptable cations. Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids.

[0213] In the present invention, a pharmaceutically acceptable excipient refers to an inactive ingredient approved by a relevant administrative agency (e.g., the Ministry of Food and Drug Safety of the Republic of Korea, the Federal Food and Drug Administration (FDA) of the United States) as being suitable for use together with an active pharmaceutical ingredient for the purpose of manufacturing a medicine for treating a disease in humans or livestock. Such pharmaceutically acceptable excipients include, but are not limited to, carriers, lubricants, fluidizing agents, disintegrating agents, sweeteners, diluents, preservatives, coloring agents, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvent emulsifiers, and adjuvants.

[0214] The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained-release preparation, solution, or suspension; in a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; in a form suitable for topical administration, such as an ointment or cream; or in a form suitable for rectal administration, such as a suppository.

[0215] The pharmaceutical composition according to the present invention can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar-coated tablet preparation, powdering, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The appropriate formulation will vary depending on the chosen route of administration.

[0216] Pharmaceutical compositions suitable for oral administration can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Using such excipients and carriers, the compounds disclosed herein can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by a subject to be treated. Oral pharmaceutical preparations can be obtained by adding the compounds of the present invention together with solid excipients, grinding the resulting mixture if necessary, adding suitable auxiliaries if necessary, and then processing the granulated mixture to form tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

[0217] For pharmaceutical compositions for oral administration of a therapeutically effective amount of a compound of the present disclosure, the compositions are generally in the form of solid (e.g., tablets, capsules, pills, powders, or troches) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

[0218] When administered in tablet form, the composition may additionally contain functional solids and / or solid carriers such as gelatin or adjuvants. Compositions in the form of tablets, capsules, and powders may contain from about 1 to about 95 wt% of the compound of the present invention, preferably from about 15 to about 90 wt% of the compound of the present invention, based on the total weight of the composition. An example of a tablet composition may contain, for example, up to about 80 wt% of the active pharmaceutical ingredient, from about 10 wt% to about 90 wt% of a binder, from about 0 wt% to about 85 wt% of a diluent, from about 2 wt% to about 10 wt% of a disintegrant, and from about 0.25 wt% to about 10 wt% of a lubricant.

[0219] When administered in liquid or suspension form, a functional liquid and / or liquid carrier such as water, petroleum, or animal or vegetable oil may be added. Liquid compositions may further contain saline, sugar alcohol solutions, dextrose or other sugar solutions, or glycols. When administered in liquid or suspension form, the composition may contain from about 0.5% to about 90% by weight of the compound of the present invention, preferably from about 1% to about 50% by weight of the compound of the present invention. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

[0220] When the pharmaceutical composition of the present invention is administered intravenously, transdermally, or subcutaneously, it is in the form of a parenteral aqueous solution that does not contain a pyrogen. Preparation of such parenteral solutions, taking into account pH, isotonicity, stability, etc., is within the skill of the art. Preferred compositions for intravenous, transdermal, or subcutaneous injection generally contain an isotonic vehicle. Such compositions may be prepared for administration as a solution of the free base or a pharmacologically acceptable salt in water suitably mixed with a surfactant such as hydroxypropyl cellulose. Dispersions in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as dispersions in oils, may also be prepared. Under normal storage and use conditions, such preparations may optionally contain a preservative to prevent the growth of microorganisms.

[0221] Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. Sterile injectable solutions are prepared by incorporating the active compound in the required amount in an appropriate solvent with various other ingredients, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterile active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In embodiments of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient and any additional required ingredients from a previously sterile-filtered solution thereof.

[0222] To achieve controlled release of the active compound upon contact with body fluids in the gastrointestinal tract and to provide substantially constant and effective levels of the active compound in the plasma, sustained-release or sustained-release formulations may be prepared. For example, release may be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, sustained-release approaches may enhance absorption through saturation or restriction pathways within the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix comprising a biodegradable polymer, a water-soluble polymer, or a mixture thereof, and optionally a suitable surfactant. Embedding in this context may mean incorporating microparticles into the polymer matrix. Controlled-release formulations may also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating techniques.

[0223] The pharmaceutical composition of the present invention may be formulated for parenteral administration by injection (e.g., bolus injection or continuous infusion). The injectable formulation may be presented in unit dosage form (e.g., ampoules or multi-dose containers) with an added preservative. The composition may take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0224] The pharmaceutical composition may be presented in unit dosage form suitable for single administration of precise dosages.

[0225] A pharmaceutical composition containing the compound of the present invention can be used according to the method described below.

[0226] Treatment or prevention methods

[0227] In another aspect, the present invention provides a method for treating or preventing cancer. This method comprises administering a therapeutically effective amount of a compound of the present invention, such as a compound of the present invention defined by Formula 1, to a subject in need of such treatment or prevention. Alternatively, the present invention comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable excipient to a subject in need of such treatment.

[0228] In a method for treating cancer, the compound of the present invention may be administered alone or in combination with at least one other drug. These other drugs and the compound of the present invention may be administered simultaneously or sequentially.

[0229] As used herein, unless specifically stated otherwise, a “therapeutically effective amount” of a compound refers to an amount of the compound sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or condition, or to provide a therapeutic effect for a disease, disorder, or condition. The term “therapeutically effective amount” encompasses an amount that improves overall healing, an amount that alleviates or avoids a symptom or cause of a disease or condition, and an amount that enhances the therapeutic effectiveness of another therapeutic agent.

[0230] The amount of compound administered may vary depending on the subject requiring treatment or prevention, the subject's age, health, sex, and body weight, the type (if any) of concurrent treatment, the severity of the pain, the nature of the desired effect, the treatment regimen and frequency, and the prescribing physician's judgment. The frequency of administration may also vary depending on the pharmacodynamic effects on arterial oxygen pressure. However, the most desirable dosage can be tailored to the individual. This typically involves adjusting the standard dose (e.g., reducing the dose if the subject is underweight).

[0231] When administered to humans for the therapeutic or prophylactic treatment of conditions and disorders using the compounds of the present invention, for example, a typical dosage of the compounds of the present invention may be from about 0.01 mg / kg / day to about 100 mg / kg / day, for example from about 5 mg / day to about 500 mg / day. Such dosages may be administered as a single dose or divided into multiple doses.

[0232] In another aspect of the present invention, a use of a compound according to formula 1 is provided as a medicament. The medicament may be a medicament for the treatment of cancer. In one embodiment, a use of a compound according to formula 1 is provided for the treatment or prevention of cancer.

[0233] In another aspect of the present invention, a composition comprising a compound according to Formula 1 and a pharmaceutically acceptable excipient is provided for use as a medicament. The medicament may be a medicament for the treatment of cancer. In one embodiment, the composition is used for the treatment or prevention of cancer.

[0234] In another aspect of the present invention, there is provided a use of a compound according to formula 1 or a composition thereof, for the manufacture of a medicament, such as a composition comprising a therapeutically effective amount of a compound according to formula 1 and a pharmaceutically acceptable salt. The medicament may be a medicament for the treatment of cancer. In one embodiment, there is provided a use of a compound according to formula 1 or a composition thereof for the manufacture of a medicament for the treatment or prevention of cancer.

[0235] In another aspect of the present invention, a method for reducing the amount of EP300 in a cell is provided. The method comprises the step of contacting a cell in which the amount of EP300 is to be suppressed with an effective amount of a compound of the present invention, e.g., a compound defined by Formula 1.

[0236] [Example]

[0237] Hereinafter, the present invention will be described in more detail through the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way. Various changes and modifications may be made to the present examples, and such changes and modifications also fall within the scope of the appended claims.

[0238] Compounds of Examples 1 to 96 shown in Table 1 below were prepared according to the manufacturing examples and synthesis examples described below.

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] The full names of the abbreviations described in the synthetic method of the manufacturing example below are as follows.

[0259] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0260] THF: Tetrahydrofuran Boc: Tert-butyloxycarbonyl t-Bu: Tert-butyl

[0261] AcOH: Acetic acid OAc: CH3COO

[0262] DMA: N,N-dimethylacetamide DCM: Dichloromethane

[0263] dppf: 1,1'-bis(diphenylphosphino)ferrocene MTBE: methyl tertiary butyl ether

[0264] Ts: paratoluenesulfonyl DIPEA:N,N-diisopropylethylamine

[0265] NMP:N-methyl-2-pyrrolidone Bn: Benzyl

[0266] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate

[0267] TEA: Triethylamine DMF: N,N-dimethylformamide

[0268] RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0269] Pd(dba)2: bis(dibenzylideneacetone)palladium(0)

[0270] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)

[0271] HOBt: Hydroxybenzotriazole ACN: Acetonitrile

[0272] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0273] XantPhos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0274] Cbz: Benzyloxycarbonyl MeOH: Methanol Et3N: Triethylamine

[0275] LiHDMS: lithium bis(trimethylsilyl)amide

[0276] SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate

[0277]

[0278] Manufacturing Example 1: Manufacturing of 1-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0279]

[0280] Step 1) Preparation of tert-butyl 4-(4-((3-ethoxy-3-oxopropyl)amino)phenyl)piperazine-1-carboxylate

[0281] 43.6 mL (285.72 mmol) of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) was diluted in 300 mL of diethyl ether, and 25.0 mL (285.72 mmol) of lactic acid was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 21 hours. The resulting reaction mixture was distilled under reduced pressure and diluted in 500 mL of 1,4-dioxane. 31.7 g (114.29 mmol) of tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate and 30.7 mL (285.72 mmol) of ethyl acrylate were added, and the reaction mixture was stirred at 110°C for 23 hours. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4:1 (volume ratio)) to obtain 24.3 g (yield: 56%) of the title compound.

[0282] 1 H-NMR (300 MHz, CDCl3): δ6.84 (m, 2H), 6.60 (m, 2H), 4.15 (q, 2H), 3.80 (brs, 1H), 3.55 (m, 4H), 3.40 (t, 2H), 2.96 (m, 4H), 2.58 (t, 2H), 1.48 (s, 9H), 1.26 (t, 3H).

[0283] Step 2) Preparation of tert-butyl 4-(4-(N-(3-ethoxy-3-oxopropyl)cyanamido)phenyl)piperazine-1-carboxylate

[0284] 24.3 g (63.37 mmol) of the compound prepared in the above step 1) was diluted in 450 mL of tetrahydrofuran, and 14.1 g (128.75 mmol) of cyanogen bromide and 32.8 g (386.25 mmol) of sodium bicarbonate were added. The resulting reaction mixture was stirred at room temperature under a nitrogen atmosphere for 23 hours, and upon completion of the reaction, it was diluted with ethyl acetate and washed with distilled water. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 9: 1 (volume ratio)) to obtain 24.5 g (yield: 94%) of the title compound.

[0285] 1 H-NMR (300 MHz, CDCl3): δ7.09 (m, 2H), 6.92 (m, 2H), 4.17 (m, 2H), 3.85 (t, 2H), 3.57 (m, 4H), 3.07 (m, 4H), 2.78 (t, 2H), 1.48 (s, 9H), 1.26 (t, 3H).

[0286] Step 3) Preparation of tert-butyl 4-(4-(1-(3-ethoxy-3-oxopropyl)ureido)phenyl)piperazine-1-carboxylate

[0287] 24.5 g (60.87 mmol) of the compound prepared in the above step 2) was diluted in 400 mL of toluene, and 11.2 mL (182.61 mmol) of acetaldoxime and 4.0 g (18.26 mmol) of anhydrous indium(III) chloride were added. The resulting reaction mixture was stirred at 130°C for 1 hour and 30 minutes, and upon completion of the reaction, it was cooled to room temperature, diluted with ethyl acetate, and washed three times with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 19: 1 (volume ratio)) to obtain 16.6 g (yield: 65%) of the title compound.

[0288] 1 H-NMR (300 MHz, CDCl3): δ7.13 (m, 2H), 6.92 (m, 2H), 4.29 (brs, 2H), 4.17 (q, 2H), 3.92 (t, 2H), 3.58 (m, 4H), 3.15 (m, 4H), 2.56 (t, 2H), 1.48 (s, 9H), 1.28 (t, 3H).

[0289] Step 4) Preparation of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate

[0290] 16.6 g (39.38 mmol) of the compound prepared in the above step 3) was diluted in 170 mL of acetonitrile, 26.8 mL (59.1 mmol) of benzyltrimethylammonium hydroxide (40% methanol solution) was added, and the resulting reaction mixture was stirred at 90°C for 30 minutes. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed twice with distilled water. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. 11.6 g (yield: 79%) of the title compound was obtained.

[0291] 1H-NMR (300 MHz, DMSO-d6): δ10.26 (s, 1H), 7.14 (d, 2H), 6.95 (d, 2H), 3.69 (t, 2H), 3.46 (m, 4H), 3.08 (m, 4H), 2.68 (t, 2H), 1.42 (s, 9H).

[0292] Step 5) Preparation of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; hydrochloride

[0293] 5.0 g (13.35 mmol) of the compound prepared in the above step 4) was diluted in 70 mL of dichloromethane, and 35 mL (133.53 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure and washed with dichloromethane to obtain 4.1 g (yield: 98%) of the title compound.

[0294] 1 H-NMR (300 MHz, DMSO-d6): δ10.28 (s, 1H), 9.06 (brs, 2H), 7.21 (d, 2H), 6.99 (d, 2H), 3.71 (t, 2H), 3.36 (m, 4H), 3.22 (m, 4H), 2.68 (t, 2H).

[0295] Step 6) Preparation of tert-butyl 4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0296] 2.0 g (6.44 mmol) of the compound prepared in the above step 5) and 2.1 g (9.65 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 40 mL of N,N-dimethylacetamide, and 0.81 mL (14.16 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 30 minutes, and 6.8 g (32.18 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mass was stirred at room temperature for 2 hours, and when the reaction was completed, a saturated aqueous sodium bicarbonate solution was slowly added, followed by stirring for 1 hour. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 2.2 g (yield: 74%) of the title compound.

[0297] 1 H-NMR (300 MHz, DMSO-d6): δ10.24 (s, 1H), 7.16 (d, 2H), 6.94 (d, 2H), 3.93 (m, 2H), 3.71 (t, 2H), 2.70 (m, 4H), 2.46 (m, 2H), 2.16 (d, 2H), 1.70 (m, 3H), 1.38 (s, 9H), 0.98 (m, 2H).

[0298] Step 7) Preparation of 1-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; hydrochloride

[0299] 2.2 g (4.77 mmol) of the compound prepared in step 6) above was diluted in 50 mL of dichloromethane, and 12 mL (47.71 mmol) of 4N-hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure and washed with dichloromethane. The resulting solid was dried under reduced pressure to obtain 2.1 g (final yield: 99%) of the title compound.

[0300] 1H-NMR (300 MHz, DMSO-d6): δ10.71 (brs, 1H), 10.24 (s, 1H), 8.85 (m, 2H), 7.23 (d, 2H), 7.03 (d, 2H), 3.77 (m, 4H), 3.61 (m, 1H), 3.62 (m, 1H), 3.27 (m, 4H), 3.10 (m, 4H), 2.88 (m, 2H), 2.71 (m, 2H), 2.08 (m, 2H), 1.38 (m, 2H);

[0301] MS (ESI + ):m / z= 372.23 [M+H] + .

[0302] Manufacturing Example 2: Manufacturing of (S)-1-(4-((5-amino-3-methylpentyl)amino)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0303]

[0304] Step 1) Preparation of tert-butyl (4-nitrophenyl)carbamate

[0305] 20.0 g (144.79 mmol) of 4-nitroaniline was diluted in 300 mL of dichloromethane, and 61.2 mL (434.37 mmol) of triethylamine and 8.9 g (72.396 mmol) of 4-dimethylaminopyridine (DMAP) were added. The resulting reaction mixture was stirred at room temperature for 10 minutes, cooled to 0°C, and 50.4 mL (217.19 mmol) of di-tert-butyl dicarbonate was added. The resulting reaction mixture was stirred at room temperature for 3 hours, and upon completion of the reaction, it was distilled and washed with saturated brine and extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4:1 (volume ratio)) to obtain 18.0 g (yield: 52%) of the title compound.

[0306] Step 2) Preparation of tert-butyl (4-aminophenyl)carbamate

[0307] 18.0 g (75.55 mmol) of the compound prepared in the above step 1) was diluted in 270 mL of ethyl acetate and degassed under nitrogen gas for 10 minutes. Then, 2.7 g (0.15 v / w) of 10% Pd / C was added and degassed under hydrogen gas for 10 minutes. The resulting reaction mixture was stirred at room temperature under hydrogen gas for 24 hours. Upon completion of the reaction, the resulting filtrate was filtered under reduced pressure, washed with ethyl acetate through a Celite-filled filter, and the resulting filtrate was distilled under reduced pressure to obtain 15.7 g (yield: 99%) of the title compound.

[0308] Step 3) Preparation of ethyl 3-((4-((tert-butoxycarbonyl)amino)phenyl)amino)propanoate

[0309] 28.8 mL (188.47 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was diluted in 150 mL of ether, and 16.5 mL (188.47 mmol) of lactic acid was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 21 hours. The resulting reaction mixture was distilled under reduced pressure and diluted in 300 mL of 1,4-dioxane. 15.7 g (75.39 mmol) of the compound prepared in step 2) and 20.3 mL (188.47 mmol) of ethyl acrylate were added, and the reaction mixture was stirred at 110°C for 23 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4:1 (volume ratio)) to obtain 12.7 g (yield: 54%) of the title compound.

[0310] 1H-NMR (300 MHz, CDCl3): δ7.14 (d, 2H), 6.56 (d, 2H), 6.26 (brs, 1H), 4.14 (q, 2H), 3.90 (brs, 1H), 3.40 (t, 2H), 2.57 (t, 2H), 1.49 (s, 9H), 1.25 (t, 3H).

[0311] Step 4) Preparation of ethyl 3-(1-(4-((tert-butoxycarbonyl)amino)phenyl)ureido)propanoate

[0312] 12.7 g (41.05 mmol) of the compound prepared in the above step 3) was diluted in 100 mL of acetic acid, 4.16 g (49.26 mmol) of potassium cyanate was added, and the resulting reaction mixture was stirred at room temperature for 6 hours. Upon completion of the reaction, the mixture was distilled under reduced pressure, diluted in 100 mL of acetonitrile, and distilled under reduced pressure again. The resulting residue was diluted in MTBE, stirred for 1 hour, filtered under reduced pressure, and washed with MTBE. The resulting solid was dried under reduced pressure to obtain 14.4 g (yield: 99%) of the title compound.

[0313] 1 H-NMR (300 MHz, DMSO-d6): δ9.44 (s, 1H), 7.45 (d, 2H), 7.08 (d, 2H), 5.45 (brs, 1H), 3.94 (q, 2H), 3.69 (t, 2H), 2.40 (t, 2H), 1.46 (s, 9H), 1.10 (t, 3H).

[0314] Step 5) Preparation of 1-(4-aminophenyl)dihydropyrimidine-2,4(1H,3H)-dione; hydrochloride

[0315] 14.4 g (41.04 mmol) of the compound prepared in the above step 4) was added to 125 mL of concentrated hydrochloric acid, and the resulting reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the mixture was distilled under reduced pressure, diluted in 75 mL of acetonitrile, and the resulting mixture was washed with acetonitrile and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 8.6 g (yield: 87%) of the title compound.

[0316] 1 H-NMR (300 MHz, DMSO-d6): δ10.40 (s, 1H), 7.38 (m, 4H), 7.08 (d, 2H), 3.78 (t, 2H), 2.69 (t, 2H).

[0317] Step 6) Preparation of (S)-3,7-dimethyloct-6-enal

[0318] 348.2 g (796.44 mmol) of Dess-Martin periodinane was diluted in 1500 mL of dichloromethane, and 116.8 mL (627.12 mmol) of (3S)-3,7-dimethyloct-6-en-1-ol was added dropwise. The resulting reaction mixture was stirred at room temperature for 5 hours. When the reaction was complete, it was slowly added to 3 L of a saturated aqueous sodium bicarbonate solution, and the resulting solid was removed by filtration under reduced pressure and washed with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 9: 1 (volume ratio)) to obtain 72.0 g (yield: 75%) of the title compound.

[0319] 1 H-NMR (300 MHz, DMSO-d6): δ9.65 (t, 1H), 5.09 (tt, 1H), 2.50 (m, 1H), 2.48 (m, 1H), 2.31 (m, 1H), 1.91 (m, 3H), 1.42 (d, 6H), 1.18 (m, 2H), 0.88 (d, 3H).

[0320] Step 7) Preparation of (S)-3,7-dimethyloct-6-enoic acid

[0321] Sodium hydroxide (96.4 g, 2336.80 mmol) was diluted in 500 mL of distilled water, and 198.9 g (1168.40 mmol) of silver nitrate diluted in 500 mL of distilled water was added dropwise at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes in a light-shielded environment, and then the compound prepared in step 6) (1.00 eq, 72.09 g, 467.36 mmol) was added dropwise at the same temperature. The resulting reaction mixture was stirred at room temperature for 16 hours in a light-shielded environment. Upon completion of the reaction, it was filtered under reduced pressure and washed with hot distilled water. The resulting filtrate was acidified (pH~1) with concentrated hydrochloric acid. The resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 79.5 g (yield: 99%) of the title compound.

[0322] 1 H-NMR (300 MHz, DMSO-d6): δ5.07 (tt, 1H), 2.18 (m, 1H), 1.96 (m, 3H), 1.77 (m, 1H), 1.65 (d, 6H), 1.48 (m, 2H), 1.34 (t, 1H), 0.88 (d, 3H).

[0323] Step 8) Preparation of methyl (S)-3,7-dimethyloct-6-enoate

[0324] 79.5 g (466.96 mmol) of the compound prepared in the above step 7) was diluted in 1.6 L of acetone, and 259.4 g (1867.80 mmol) of potassium carbonate and 290.7 mL (4669.60 mmol) of methyl iodide were added. The resulting reaction product was stirred at 60°C for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with distilled water, and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 79.4 g (yield: 92%) of the title compound.

[0325] 1 H-NMR (300 MHz, DMSO-d6): δ5.08 (tt, 1H), 3.66 (s, 3H), 2.28 (m, 1H), 2.15 (m, 1H), 1.96 (m, 3H), 1.63 (d, 6H), 1.34 (m, 2H), 0.88 (d, 3H).

[0326] Step 9) Preparation of (S)-6-methoxy-4-methyl-6-oxohexanoic acid

[0327] The compound 39.5 g (214.35 mmol) prepared in the above step 8) was diluted in 1.4 L of a 1,2-dichloroethane : distilled water = 1:1 (volume ratio) solution, and 1.4 g (6.64 mmol) of ruthenium chloride hydrate and 137.5 g (643.04 mmol) of sodium periodate were slowly added. The resulting reaction mixture was stirred at room temperature for 18 hours. When the reaction was complete, a 2 M hydrochloric acid aqueous solution was added dropwise until the pH became 1 to 2. The resulting mixture was extracted twice with dichloromethane, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was diluted with ethyl acetate and extracted twice with a saturated sodium bicarbonate aqueous solution. Concentrated hydrochloric acid was added dropwise to the resulting aqueous layer until the pH became 1, and then extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 34.6 g (yield: 93%) of the title compound.

[0328] 1 H-NMR (300 MHz, DMSO-d6): δ12.03 (brs, 1H), 3.58 (s, 3H), 2.32 (m, 1H), 2.27 (m, 2H), 2.14 (m, 1H), 1.84 (m, 1H), 1.57 (m, 1H), 1.54 (m, 1H), 0.88 (d, 3H).

[0329] Step 10) Preparation of methyl (S)-5-((tert-butoxycarbonyl)amino)-3-methylpentanoate

[0330] 34.6 g (198.45 mmol) of the compound prepared in the above step 9) was diluted in 1.6 L of tertiary butyl alcohol, and 52.8 mL (238 mmol) of diphenylphosphoryl azide and 41.9 mL (297.68 mmol) of triethylamine were added. The resulting reaction product was stirred under reflux at 110°C for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to 1 / 3 of the volume. The reaction was quenched with a saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 20.4 g (yield: 41%) of the title compound.

[0331] 1 H-NMR (300 MHz, CDCl3): δ4.53 (brs, 1H), 3.67 (s, 3H), 3.18 (m, 2H), 2.30 (m, 1H), 2.20 (m, 1H), 2.01 (m, 1H), 1.55 (m, 2H), 1.42 (s, 9H), 0.94 (d, 3H).

[0332] Step 11) Preparation of tert-butyl (S)-(5-hydroxy-3-methylpentyl)carbamate

[0333] The compound prepared in step 10) above was diluted in 400 mL of tetrahydrofuran, cooled to 0°C, and 70 mL (166.31 mmol) of a 2.4 M tetrahydrofuran solution of lithium aluminum hydride was added dropwise under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 30 minutes. When the reaction was completed, a saturated aqueous ammonium chloride solution was added dropwise at the same temperature. The resulting mixture was extracted with ethyl acetate and washed twice with a 30% aqueous solution of sodium potassium tartrate and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 5.0 g (yield: 28%) of the title compound.

[0334] 1 H-NMR (300 MHz, CDCl3): δ4.52 (brs, 1H), 3.69 (m, 2H), 3.25 (m, 1H), 3.06 (m, 1H), 1.65 (m, 3H), 1.42 (s, 9H), 1.35 (m, 2H), 0.94 (d, 3H).

[0335] Step 12) Preparation of (S)-5-((tert-butoxycarbonyl)amino)-3-methylpentyl 4-methylbenzenesulfonate

[0336] 3.5 g (16.06 mmol) of the compound prepared in the above step 11) was diluted in 70 mL of dichloromethane, and 9.0 mL (64.24 mmol) of triethylamine and 9.3 g (48.18 mmol) of 4-toluenesulfonyl chloride were added. The resulting reaction mixture was stirred at room temperature for 17 hours. Upon completion of the reaction, the reaction mixture was washed with distilled water and extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 4.2 g (yield: 71%) of the title compound.

[0337] 1 H-NMR (300 MHz, CDCl3): δ7.78 (d, 2H), 7.35 (d, 2H), 4.44 (brs, 1H), 4.07 (m, 2H), 3.17~2.98 (m, 2H), 2.45 (s, 3H), 1.74~1.44 (m, 3H), 1.41 (s, 9H), 1.40-1.37 (m, 2H), 0.85 (d, 3H).

[0338] Step 13) Preparation of tert-butyl (R)-(5-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)amino)-3-methylpentyl)carbamate

[0339] In step 12), 895 mg (2.41 mmol) of the compound prepared was diluted in 20 mL of acetone, and 819 mg (5.38 mmol) of sodium iodide was added. The resulting reaction mixture was stirred at 60°C for 2 hours, and then the solid was removed by filtration under reduced pressure. The resulting filtrate was distilled under reduced pressure, diluted in 20 mL of N-methylpyrrolidone, and 781 mg (3.23 mmol) of the compound prepared in step 5) and 1.9 mL (10.89 mmol) of N,N-diisopropylethylamine were added. The resulting reaction mixture was stirred at 120°C for 18 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed five times with distilled water, and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 212 mg (yield: 19%) of the title compound.

[0340] 1 H-NMR (300 MHz, CDCl3): δ7.07 (d, 2H), 6.59 (d, 2H), 3.78 (t, 2H), 3.11 (m, 3H), 2.80 (t, 3H), 1.65 (m, 1H), 1.45 (s, 9H), 1.44~1.20 (m, 4H), 0.96 (d, 3H), 0.79 (m, 1H).

[0341] Step 14) Preparation of (S)-1-(4-((5-amino-3-methylpentyl)amino)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; hydrochloride

[0342] 212 mg (0.52 mmol) of the compound prepared in step 13) above was diluted in 4 mL of dichloromethane, and 1.3 mL (5.24 mmol) of 4N-hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure and washed with dichloromethane. The resulting solid was dried under reduced pressure to obtain 178 mg (final stage yield: 99%) of the title compound.

[0343] MS (ESI + ):m / z= 305.19 [M+H] + .

[0344] Manufacturing Example 3: Manufacturing of 3-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione hydrochloride

[0345]

[0346] Step 1) Preparation of tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate

[0347] 30 g (121.93 mmol) of 1-(4-bromophenyl)piperazine was diluted in 900 mL of dichloromethane, and 25.75 mL (182.89 mmol) of triethylamine was added at room temperature, followed by dropwise addition of 31.12 mL (134.12 mmol) of di-tert-butyl dicarbonate. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was stirred in hexane and then filtered under reduced pressure to obtain 39.35 g (yield: 95%) of the title compound.

[0348] 1H-NMR (300 MHz, CDCl3): δ7.35~7.30 (m, 2H), 6.79~6.73 (m, 2H), 3.56~3.52 (m, 4H), 3.09~3.05 (m, 4H), 1.46 (s, 9H).

[0349] Step 2) Preparation of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate

[0350] 39.35 g (109.55 mmol) of the compound prepared in the above step 1) and 42.58 g (164.32 mmol) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), 38.79 g (383.41 mmol) of potassium acetate, and 4.56 g (5.48 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex were diluted in 800 mL of 1,4-dioxane and stirred under reflux at 110°C for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate on a Celite-filled filter, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 50:1 (volume ratio)) to obtain 41.6 g of the title compound (yield: 98%).

[0351] 1 H-NMR (300 MHz, CDCl3): δ7.73~7.70 (m, 2H), 6.90~6.87 (m, 2H), 3.59~3.55 (m, 4H), 3.24~3.20 (m, 4H), 1.46 (s, 9H), 1.33 (s, 12H).

[0352] Step 3) Preparation of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate

[0353] 32.08 g (86.66 mmol) of 2,6-bis(benzyloxy)-3-bromopyridine, 40.38 g (103.99 mmol) of the compound prepared in step 2) above, and 30.35 g (219.62 mmol) of potassium carbonate were diluted in 660 mL of 1,4-dioxane:water=5:1 and stirred for 10 minutes under a nitrogen atmosphere. 3.61 g (4.33 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex was added and stirred at 100°C for 18 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate on a Celite-packed filter, filtered under reduced pressure, and the resulting filtrate was washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 40:1 (volume ratio)) to obtain 24.6 g (yield: 51%) of the title compound.

[0354] 1 H-NMR (300 MHz, CDCl3): δ7.50~7.23 (m, 13H), 6.94~6.90 (m, 2H), 6.45~6.41 (m, 1H), 5.41 (s, 2H), 5.34 (s, 2H), 3.59~3.56 (m, 4H), 3.17~3.13 (m, 4H), 1.48 (s, 9H).

[0355] Step 4) Preparation of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate

[0356] 24.6 g (44.59 mmol) of the compound prepared in step 3) above was diluted in 750 mL of ethanol and stirred for 10 minutes under a nitrogen atmosphere. 23.72 g (22.30 mmol) of 10% Pd / C and 0.53 g (2.23 mmol) of platinum (IV) oxide were added and stirred for 12 hours under a hydrogen atmosphere (70 psi). Upon completion of the reaction, the mixture was washed with ethyl acetate through a Celite-filled filter and filtered under reduced pressure. The filtrate was distilled under reduced pressure. The obtained solid was stirred in MTBE and then filtered under reduced pressure to obtain 13.3 g (yield: 80%) of the title compound.

[0357] 1 H-NMR (300 MHz, DMSO-d6): δ10.75 (bs, 1H), 7.06~7.04 (m, 2H), 6.91~6.88 (m, 2H), 3.74~3.69 (m, 1H), 3.45~3.42 (m, 4H), 3.07~3.03 (m, 4H), 2.67~2.56 (m, 1H), 2.42~2.39 (m, 1H), 2.18~2.00 (m, 2H), 1.47 (s, 9H).

[0358] Step 5) Preparation of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione; hydrochloride

[0359] 13.3 g (35.61 mmol) of the compound prepared in the above step 4) was diluted in 130 mL of dichloromethane, 89 mL (356.14 mmol) of 4N-hydrochloric acid was slowly added dropwise at room temperature, and the mixture was stirred for 2 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 11.03 g (yield: 99%) of the title compound.

[0360] Step 6) Preparation of tert-butyl 4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0361] 9.7 g (35.49 mmol) of the compound prepared in the above step 5) and 11.71 g (53.23 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 200 mL of N,N-dimethylacetamide, 4.49 mL (78.07 mmol) of acetic acid was added, and the mixture was stirred at room temperature for 30 minutes. 45.13 g (212.92 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 4 hours. When the reaction was complete, a saturated aqueous sodium bicarbonate solution and water were added to produce a solid, which was stirred at room temperature for 16 hours. The produced solid was washed with water and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 12.6 g (yield: 75%) of the title compound.

[0362] 1 H-NMR (300 MHz, CDCl3): δ8.17 (bs, 1H), 7.09~7.06 (m, 2H), 6.91~6.87 (m, 2H), 4.10~4.06 (m, 2H), 3.73~3.68 (m, 1H), 3.18~3.15 (m, 4H), 2.75~2.57 (m, 4H), 2.26~2.16 (m, 4H), 1.76~1.61 (m, 4H), 1.45 (s, 9H), 1.15~1.00 (m, 2H).

[0363] Step 7) Preparation of 1-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4-(1H,3H)-dione; hydrochloride

[0364] 12.6 g (26.77 mmol) of the compound prepared in the above step 6) was diluted in 130 mL of dichloromethane, and 67 mL (267.74 mmol) of 4N-hydrochloric acid was slowly added dropwise at room temperature, followed by stirring for 4 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 11.87 g of the title compound (final yield: 99%).

[0365] MS (ESI + ):m / z= 372.23 [M+H] + .

[0366] Manufacturing Example 4: Manufacturing of 3-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione hydrochloride

[0367]

[0368] Step 1) Preparation of (1-(4-bromophenyl)-4-piperidyl)methanol

[0369] 39 g (134.75 mmol) of 1-bromo-4-iodo-benzene and 20 g (168.43 mmol) of 4-piperidylmethanol were diluted in 200 mL of dimethyl sulfoxide, and 53.6 g (253 mmol) of potassium phosphate tribasic was added. The mixture was stirred for 20 minutes under a nitrogen atmosphere. 2.9 g (25.3 mmol) of L-proline and 5.1 g (25.3 mmol) of copper iodide were added, and the mixture was stirred at 80°C for 4 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, water was added, and a solid was formed. The mixture was stirred at room temperature for 30 minutes. The formed solid was washed with water and filtered under reduced pressure. The resulting solid was stirred in ethyl acetate and filtered under reduced pressure to obtain 32.99 g (yield: 73%) of the title compound.

[0370] Step 2) Preparation of (1-(4-bromophenyl)piperidin-4-yl)methanol

[0371] 22.3 g (82.54 mmol) of the compound prepared in the above step 1) was diluted in 500 mL of dichloromethane, and 136.1 g (288.89 mmol) of Dess-Martin periodinane was added at 0°C, followed by stirring at 25°C for 1 hour. When the reaction was complete, a saturated aqueous sodium sulfite solution was added to the reaction mixture to quench the reaction, and the mixture was extracted twice with dichloromethane. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 9: 1 (volume ratio)) to obtain 9.0 g (yield: 41%) of the title compound.

[0372] 1 H-NMR (300 MHz, CDCl3): δ9.73 (s, 1H), 7.36 (d, 2H), 6.82 (d, 2H), 3.62~3.55 (m, 2H), 2.92~2.82 (m, 2H), 2.44~2.40 (m, 1H), 1.86~1.81 (m, 2H), 1.35~1.24 (m, 2H), 0.93~0.85 (m, 2H)

[0373] Step 3) Preparation of tert-butyl 4-((1-(4-bromophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0374] 9.0 g (33.56 mmol) of the compound prepared in the above step 2) and 5.0 g (26.31 mmol) of tert-butyl piperazine-1-carboxylate were diluted in 150 mL of N,N-dimethylacetamide, 3.7 mL (64.28 mmol) of acetic acid was added, and the mixture was stirred at room temperature for 30 minutes. 16.7 g (78.92 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, a saturated aqueous sodium bicarbonate solution and water were added, washed, and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 5:1 (volume ratio)) to obtain 7.4 g (yield: 64%) of the title compound.

[0375] Step 4) Preparation of tert-butyl 4-((1-(4-(2,6-bis(benzyloxy)pyridin-3-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0376] 5.2 g (11.86 mmol) of the compound prepared in the above step 3), 7.42 g (17.79 mmol) of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and 11.59 g (35.58 mmol) of potassium carbonate were diluted in 50 mL of 1,4-dioxane:water=4:1, and stirred for 10 minutes under a nitrogen atmosphere. 0.97 g (1.18 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex was added, and the mixture was stirred at 100°C for 15 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the resulting filtrate was washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The residue thus obtained was separated by column chromatography (hexane: ethyl acetate = 7:1 (volume ratio)) to obtain 3.2 g (yield: 41%) of the title compound.

[0377] 1 H-NMR (300 MHz, DMSO-d6): δ7.69 (d, 1H), 7.45~2.31 (m, 12H), 6.91 (dd, 2H), 6.51 (d, 1H), 6.51 (d, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 3.73~3.63 (m, 2H), 3.38~3.26 (m, 2H), 3.08~2.91 (m, 1H), 2.70~2.65 (m, 2H), 2.32~2.25 (t, 5H), 2.20~2.12 (m, 2H), 1.83~1.65 (m, 4H), 1.39 (s, 9H) 1.30~1.25 (m, 1H).

[0378] Step 5) Preparation of tert-butyl 4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0379] 3.2 g (4.93 mmol) of the compound prepared in the above step 4) was diluted in 40 mL of tetrahydrofuran and stirred for 10 minutes under a nitrogen atmosphere. 5.2 g (4.93 mmol) of activated 10% Pd / C was added and stirred for 14 hours under a hydrogen atmosphere. Upon completion of the reaction, the mixture was filtered under reduced pressure, washed with ethyl acetate through a Celite-filled filter, and the filtrate was distilled under reduced pressure to obtain 1.0 g (yield: 43%) of the title compound.

[0380] 1 H-NMR (300 MHz, CDCl3): δ7.12 (d, 2H), 6.95 (d, 2H), 3.81~3.672 (m, 3H), 3.50~3.41 (t, 4H) 2.78~2.69 (m, 4H), 2.42~2.31 (t, 4H), 2.29~2.21 (m, 4H), 1.92~1.84 (m, 2H), 1.70~1.57 (m, 4H), 1.49 (s, 9H).

[0381] Step 6) Preparation of 3-(4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)piperidine-2,6-dione; hydrochloride

[0382] 1.0 g (2.15 mmol) of the compound prepared in step 5) above was diluted in 1 mL of dichloromethane, and 6 mL (24.0 mmol) of 4N-hydrochloric acid was slowly added dropwise at room temperature, followed by stirring for 2 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 0.85 g (final yield: 99%) of the title compound.

[0383] 1H-NMR (300 MHz, DMSO-d6): δ10.87 (s, 1H), 7.59 (d, 2H), 7,34 (d, 2H), 4.00~3.91 (m, 2H), 3.52~3.44 (m, 8H), 3.28~3.12 (m, 3H), 3.08~2.91 (m, 1H), 2.78~2.67 (m, 1H), 2.63~2.59 (t, 2H), 2.40~2.33 (m, 4H), 2.21 (d, 1H), 1.82~1.78 (m, 2H)

[0384] MS (ESI + ):m / z= 406.21 [M+H] + .

[0385] Manufacturing Example 5: Manufacturing of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)benzamide hydrochloride

[0386]

[0387] Step 1) Preparation of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0388] 37.5 g (161.07 mmol) of methyl 4-bromo-2-fluoro-benzoate and 30 g (161.07 mmol) of tert-butyl piperazine-1-carboxylate were dissolved in 300 mL of toluene, and 1.7 g (16.11 mmol) of palladium (II) acetate, 20.1 g (32.22 mmol) of (±)-2,2-bis(diphenylphosphino)-1,1-binaphthalene, and 157.4 g (483.22 mmol) of cesium carbonate were added, and the mixture was stirred at 80°C for 18 hours. When the reaction was complete, the reaction mixture was washed with ethyl acetate in a hot state through a Celite-packed filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2:1 (volume ratio)) to obtain 14.0 g (yield: 26%) of the title compound.

[0389] 1H-NMR (300 MHz, CDCl3): δ7.85 (m, 1H), 6.64 (m, 1H), 6.50 (m, 1H), 3.90 (s, 3H), 3.61 (m, 4H), 3.33 (m, 4H), 1.50 (s, 9H).

[0390] Step 2) Preparation of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

[0391] 14 g (41.37 mmol) of the compound prepared in the above step 1) was diluted with 42 mL of methanol: tetrahydrofuran: distilled water (1:1:1 (volume ratio)), 3.5 g (82.75 mmol) of lithium hydroxide was added, and the mixture was stirred at room temperature for 14 hours. Upon completion of the reaction, the reaction mixture was cooled to 0°C and acidified with 1 N aqueous hydrochloric acid (pH 3-4). The obtained solid was filtered under reduced pressure and dried under reduced pressure to obtain 15.2 g (yield: 72%) of the title compound.

[0392] 1 H-NMR (300 MHz, DMSO-d6): δ7.69 (t, 1H), 6.72 (m, 2H), 3.44 (m, 4H), 3.27 (m, 4H), 1.42 (s, 9H).

[0393] Step 3) Preparation of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidine-1-carboxylate

[0394] 15.2 g (48.86 mmol) of the compound prepared in the above step 2) and 9.4 g (56.24 mmol) of 3-aminopiperidine-2,6-dione hydrochloride were diluted in 304 mL of N,N-dimethylformamide, and 26.7 g (70.29 mmol) of (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) and 24.5 mL (140.59 mmol) of N,N-diethylisopropylamine were added, and the mixture was stirred at room temperature for 14 hours. When the reaction was complete, water was added, and the resulting solid was filtered under reduced pressure and dried under reduced pressure to obtain 19.1 g (yield: 94%) of the title compound.

[0395] Step 4) Preparation of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)benzamide; hydrochloride

[0396] Except for using the compound prepared in step 3) instead of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate in step 5) of the above Preparation Example 1, the same process as steps 5), 6), and 7) of the above Preparation Example 1 was performed sequentially to obtain 12.3 g of the title compound (final yield: 76%).

[0397] MS (ESI + ):m / z= 468.21 [M+H] + .

[0398] Manufacturing Example 6: Manufacturing of 3-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0399]

[0400] Step 1) Preparation of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate

[0401] 35.4 g (161.07 mmol) of 1-bromo-2-fluoro-4-nitrobenzene and 30.0 g (161.07 mmol) of tert-butyl piperazine-1-carboxylate were diluted in 600 mL of N,N-dimethylformamide, 67.4 mL (483.22 mmol) of triethylamine was added, and the mixture was stirred at 100°C for 12 hours. Upon completion of the reaction, water was added, and the resulting solid was filtered under reduced pressure and dried under reduced pressure to obtain 51 g (yield: 97%) of the title compound.

[0402] 1 H-NMR (300 MHz, CDCl3): δ8.00 (m, 2H), 6.94 (t, 1H), 3.63 (m, 4H), 3.27 (m, 4H), 1.51 (s, 9H).

[0403] Step 2) Preparation of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate

[0404] 51 g (156.76 mmol) of the compound prepared in the above step 1) was diluted in 510 mL of tetrahydrofuran: methanol (1:1, volume ratio), 51.3 (783.8 mmol) of zinc and 83.9 g (1567.6 mmol) of ammonium chloride were added, and the mixture was stirred at 45°C for 12 hours. After the reaction was completed, the reaction mixture was filtered through a Celite-filled filter to remove zinc, and the resulting filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4:1 (volume ratio)) to obtain 33.1 g (yield: 72%) of the title compound.

[0405] 1 H-NMR (300 MHz, DMSO-d6): δ6.78 (m, 1H), 6.32 (m, 2H), 5.01 (s, 2H), 3.44 (m, 4H), 2.76 (m, 4H), 1.42 (s, 9H).

[0406] Step 3) Preparation of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate

[0407] 15 g (50.79 mmol) of the compound prepared in the above step 2) and 24.4 g (126.96 mmol) of 3-bromopiperidine-2,6-dione were diluted in 150 mL of N,N-dimethylformamide, 26.5 mL (152.36 mmol) of N,N-diethylisopropylamine were added, and the mixture was stirred at 80°C for 14 hours. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 1: 1 (volume ratio)) to obtain 17.0 g (yield: 82%) of the title compound.

[0408] 1 H-NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 6.85 (t, 1H), 6.55 (m, 1H), 6.44 (m, 1H), 5.84 (d. 1H), 4.29 (m, 1H), 3.44 (m, 4H), 2.79 (m, 4H), 2.21~1.86 (m, 4H), 1.42 (s, 9H).

[0409] Step 4) Preparation of 3-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; hydrochloride

[0410] Except for using the compound prepared in step 3) instead of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate in step 5) of the above Preparation Example 1, the same process as steps 5), 6), and 7) of the above Preparation Example 1 was performed sequentially to obtain 7.2 g of the title compound (final yield: 76%).

[0411] MS (ESI +):m / z= 440.22 [M+H] + .

[0412] Manufacturing Example 7: Manufacturing of 3-(1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride

[0413]

[0414] Step 1) Preparation of 6-bromo-3-iodo-1H-indazole

[0415] 6-Bromo-1H-indazole 10.0 g (49.74 mmol) was diluted in 150 mL of tetrahydrofuran, and 11.4 g (99.47 mmol) of potassium tert-butoxide was slowly added at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes. Iodine 38.2 g (149.21 mmol) was diluted in 80 mL of tetrahydrofuran, and added dropwise to the reaction mixture at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour and 30 minutes. When the reaction was complete, it was diluted in 1 L of dichloromethane, and 700 mL of a saturated sodium thiosulfate aqueous solution was added. The resulting organic layer was separated, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 16.1 g (yield: 99%) of the title compound.

[0416] 1 H-NMR (300 MHz, CDCl3): δ13.60 (brs, 1H), 7.81 (s, 1H), 7.41~7.30 (dd, 2H).

[0417] Step 2) Preparation of 6-bromo-3-iodo-1-methyl-1H-indazole

[0418] 16.1 g (49.73 mmol) of the compound prepared in the above step 1) was diluted in 100 mL of acetone, and 7.5 g (124.33 mmol) of potassium hydroxide was slowly added at 20°C, stirred for 20 minutes, and then 4.7 mL (74.60 mmol) of methyl iodide was added dropwise. The resulting reaction mixture was stirred at 20°C for 5 hours. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure to remove the solid and washed with acetone. The filtrate was distilled under reduced pressure, and the residue was diluted with ethyl acetate and washed with distilled water. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 10: 1 (volume ratio)) to obtain 11.9 g (yield: 71%) of the title compound.

[0419] 1 H-NMR (300 MHz, DMSO-d6): δ8.04 (s, 1H), 7.36 (q, 2H), 4.05 (s, 3H).

[0420] Step 3) Preparation of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0421] 12.8 g (30.58 mmol) of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 10.0 g (29.68 mmol) of the compound prepared in step 2) above were diluted in 150 mL of tetrahydrofuran and 25 mL of distilled water, and 24.4 g (74.19 mmol) of cesium carbonate and 1.2 g (1.48 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex were added. The resulting reaction mixture was stirred at 60°C for 14 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with distilled water, and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 10:1 (volume ratio)) to obtain 6.4 g (yield: 43%) of the title compound.

[0422] 1 H-NMR (300 MHz, CDCl3): δ7.87 (d, 1H), 7.55 (m, 2H), 7.54~7.27 (m, 10H), 7.08 (m, 1H), 6.52 (d, 1H), 5.43 (d, 4H), 4.06 (s, 3H).

[0423] Step 4) Preparation of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0424] 6.4 g (12.7 mmol) of the compound prepared in the above step 3), 3.6 g (19.12 mmol) of tert-butyl piperazine-1-carboxylate, and 12.6 g (38.25 mmol) of cesium carbonate were diluted in 120 mL of 1,4-dioxane and degassed under nitrogen gas for 10 minutes, and then 2.2 g (2.55 mmol) of Ruphos Pd G3 and 2756 mg (1.27 mmol) of Pd(dba) were added. The resulting reaction mixture was stirred at 100°C for 18 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate on a Celite-packed filter, filtered under reduced pressure, washed with distilled water, and extracted with ethyl acetate. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6:1 (volume ratio)) to obtain 3.7 g (yield: 48%) of the title compound.

[0425] 1 H-NMR (300 MHz, CDCl3): δ7.92 (s, 1H), 7.59 (d, 1H), 7.45~7.27 (m, 10H), 6.79 (d, 1H), 6.65 (brs, 1H), 6.50 (d, 1H), 5.43 (d, 4H), 4.03 (s, 3H), 3.63 (m, 4H), 3.20 (m, 4H), 1.50 (s, 9H).

[0426] Step 5) Preparation of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0427] 3.7 g (6.12 mmol) of the compound prepared in the above step 4) was diluted in a mixed solution of 20 mL of tetrahydrofuran, 20 mL of ethanol, and 1.1 mL of acetic acid. The resulting reaction mixture was degassed under nitrogen gas, and 665 mg (6.12 mmol) of 10% Pd / C and 2905 mg (6.12 mmol) of 20% Pd(OH) were added. The resulting reaction mixture was stirred at 60°C for 24 hours under a hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 30: 1 (volume ratio)) to obtain 2.1 g (yield: 79%) of the title compound.

[0428] 1 H-NMR (300 MHz, CDCl3): δ7.90 (s, 1H), 7.53 (d, 1H), 6.90 (dd, 1H), 6.63 (d, 1H), 4.25 (t, 1H), 3.94 (s, 3H), 3.63 (m, 4H), 3.20 (m, 4H), 2.98 (m, 1H), 2.69 (m, 1H), 2.62 (m, 1H), 2.52 (m, 1H), 1.50 (s, 9H).

[0429] Step 6) Preparation of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione; hydrochloride

[0430] 2.1 g (4.82 mmol) of the compound prepared in the above step 5) was diluted in 40 mL of dichloromethane, and 12 mL (48.19 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure to obtain 1.8 g (yield: 99%) of the title compound.

[0431] Step 7) Preparation of tert-butyl 4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0432] 1.7 g (4.81 mmol) of the compound prepared in the above step 6) and 1.6 g (7.21 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 35 mL of N,N-dimethylacetamide, and 0.61 mL (10.58 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 30 minutes, and 6.1 g (28.86 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mixture was stirred at room temperature for 1 hour, and when the reaction was completed, a saturated aqueous sodium bicarbonate solution was slowly added, followed by stirring for 2 hours. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. 2.3 g (yield: 90%) of the title compound was obtained.

[0433] 1 H-NMR (300 MHz, CDCl3): δ7.89 (s, 1H), 7.50 (d, 1H), 6.91 (d, 2H), 6.60 (d, 1H), 4.24 (m, 1H), 4.12 (m, 2H), 3.93 (s, 3H), 3.25 (m, 4H), 2.94 (m, 1H), 2.68 (m, 2H), 2.63 (m, 4H), 2.55~2.23 (m, 6H), 1.73 (m, 3H), 1.46 (s, 9H), 1.15 (m, 1H).

[0434] Step 8) Preparation of 3-(1-methyl-6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione; hydrochloride

[0435] 2.5 g (4.71 mmol) of the compound prepared in step 7) above was diluted in 50 mL of dichloromethane, and 12 mL (47.08 mmol) of 4N-hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, diluted with ethyl acetate, and stirred at room temperature for 1 hour. The resulting mixture was filtered under reduced pressure and washed with ethyl acetate. The resulting solid was dried under reduced pressure to obtain 2.2 g (final yield: 99%) of the title compound.

[0436] 1 H-NMR (300 MHz, DMSO-d6): δ8.86 (brs, 1H), 8.70 (m, 1H), 7.56 (d, 1H), 6.96 (m, 2H), 4.28 (m, 1H), 3.92 (s, 3H), 3.87 (m, 2H), 3.56~3.10 (m, 10H), 2.89 (m, 2H), 2.68 (m, 2H), 2.55~2.11 (m, 4H), 2.08 (m, 1H), 1.46 (m, 2H);

[0437] MS (ESI + ):m / z= 425.26 [M+H] + .

[0438] Manufacturing Example 8: Preparation of 3-(4-(((S)-5-amino-3-methylpentyl)amino)phenyl)piperidine-2,6-dione

[0439]

[0440] Step 1) Preparation of ethyl 2-cyano-2-(4-nitrophenyl)acetate

[0441] 27.7 mL (255.14 mmol) of ethyl cyanoacetate was diluted in 300 mL of N,N-dimethylformamide, and 10.2 g (255.14 mmol) of sodium hydride (60% concentration dispersed in mineral oil) was added at 0°C, and the mixture was stirred at the same temperature for 1 hour. 30 g (212.62 mmol) of 1-fluoro-4-nitrobenzene was diluted in 230 mL of 1,4-dioxane, and added to the reaction mixture at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, it was washed with distilled water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6:1 (volume ratio)) to obtain 36.3 g (yield: 73%) of the title compound.

[0442] 1 H-NMR (300 MHz, CDCl3): δ8.28 (dd, 2H), 7.68 (dd, 2H), 4.67 (s, 1H), 4.28 (m, 2H), 1.33 (m, 3H).

[0443] Step 2) Preparation of diethyl 2-cyano-2-(4-nitrophenyl)pentanedioate

[0444] 36.3 g (154.86 mmol) of the compound prepared in the above step 1) was diluted in 300 mL of tetrahydrofuran, and 25.8 mL (232.29 mmol) of N-methylmorpholine and 26.2 mL (246.23 mmol) of ethyl acrylate were added. The resulting reaction mixture was stirred at 55°C for 4 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with distilled water and saturated brine, and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 34.9 g (yield: 68%) of the title compound.

[0445] 1 H-NMR (300 MHz, CDCl3): δ8.28 (dd, 2H), 7.78 (dd, 2H), 4.33 (m, 3H), 4.14 (q, 2H), 2.85 (m, 1H), 2.50 (m, 1H), 2.35 (m, 1H), 1.36~1.23 (m, 6H).

[0446] Step 3) Preparation of ethyl 4-cyano-4-(4-nitrophenyl)butanoate

[0447] 34.9 g (104.39 mmol) of the compound prepared in the above step 2) was diluted in a mixed solution of 100 mL of tetrahydrofuran and 200 mL of distilled water, and 22.1 g (208.78 mmol) of sodium carbonate was added. The resulting reaction mixture was stirred at 90°C for 24 hours under a nitrogen atmosphere. Upon completion of the reaction, it was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution was added dropwise until the pH became 1. The resulting mixture was extracted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 21.1 g (yield: 77%) of the title compound.

[0448] 1 H-NMR (300 MHz, CDCl3): δ8.26 (dd, 2H), 7.57 (dd, 2H), 4.18 (m, 3H), 2.55 (m, 2H), 2.20 (m, 2H), 1.29 (t, 3H).

[0449] Step 4) Preparation of 3-(4-nitrophenyl)piperidine-2,6-dione

[0450] 21.1 g (80.42 mmol) of the compound prepared in step 4) above was diluted in 130 mL of acetic acid, and 3.4 mL (64.33 mmol) of sulfuric acid was added. The resulting reaction mixture was stirred at 120°C for 2 hours. Upon completion of the reaction, it was cooled to room temperature, slowly added to 210 mL of distilled water, and stirred at room temperature for 30 minutes. The resulting mixture was washed with distilled water and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 16.5 g (yield: 88%) of the title compound.

[0451] 1 H-NMR (300 MHz, DMSO-d6): δ10.93 (s, 1H), 8.20 (dd, 2H), 7.55 (dd, 2H), 4.10 (dd, 1H), 2.62 (m, 1H), 2.45 (m, 1H), 2.27 (m, 1H), 2.06 (m, 1H).

[0452] Step 5) Preparation of 3-(4-aminophenyl)piperidine-2,6-dione

[0453] 16.4 g (70.15 mmol) of the compound prepared in step 4) above was diluted in 200 mL of ethanol. 22.74 g (420.9 mmol) of ammonium chloride was diluted in 80 mL of distilled water and added to the reaction mixture, followed by the addition of 19.8 g (350.75 mmol) of iron powder. The resulting reaction mixture was stirred at 80°C for 1 hour. Upon completion of the reaction, the reaction mixture was washed with ethanol in a hot state through a Celite-packed filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure. The resulting residue was diluted in a chloroform: isopropyl alcohol = 4: 1 (volume ratio) solution and washed with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. MTBE was added to the resulting residue, stirred at room temperature for 1 hour, and the resulting mixture was filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 12.5 g (yield: 87%) of the title compound.

[0454] 1 H-NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 8.85 (dd, 2H), 6.50 (dd, 2H), 4.95 (s, 2H), 3.62 (dd, 1H), 2.62 (m, 1H), 2.55 (m, 1H), 2.08 (m, 2H).

[0455] Step 6) Preparation of tert-butyl ((3R)-5-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)-3-methylpentyl)carbamate

[0456] In step 12 of Manufacturing Example 3, 450 mg (1.21 mmol) of (S)-5-((tert-butoxycarbonyl)amino)-3-methylpentyl 4-methylbenzenesulfonate was diluted in 9 mL of acetone, and 369 mg (2.42 mmol) of sodium iodide was added. The resulting reaction mixture was stirred at 50°C for 2 hours, and then the solid was removed by filtration under reduced pressure. The resulting filtrate was distilled under reduced pressure, diluted in 9 mL of N-methylpyrrolidone, and 297 mg (1.45 mmol) of the compound prepared in step 5) and 0.6 mL (3.63 mmol) of N,N-diisopropylethylamine were added. The resulting reaction mixture was stirred at 90°C for 3 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed five times with distilled water, and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 125 mg (yield: 26%) of the title compound.

[0457] 1H-NMR (300 MHz, CDCl3): δ7.85 (brs, 1H), 7.00 (d, 2H), 6.59 (d, 2H), 4.48 (m, 1H), 3.74 (m, 1H), 3.28~3.04 (m, 4H), 2.77~2.57 (m, 2H), 2.26 (m, 2H), 1.65 (m, 2H), 1.45 (s, 9H), 0.96 (d, 3H), 0.85 (m, 1H).

[0458] Step 7) Preparation of 3-(4-(((S)-5-amino-3-methylpentyl)amino)phenyl)piperidine-2,6-dione; hydrochloride

[0459] 125 mg (0.31 mmol) of the compound prepared in step 6) above was diluted in 2 mL of dichloromethane, and 0.8 mL (3.10 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 6 hours. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure and washed with dichloromethane. The resulting solid was dried under reduced pressure to obtain 105 mg (final yield: 99%) of the title compound.

[0460] MS (ESI + ):m / z= 304.19 [M+H] + .

[0461] Manufacturing Example 9: Manufacturing of 3-(4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenyl)piperidine-2,6-dione hydrochloride

[0462]

[0463] Step 1) Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine; hydrochloride

[0464] 43.0 g (110.72 mmol) of the compound prepared in step 2) of Manufacturing Example 4 was diluted in 430 mL of dichloromethane, and 277 mL (1107.2 mmol) of 4N hydrochloric acid was added dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 6 hours. The resulting reaction mixture was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 24.8 g (yield: 69%) of the title compound.

[0465] 1 H-NMR (300 MHz, DMSO-d6): δ9.62 (brs, 2H), 7.53 (d, 2H), 6.93 (d, 2H), 3.44 (m, 4H), 3.14 (m, 4H), 1.24 (s, 12H).

[0466] Step 2) Preparation of tert-butyl 4-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0467] 20 g (61.60 mmol) of the compound prepared in the above step 1) and 21.62 g (92.40 mmol) of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid were diluted in 400 mL of N,N-dimethylformamide, and 23.62 g (123.21 mmol) of EDCI, 12.5 g (92.40 mmol) of HOBt, and 32.2 mL (184.81 mmol) of N,N-diisopropylethylamine were added. The resulting reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, it was washed twice with distilled water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. MTBE was added to the resulting residue, stirred for 1 hour, and then the resulting mixture was washed with MTBE and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 14.0 g (yield: 45%) of the title compound.

[0468] 1H-NMR (300 MHz, CDCl3): δ7.72 (d, 2H), 6.88 (d, 2H), 4.14 (m, 2H), 3.68 (m, 4H), 3.23 (m, 4H), 2.81~2.65 (m, 4H), 1.76 (m, 3H), 1.46 (s, 12H), 1.33 (s, 9H).

[0469] Step 3) Preparation of tert-butyl 4-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0470] 2,6-Bis(benzyloxy)-3-bromopyridine 5.19 g (14.01 mmol), the compound prepared in step 2), 7.0 g (14.01 mmol), potassium carbonate 4.9 g (35.04 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex 1.1 g (1.40 mmol) were diluted in 120 mL of a 1,4-dioxane : distilled water = 5 : 1 (volume ratio) solution. The resulting reaction mixture was stirred at 100°C for 20 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate through a Celite-packed filter, filtered under reduced pressure, and the resulting filtrate was washed with distilled water and saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 1: 1 (volume ratio)) to obtain 5.1 g (yield: 55%) of the title compound.

[0471] 1 H-NMR (300 MHz, DMSO-d6): δ7.70 (d, 1H), 7.67~7.31 (m, 12H), 6.97 (d, 2H), 6.52 (d, 2H), 5.37 (d, 4H), 3.93 (m, 2H), 3.63 (m, 4H), 3.15 (m, 4H), 2.91~2.80 (m, 3H), 1.61 (m, 3H), 1.57 (m, 2H), 1.39 (s, 9H).

[0472] Step 4) Preparation of tert-butyl 4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0473] 5.1 g (7.68 mmol) of the compound prepared in the above step 3) was diluted in 100 mL of tetrahydrofuran. The resulting reaction mixture was degassed under nitrogen gas for 10 minutes, and 5.3 g (4.60 mmol) of activated 10% Pd / C was added. The resulting reaction mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure to obtain 2.2 g (yield: 60%) of the title compound.

[0474] 1 H-NMR (300 MHz, DMSO-d6): δ10.76 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 6.97 (d, 2H), 3.93 (m, 2H), 3.73 (m, 5H), 3.10 (m, 4H), 2.86~2.80 (m, 4H), 2.49 (m, 1H), 2.13 (m, 2H), 1.65 (m, 2H), 1.48 (m, 2H), 1.45 (s, 9H).

[0475] Step 5) Preparation of 3-(4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenyl)piperidine-2,6-dione; hydrochloride

[0476] 2.2 g (4.62 mmol) of the compound prepared in step 4) above was diluted in 50 mL of dichloromethane, and 12 mL (46.22 mmol) of 4N-hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 6 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 1.9 g (final yield: 99%) of the title compound.

[0477] MS (ESI + ):m / z= 385.22 [M+H] + .

[0478] Manufacturing Example 10: Manufacturing of 3-(4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione hydrochloride

[0479]

[0480] Step 1) Preparation of (3S,5R)-1-(4-bromophenyl)-3,5-dimethylpiperazine

[0481] (2R,6S)-2,6-dimethylpiperazine 6.0 g (51.96 mmol), 1-bromo-4-iodo-benzene 10.00 g (34.64 mmol), and sodium tert-butoxide 6.9 g (69.28 mmol) were diluted in 200 mL of 1,4-dioxane and degassed under nitrogen gas for 20 minutes, and then 0.8 g (3.46 mmol) of palladium(II) acetate and 4.1 g (6.93 mmol) of XantPhos were added. The resulting reaction mass was stirred at 90°C for 4 hours under a nitrogen atmosphere. After the reaction was completed, the resulting reaction mass was cooled to room temperature, washed with ethyl acetate on a Celite-packed filter, and filtered under reduced pressure. The filtrate was washed with distilled water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 9:1 (volume ratio)) to obtain 8.3 g (yield: 89%) of the title compound.

[0482] 1 H-NMR (300 MHz, CDCl3): δ7.33 (d, 2H), 6.78 (d, 2H), 3.46 (d, 2H), 3.06~3.01 (m, 2H), 2.28 (t, 2H), 1.13 (s, 6H).

[0483] Step 2) Preparation of (3S,5R)-3,5-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine

[0484] 8.3 g (30.80 mmol) of the compound prepared in the above step 1), 12.0 g (46.19 mmol) of bis(pinacolato)diboron, and 7.8 g (76.99 mmol) of potassium acetate were diluted in 160 mL of 1,4-dioxane and degassed under nitrogen gas for 20 minutes, and then 2.5 g (3.08 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex was added. The resulting reaction mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure through a Celite-packed filter, washed with ethyl acetate, and the filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 9:1 (volume ratio)) to obtain 2.9 g (yield: 30%) of the title compound.

[0485] 1 H-NMR (300 MHz, CDCl3): δ7.69 (d, 2H), 6.88 (d, 2H), 3.64 (dd, 2H), 3.15~3.05 (m, 2H), 2.45 (t, 2H), 1.32 (s, 12H), 1.20 (d, 6H).

[0486] Step 3) Preparation of (3S,5R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,5-dimethylpiperazine

[0487] 2.9 g (9.14 mmol) of the compound prepared in the above step 2), 4.1 g (11.0 mmol) of 2,6-bis(benzyloxy)-3-bromopyridine, 3.8 g (27.41 mmol) of potassium carbonate, and 0.4 g (0.46 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex were diluted in 60 mL of a 1,4-dioxane:distilled water = 5:1 (volume ratio) solution. The resulting reaction mixture was stirred at 100°C for 15 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with ethyl acetate through a Celite-packed filter, filtered under reduced pressure, and the resulting filtrate was washed with distilled water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 9:1 (volume ratio)) to obtain 3.1 g (yield: 70%) of the title compound.

[0488] 1 H-NMR (300 MHz, CDCl3): δ7.48 (d, 1H), 7.57~7.28 (m, 12H), 6.97 (d, 2H), 6.45 (d, 1H), 5.33 (d, 4H), 3.56 (m, 2H), 3.04 (m, 2H), 2.31 (t, 2H), 1.15 (d, 6H).

[0489] Step 4) Preparation of tert-butyl 4-(((2R,6S)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0490] 3.0 g (6.19 mmol) of the compound prepared in the above step 3) and 2.7 g (12.38 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 60 mL of N,N-dimethylacetamide, and 0.78 mL (13.62 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 30 minutes, and 7.9 g (37.15 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mixture was stirred at 70°C for 7 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was slowly added thereto, followed by stirring at room temperature for 16 hours. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4:1 (volume ratio)) to obtain 0.4 g (yield: 10%) of the title compound.

[0491] 1 H-NMR (300 MHz, CDCl3): δ7.57 (d, 1H), 7.49~7.29 (m, 12H), 6.91 (d, 2H), 6.44 (d, 1H), 5.37 (d, 4H), 4.12 (t, 3H), 3.45 (m, 2H), 2.74~2.55 (m, 6H), 2.40 (d, 2H), 1.78 (d, 2H), 1.46 (s, 9H), 1.14 (d, 6H), 0.83 (m, 2H).

[0492] Step 5) Preparation of tert-butyl 4-(((2R,6S)-4-(4-(2,6-dioxapiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0493] 400 mg (0.59 mmol) of the compound prepared in the above step 4) was diluted in 10 mL of tetrahydrofuran. The resulting reaction mixture was degassed under nitrogen gas for 10 minutes, and 160 mg (0.15 mmol) of active 10% Pd / C was added. The resulting reaction mixture was stirred at room temperature for 21 hours under a hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure to obtain 295 mg (yield: 99%) of the title compound.

[0494] 1 H-NMR (300 MHz, CDCl3): δ7.89 (s, 1H), 7.08 (d, 2H), 6.86 (d, 2H), 4.12 (m, 2H), 3.71 (m, 1H), 3.38 (d, 2H), 2.75~2.62 (m, 8H), 2.49 (d, 2H), 2.25 (m, 2H), 1.78 (m, 2H), 1.46 (s, 9H), 1.16 (d, 6H), 1.06 (m, 2H), 0.85 (m, 1H).

[0495] Step 6) Preparation of 3-(4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)piperidine-2,6-dione; hydrochloride

[0496] 295 mg (0.59 mmol) of the compound prepared in step 5) above was diluted in 6 mL of dichloromethane, and 1.5 mL (5.92 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 257 mg (final yield: 99%) of the title compound.

[0497] MS (ESI + ):m / z= 399.27 [M+H]+ .

[0498] Manufacturing Example 11: Manufacturing of 3-(4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-3-fluorophenyl)piperidine-2,6-dione hydrochloride

[0499]

[0500] Step 1) Preparation of (3R,5S)-1-(2-fluoro-4-nitrophenyl)-3,5-dimethylpiperazine

[0501] 40.0 g (246.4 mmol) of 1,2-difluoro-4-nitrobenzene and 34.45 g (295.68 mmol) of (2R,6S)-2,6-dimethylpiperazine were diluted in 800 mL of acetonitrile under a nitrogen atmosphere, and 87 mL (492.8 mmol) of N,N-diisopropylethylamine was added. The reaction mixture was stirred at 80°C for 3 hours. Upon completion of the reaction, it was cooled to room temperature, and 3,000 mL of water was added to the reaction mixture, which was stirred at room temperature for 1 hour. The resulting solid was washed with water and filtered under reduced pressure. The resulting solid was dried in a drying oven (at 50°C for 24 hours to obtain 58.5 g (yield: 94%) of the title compound.

[0502] 1 H-NMR (300 MHz, CDCl3): δ7.97~7.84 (m, 2H), 6.90~6.84 (m, 1H), 3.54~3.50 (m, 2H), 3.11~3.01 (m, 2H), 2.51~2.43 (m, 2H), 1.12~1.10 (d, 6H).

[0503] Step 2) Preparation of tert-butyl (2R,6S)-4-(2-fluoro-4-nitrophenyl)-2,6-dimethylpiperazine-1-carboxylate

[0504] 40 g (157.93 mmol) of the compound prepared in step 1) above was diluted in 240 mL of tetrahydrofuran, and 73.3 mL (315.86 mmol) of di-tert-butyl dicarbonate was added. An aqueous solution of 32.7 g (236.89 mmol) of potassium carbonate dissolved in 240 mL of distilled water was slowly added dropwise to the reaction mixture at 0°C, and the mixture was stirred for 10 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. Upon completion of the reaction, the reaction mixture was washed with saturated brine and extracted twice with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was stirred in MTBE and then filtered under reduced pressure to obtain 49.7 g (yield: 89%) of the title compound.

[0505] 1 H-NMR (300 MHz, CDCl3): δ8.00~7.96 (m, 1H), 7.93~7.88 (m, 1H), 6.94~6.88 (t, 1H), 4.28~4.24 (m, 2H), 3.46~3.42 (m, 2H), 3.04~2.98 (m, 2H), 1.48 (s, 9H), 1.12~1.10 (d, 6H).

[0506] Step 3) Preparation of tert-butyl (2R,6S)-4-(4-amino-2-fluorophenyl)-2,6-dimethylpiperazine-1-carboxylate

[0507] 44 g (124.51 mmol) of the compound prepared in the above step 2) was diluted in 1,000 mL of tetrahydrofuran:ethanol = 4:1. The resulting reaction mixture was degassed under nitrogen gas for 10 minutes, and 4.4 g (41.35 mmol) of 10% Pd / C was added. The resulting reaction mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure to obtain 40 g (yield: 99%) of the title compound.

[0508] 1 H-NMR (300 MHz, CDCl3): δ6.77 (t, 1H), 6.45 (dd, 1H), 6.42 (s, 1H), 4.21~4.13 (m, 2H), 3.56 (br, 2H), 3.05 (d, 2H), 2.79 (dd, 2H), 1.53 (s, 9H), 1.39 (s, 3H), 1.30(s, 3H).

[0509] Step 4) Preparation of tert-butyl (2R,6S)-4-(4-bromo-2-fluorophenyl)-2,6-dimethylpiperazine-1-carboxylate

[0510] 40 g (123.68 mmol) of the compound prepared in the above step 3) was diluted in 600 mL of acetonitrile and cooled to 0°C. 12.8 g (185.52 mmol) of tert-butyl nitrite was slowly added dropwise, stirred for 30 minutes, and then 30.4 g (136.05 mmol) of cupric bromide was added. The reaction mixture was warmed to room temperature and stirred for 18 hours. Upon completion of the reaction, the reaction mixture was washed with saturated brine and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 20: 1 (volume ratio)) to obtain 23 g (yield: 48%) of the title compound.

[0511] 1 H-NMR (300 MHz, CDCl3): δ7.68 (dd, 1H), 7.20 (s, 1H), 6.78 (t, 1H), 4.28~4.19 (m, 2H), 3.18 (d, 2H), 2.85 (dd, 2H), 1.53 (s, 9H), 1.41 (s, 3H), 1.39(s, 3H).

[0512] Step 5) Preparation of tert-butyl (2R,6S)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazine-1-carboxylate

[0513] 15 g (38.73 mmol) of the compound prepared in the above step 4) and 17.8 g (42.60 mmol) of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were diluted in 500 mL of a 1,4-dioxane:distilled water = 4:1 (volume ratio) solution, and 39.03 g (116.19 mmol) of potassium carbonate and 3.16 g (3.87 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex were added. The resulting reaction mixture was stirred at 100°C for 3 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure through a filter filled with Celite, and the filtrate was washed with distilled water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 10:1 (volume ratio)) to obtain 13 g (yield: 56%) of the title compound.

[0514] 1 H-NMR (300 MHz, CDCl3): δ7.60 (d,1H), 7.57~7.45 (m, 12H), 6.93 (t, 1H), 6.48 (d, 1H), 5.46 (s, 2H), 5.37 (s, 2H), 4.27~4.19 (m, 2H), 3.27 (d, 2H), 2.86 (dd, 2H), 1.54 (s, 9H), 1.44 (s, 3H), 1.41(s, 3H).

[0515] Step 6) Preparation of (3R,5S)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-3,5-dimethylpiperazine

[0516] 14 g (23.42 mmol) of the compound prepared in the above step 5) was diluted in 300 mL of dichloromethane, and 35.8 mL (468.44 mmol) of trifluoroacetic acid was slowly added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. When the reaction was complete, the reaction mixture was distilled under reduced pressure. The obtained residue was diluted with dichloromethane, neutralized (~pH 7) with a saturated aqueous sodium bicarbonate solution, washed with distilled water, and extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 11 g (yield: 94%) of the title compound.

[0517] 1 H-NMR (300 MHz, CDCl3): δ7.60 (d,1H), 7.58~7.46 (m, 12H), 6.96 (t, 1H), 6.47 (d, 1H), 5.45 (s, 2H), 5.38 (s, 2H), 3.37 (d, 2H), 3.18~3.13 (m, 2H), 2.36 (t, 2H), 1.73 (br, 1H), 1.28 (s, 3H), 1.13(s, 3H).

[0518] Step 7) Preparation of tert-butyl 4-(((2R,6S)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0519] 11 g (22.11 mmol) of the compound prepared in the above step 6) and 17.0 g (77.37 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 300 mL of N,N-dimethylacetamide, and 2.8 mL (48.63 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 1 hour and 30 minutes, and then 28.11 g (132.63 mmol) of sodium triacetoxyborohydride was added. The reaction mixture was stirred at 25°C for 21 hours. Upon completion of the reaction, it was slowly added to a saturated aqueous sodium bicarbonate solution at 0°C and stirred for 2 hours. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 30:1 (volume ratio)) to obtain 15 g of the title compound (yield: 97%).

[0520] 1 H-NMR (300 MHz, CDCl3): δ7.60 (d,1H), 7.58~7.46 (m, 12H), 6.96 (t, 1H), 6.47 (d, 1H), 5.45 (s, 2H), 5.38 (s, 2H), 3.37 (d, 2H), 3.18~3.13 (m, 2H), 2.36 (t, 2H), 1.73 (br, 1H), 1.28 (s, 3H), 1.13(s, 3H).

[0521] Step 8) Preparation of tert-butyl 4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0522] 15 g (21.59 mmol) of the compound prepared in the above step 7) was diluted in 300 mL of tetrahydrofuran. The resulting reaction mixture was degassed under nitrogen gas for 10 minutes, and 22.9 g (21.59 mmol) of active 10% Pd / C was added. The resulting reaction mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 20: 1 (volume ratio)) to obtain 10 g (yield: 90%) of the title compound.

[0523] 1 H-NMR (300 MHz, CDCl3): δ7.99 (s, 1H), 6.92~6.88 (m, 3H), 3.71 (dd, 1H),3.52 (d, 4H), 3.26 (d, 2H), 3.18~3.13 (m, 2H), 2.80~2.71 (m, 4H), 2.55 (t, 3H), 2.41 (d, 2H), 1.75~1.71 (m, 4H), 1.42 (s, 9H), 1.28 (s, 3H), 1.13(s, 3H).

[0524] Step 9) Preparation of 3-(4-((3R,5S)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-3-fluorophenyl)piperidine-2,6-dione; hydrochloride

[0525] 10 g (19.36 mmol) of the compound prepared in step 8) above was diluted in 400 mL of dichloromethane, and 45 mL (193.55 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 3.5 g (final yield: 40%) of the title compound.

[0526] 1 H-NMR (300 MHz, DMSO-d6): δ10.83 (s, 1H), 7.12~7.07 (m, 3H), 3.87 (dd, 1H), 3.57~3.48 (m, 8H), 3.27~3.19 (m, 2H), 2.90~2.87 (m, 2H), 2.73~2.71 (m, 1H), 2.28~2.23 (m, 4H), 2.02~1.98 (m, 2H), 1.42 (s, 3H), 1.40(s, 3H), 1.33 (d, 2H);

[0527] MS (ESI + ):m / z= 417.26 [M+H] + .

[0528] Manufacturing Example 12: Manufacturing of 3-(4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-3,5-difluorophenyl)piperidine-2,6-dione hydrochloride

[0529]

[0530] Step 1) Preparation of (3R,5S)-1-(4-bromo-2,6-difluorophenyl)-3,5-dimethylpiperazine

[0531] 20.0 g (61.46 mmol) of 5-bromo-1,3-difluoro-2-iodo-benzene, 7.9 g (67.61 mmol) of (2R,6S)-2,6-dimethylpiperazine, and 40.5 g (122.92 mmol) of cesium carbonate were diluted in 400 mL of 1,4-dioxane and degassed under nitrogen gas for 10 minutes, and then 35.6 g (6.15 mmol) of Pd2(dba) and 7.3 g (12.29 mmol) of XantPhos were added. The resulting reaction mixture was stirred at 100°C under a nitrogen atmosphere for 17 hours. Upon completion of the reaction, the mixture was filtered under reduced pressure, washed with ethyl acetate through a Celite-packed filter, and the resulting filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 20:1 (volume ratio)) to obtain 4.8 g (yield: 25%) of the title compound.

[0532] 1 H-NMR (300 MHz, DMSO-d6): δ7.30~7.39 (m, 2H), 2.98 (dd, 2H), 2.75~2.90 (m, 2H), 2.58 (m, 2H), 0.95 (d, 6H).

[0533] Step 2) Preparation of (3R,5S)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,6-difluorophenyl)-3,5-dimethylpiperazine

[0534] 4.8 g (15.66 mmol) of the compound prepared in the above step 1) and 7.8 g (18.80 mmol) of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were diluted in 90 mL of a 1,4-dioxane:distilled water = 5:1 (volume ratio) solution, and 6.6 g (46.99 mmol) of potassium carbonate and 640 mg (0.78 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex were added. The resulting reaction mixture was stirred at 100°C for 14 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure through a filter filled with Celite, and the filtrate was washed with distilled water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 20:1 (volume ratio)) to obtain 5.9 g (yield: 73%) of the title compound.

[0535] 1 H-NMR (300 MHz, DMSO-d6): δ7.55 (m, 1H), 7.54~7.07 (m, 10H), 7.08 (d, 2H), 6.46 (d, 1H), 5.35 (d, 4H), 3.15~3.04 (m, 4H), 2.73 (t, 2H), 1.08 (d, 6H).

[0536] Step 3) Preparation of tert-butyl 4-(((2R,6S)-4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0537] 2.9 g (5.72 mmol) of the compound prepared in the above step 2) and 3.1 g (14.30 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 65 mL of N,N-dimethylacetamide, and 0.72 mL (12.59 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 1 hour and 30 minutes, and then 7.3 g (34.33 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mixture was stirred at 25°C for 21 hours. Upon completion of the reaction, it was slowly added to a saturated aqueous sodium bicarbonate solution at 0°C and stirred for 2 hours. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 30:1 (volume ratio)) to obtain 0.8 g (yield: 20%) of the title compound.

[0538] 1 H-NMR (300 MHz, CDCl3): δ7.56 (d, 1H), 7.53~7.29 (m, 10H), 7.08 (d, 2H), 6.45 (d, 1H), 5.37 (d, 4H), 4.12 (m, 2H), 3.35 (m, 2H), 2.93 (m, 2H), 2.88~2.57 (m, 4H), 2.40 (m, 2H), 1.85 (d, 2H), 1.53 (m, 2H), 1.46 (s, 9H), 1.07 (d, 6H).

[0539] Step 4) Preparation of tert-butyl 4-(((2R,6S)-4-(4-(2,6-dioxapiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0540] 850 mg (1.19 mmol) of the compound prepared in the above step 3) was diluted in 20 mL of tetrahydrofuran. The resulting reaction mixture was degassed under nitrogen gas for 10 minutes, and 317 mg (0.30 mmol) of active 10% Pd / C was added. The resulting reaction mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. Upon completion of the reaction, the reaction mixture was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 20: 1 (volume ratio)) to obtain 310 mg (yield: 49%) of the title compound.

[0541] 1 H-NMR (300 MHz, CDCl3): δ7.90 (s, 1H), 6.69 (d, 2H), 4.13 (m, 2H), 3.65 (m, 1H), 3.05 (d, 2H), 2.95 (t, 2H), 2.73~2.61 (m, 5H), 2.42 (d, 2H), 2.25 (m, 2H), 1.75 (m, 2H), 1.60 (m, 3H), 1.46 (s, 9H), 1.05 (d, 6H). 1.02 (m, 1H).

[0542] Step 6) Preparation of 3-(4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-3,5-difluorophenyl)piperidine-2,6-dione; hydrochloride

[0543] 310 mg (0.58 mmol) of the compound prepared in step 5) above was diluted in 6 mL of dichloromethane, and 1.5 mL (5.80 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 273 mg (final yield: 99%) of the title compound.

[0544] MS (ESI + ):m / z= 435.25 [M+H] + .

[0545] Manufacturing Example 13: Manufacturing of 3-((3-fluoro-4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0546]

[0547] Step 1) Preparation of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate

[0548] 30 g (157.85 mmol) of tert-butyl piperazine-1-carboxylate and 25.88 g (159.43 mmol) of 1,2-difluoro-4-nitrobenzene were diluted in 300 mL of N,N-dimethylformamide, and 65.78 g (473.56 mmol) of potassium carbonate was added. The reaction mixture was stirred at 90°C for 18 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and 3,000 mL of water was added to the reaction mixture, which was stirred at room temperature for 30 minutes. The resulting solid was washed with water and filtered under reduced pressure. The resulting solid was dried in a drying oven (at 50°C for 24 hours to obtain 47.6 g (yield: 93%) of the title compound.

[0549] 1 H-NMR (300 MHz, CDCl3): δ8.01~7.89 (m, 2H), 6.94~6.89 (t, 1H), 3.63~3.59 (m, 4H), 3.26~3.23 (m, 4H), 1.49 (s, 9H).

[0550] Step 2) Preparation of 1-(2-fluoro-4-nitrophenyl)piperazine hydrochloride

[0551] 47.6 g (146.31 mmol) of the compound prepared in the above step 1) was diluted in 480 mL of dichloromethane, and 366 mL (1463.1 mmol) of 4N hydrochloric acid was slowly added dropwise at room temperature and stirred for 4 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 38.3 g (yield: 100%) of the title compound.

[0552] 1 H-NMR (300 MHz, DMSO-d6): δ8.05~7.97 (m, 2H), 7.27~7.21 (m, 1H), 3.51~3.49 (m, 4H), 3.19 (m, 4H).

[0553] Step 3) Preparation of tert-butyl 4-(4-(2-fluoro-4-nitrophenyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0554] 20 g (76.429 mmol) of the compound prepared in the above step 2) and 26.82 g (114.64 mmol) of 1-tert-butoxycarbonylpiperidine-4-carboxylic acid were diluted in 400 mL of N,N-dimethylformamide, and 29.3 g (152.86 mmol) of EDCI, 15.49 g (114.64 mmol) of HOBt, and 39.94 mL (229.29 mmol) of N,N-diisopropylethylamine were added. The reaction mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained solid was stirred in MTBE and then filtered under reduced pressure to obtain 24.3 g (yield: 73%) of the title compound.

[0555] 1H-NMR (300 MHz, CDCl3): δ8.01~7.89 (m, 2H), 6.94~6.88 (t, 1H), 4.17~4.13 (m, 2H), 3.79~3.69 (m, 4H), 3.29~3.25 (m, 4H), 2.81~2.73 (m, 2H), 2.69~2.59 (m, 1H), 1.81~1.64 (m, 4H), 1.44 (s, 9H).

[0556] Step 4) Preparation of tert-butyl 4-(4-(4-amino-2-fluorophenyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0557] 22.2 g (50.86 mmol) of the compound prepared in the above step 3) was diluted in 450 mL of ethyl acetate:tetrahydrofuran = 1:2, 4.4 g of 10% Pd / C was added, and degassed under hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen gas for 4 hours. Upon completion of the reaction, the residue was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure to obtain 20.4 g (yield: 99%) of the title compound.

[0558] 1 H-NMR (300 MHz, CDCl3): δ6.83~6.77 (m, 1H), 6.49~6.40 (m, 2H), 4.20~4.17 (m, 2H), 3.79 (m, 2H), 3.67~3.66 (m, 4H), 2.98~2.96 (m, 4H), 2.91~2.77 (m, 2H), 2.73~2.63 (m, 1H), 1.85~1.70 (m, 4H), 1.49 (s, 9H).

[0559] Step 5) Preparation of tert-butyl 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidine-1-carboxylate

[0560] 15 g (36.9 mmol) of the compound prepared in the above step 4) and 17.71 g (92.25 mmol) of 3-bromopiperidine-2,6-dione were diluted in 150 mL of N,N-dimethylformamide, and 19.28 mL (110.7 mmol) of N,N-diethylisopropylamine was added. The reaction mixture was stirred at 120°C for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 5.0 g (yield: 26%) of the title compound.

[0561] Step 6) Preparation of 3-((3-fluoro-4-(4-(piperidine-4-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; hydrochloride

[0562] 5.0 g (9.66 mmol) of the compound prepared in the above step 5) was diluted in 100 mL of dichloromethane, and 24.2 mL (96.6 mmol) of 4N-hydrochloric acid was slowly added dropwise at room temperature, followed by stirring for 13 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 4.0 g (final yield: 91%) of the title compound.

[0563] MS (ESI + ):m / z= 418.22.

[0564] Manufacturing Example 14: Manufacturing of 3-((4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione hydrochloride

[0565]

[0566] Step 1) Preparation of (3S,5R)-1-(4-bromophenyl)-3,5-dimethylpiperazine

[0567] 1,2-Difluoro-4-nitro-benzene (17 mL, 147.84 mmol) was diluted in 500 mL of acetonitrile and degassed under nitrogen gas. To the resulting mixture, 20.7 g (177.41 mmol) of (2R,6S)-2,6-dimethylpiperazine and 52.0 mL (295.68 mmol) of N,N-diisopropylethylamine were added. The resulting reaction mixture was stirred at 80°C for 3 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 1.5 L of distilled water was added, and the mixture was stirred for 1 hour. The resulting mixture was washed with distilled water and filtered under reduced pressure. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 32.6 g (yield: 87%) of the title compound.

[0568] 1 H-NMR (300 MHz, CDCl3): δ7.98 (m, 1H), 7.88 (m, 1H), 6.89 (t, 1H), 3.55 (d, 2H), 3.08 (m, 2H), 2.48 (t, 2H), 1.12 (d, 6H).

[0569] Step 2) Preparation of tert-butyl 4-(((2R,6S)-4-(2-fluoro-4-nitrophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0570] 20.0 g (78.96 mmol) of the compound prepared in the above step 1) and 43.4 g (197.41 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 400 mL of N,N-dimethylacetamide, and 10 mL (173.72 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 1 hour and 30 minutes, and then 100.4 g (473.78 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mixture was stirred at 25°C for 21 hours. Upon completion of the reaction, the reaction mixture was slowly added to a saturated aqueous sodium bicarbonate solution at 0°C and stirred for 2 hours. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 34.9 g (yield: 98%) of the title compound.

[0571] 1 H-NMR (300 MHz, DMSO-d6): δ8.00 (m, 2H), 7.13 (t, 1H), 3.92 (m, 2H), 3.52 (d, 2H), 2.78~2.61 (m, 6H), 2.33 (d, 2H), 1.72 (d, 2H), 1.59 (m, 2H), 1.46 (s, 9H), 0.98 (d, 6H), 0.95 (m, 1H).

[0572] Step 3) Preparation of tert-butyl 4-(((2R,6S)-4-(4-amino-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0573] 15.0 g (33.29 mmol) of the compound prepared in the above step 2) was diluted in 300 mL of a 1:1 (volume ratio) mixed solution of ethyl acetate: tetrahydrofuran, and 3.5 g (3.33 mmol) of 10% wet Pd / C was added. The resulting reaction mixture was stirred at room temperature under a hydrogen atmosphere for 17 hours. Upon completion of the reaction, the mixture was washed with ethyl acetate through a Celite-filled filter, filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure to obtain 14.0 g (yield: 99%) of the title compound.

[0574] 1 H-NMR (300 MHz, DMSO-d6): δ6.71 (t, 1H), 6.29 (m, 2H), 4.94 (s, 2H), 3.92 (m, 2H), 2.91 (d, 2H), 2.78~2.51 (m, 4H), 2.31 (m, 4H), 1.71 (d, 2H), 1.59 (m, 2H), 1.38 (s, 9H), 1.01 (d, 6H), 0.98 (m, 1H).

[0575] Step 4) Preparation of tert-butyl 4-(((2R,6S)-4-(4-((2,6-dioxapiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidine-1-carboxylate

[0576] 14.0 g (33.29 mmol) of the compound prepared in the above step 3), 16.0 g (83.22 mmol) of 3-bromopiperidine-2,6-dione, and 17.4 mL (99.86 mmol) of N,N-diisopropylethylamine were diluted in 140 mL of N,N-dimethylformamide. The resulting reaction mixture was stirred at 120°C for 21 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed three times with distilled water, and extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 1: 1 (volume ratio)) to obtain 5.9 g (yield: 33%) of the title compound.

[0577] 1 H-NMR (300 MHz, CDCl3): δ7.88 (brs, 1H), 6.83 (t, 1H), 6.41 (m, 2H), 4.57 (s, 1H), 4.13 (m, 2H), 4.08 (m, 1H), 3.07 (d, 2H), 2.86~2.41 (m, 10H), 1.91 (m, 2H), 1.87 (d, 2H), 1.59 (m, 2H), 1.46 (s, 9H), 1.03 (d, 6H), 1.02 (m, 1H).

[0578] Step 5) Preparation of 3-((4-((3S,5R)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione; hydrochloride

[0579] 5.8 g (10.91 mmol) of the compound prepared in step 4) above was diluted in 100 mL of dichloromethane, and 28 mL (109.09 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, ethyl acetate was added, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 5.1 g of the title compound (final yield: 99%).

[0580] 1 H-NMR (300 MHz, DMSO-d6): δ10.80 (s, 1H), 9.14~9.01 (m, 2H), 6.95 (t, 1H), 6.89 (d, 1H), 6.50 (m, 1H), 4.33 (d, 1H), 3.55 (m, 4H), 3.27~3.01 (m, 6H), 2.87~2.51 (m, 4H), 2.35~2.06 (m, 4H), 1.95 (m, 1H), 1.56~1.47 (m, 1H), 1.47 (d, 6H), 1.35 (m, 1H).

[0581] MS (ESI + ):m / z= 432.27 [M+H] + .

[0582] Manufacturing Example 15: Preparation of 3-((3-fluoro-4-(4-(2-(piperidin-4-yl)propan-2-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0583]

[0584] Step 1) Preparation of tert-butyl 4-(1-((benzyloxy)carbonyl)piperidine-4-carbonyl)piperazine-1-carboxylate

[0585] 60 g (223.33 mmol) of 1-((benzyloxy)carbonyl)piperidine-4-carboxylic acid and 42.44 g (223.33 mmol) of tert-butyl piperazine-1-carboxylate were diluted in 900 mL of N,N-dimethylformamide, and 54.08 g (267.99 mmol) of EDCI and 46.19 g (334.99 mmol) of HOBt were added. The reaction mixture was stirred at room temperature for 18 hours. When the reaction was complete, 3,000 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The resulting solid was washed with water and filtered under reduced pressure. The resulting solid was dried in a drying oven (at 50°C for 24 hours to obtain 85.2 g (yield: 88%) of the title compound.

[0586] 1 H-NMR (300 MHz, CDCl3): δ7.38~7.32 (m, 5H), 5.15 (s, 2H), 4.26~4.22 (m, 2H), 3.60~3.44 (m, 8H), 2.92~2.85 (m, 2H), 2.71~2.61 (m, 1H), 1.85~1.72 (m, 4H), 1.49 (s, 9H).

[0587] Step 2) Preparation of tert-butyl 4-(2-(1-((benzyloxy)carbonyl)piperidin-4-yl)propan-2-yl)piperazine-1-carboxylate

[0588] 75.03 g (315.53 mmol) of zirconium(IV) chloride was diluted in 1,500 mL of tetrahydrofuran and cooled to -78°C. A solution of 85.1 g (197.21 mmol) of the compound prepared in step 1) in 2,700 mL of tetrahydrofuran was slowly added dropwise over 30 minutes. 329 mL of CH3MgBr (3 M diethyldiether solution, 986.03 mmol) was slowly added dropwise and stirred at -78°C for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. Upon completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 5:1 (volume ratio)) to obtain 40.63 g (yield: 46%) of the title compound.

[0589] Step 3) Preparation of benzyl 4-(2-(piperazin-1-yl)propan-2-yl)piperidine-1-carboxylate

[0590] 40.6 g (91.11 mmol) of the compound prepared in step 2) above was diluted in 410 mL of dichloromethane, and 70.5 mL (911.13 mmol) of trifluoroacetic acid was slowly added. The reaction mixture was stirred at room temperature for 1 hour. When the reaction was complete, the reaction mixture was distilled under reduced pressure. The resulting residue was diluted in 200 mL of dichloromethane: methanol = 4:1, neutralized (pH = 7-8) with saturated aqueous sodium bicarbonate solution, and extracted twice with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained solid was stirred in MTBE for 1 hour, washed with MTBE, and filtered under reduced pressure. The resulting solid was dried in a drying oven (50°C for 12 hours to obtain 29 g (yield: 92%) of the title compound.

[0591] 1 H-NMR (300 MHz, DMSO-d6): δ7.38~7.27 (m, 5H), 5.04 (s, 2H), 4.08~4.03 (m, 2H), 3.00 (m, 4H), 2.70~2.62 (m, 6H), 1.67~1.63 (m, 3H), 1.08~1.03 (m, 2H), 0.82 (s, 6H).

[0592] Step 4) Preparation of benzyl 4-(2-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)propan-2-yl)piperidine-1-carboxylate

[0593] 5.4 g (32.26 mmol) of 1,2-difluoro-4-nitrobenzene and 12.44 g (34.93 mmol) of the compound prepared in step 3) above were diluted in 120 mL of N,N-dimethylformamide, cooled to 0°C, and 13.86 g (99.79 mmol) of potassium carbonate was added. The reaction mixture was stirred at 80°C for 2 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 1,200 mL of water was added, and stirred for 30 minutes. The resulting solid was washed with water and filtered under reduced pressure. The resulting solid was dried in a drying oven (at 50°C for 12 hours to obtain 12.94 g (yield: 80%) of the title compound.

[0594] 1 H-NMR (300 MHz, CDCl3): δ7.95~7.91 (m, 1H), 7.87~7.82 (m, 1H), 7.35~7.24 (m, 5H), 6.86~6.80 (m, 1H), 5.08 (s, 2H), 4.24~4.22 (m, 2H), 3.23~3.20 (m, 4H), 2.67~2.64 (m, 6H), 1.74~1.50 (m, 4H), 1.22~1.09 (m, 2H), 0.89 (s, 6H).

[0595] Step 5) Preparation of benzyl 4-(2-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidine-1-carboxylate

[0596] 12.9 g (26.62 mmol) of the compound prepared in the above step 4) was diluted in 140 mL of tetrahydrofuran: methanol = 1:1, and 7.05 g (107.82 mmol) of Zn and 11.53 g (215.63 mmol) of ammonium chloride were added at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. Upon completion of the reaction, the mixture was filtered under reduced pressure through a Celite-filled filter, washed with ethyl acetate, and the residue was purified by column chromatography (hexane: ethyl acetate = 1:1 (volume ratio)) to obtain 4.7 g (yield: 39%) of the title compound.

[0597] 1 H-NMR (300 MHz, CDCl3): δ7.33~7.25 (m, 5H), 6.78~6.72 (m, 1H), 6.41~6.33 (m, 2H), 5.09 (s, 2H), 3.48 (bs, 2H), 2.89 (m, 4H), 2.66~2.63 (m, 6H), 1.75~1.58 (m, 4H), 1.20~1.09 (m, 2H), 0.88 (s, 6H).

[0598] Step 6) Preparation of benzyl 4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidine-1-carboxylate

[0599] 4.7 g (10.34 mmol) of the compound prepared in the above step 5) and 7.94 g (41.36 mmol) of 3-bromopiperidine-2,6-dione were diluted in 100 mL of N,N-dimethylformamide, and 9.0 mL (51.96 mmol) of N,N-diethylisopropylamine was added. The reaction mixture was stirred at 120°C for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 2.72 g (yield: 47%) of the title compound.

[0600] 1 H-NMR (300 MHz, CDCl3): δ7.36~7.29 (m, 5H), 6.87~6.81 (m, 1H), 6.44~6.37 (m, 2H), 5.12 (s, 2H), 4.59~4.58 (m,2H), 4.00~3.96 (m, 1H), 3.00~2.49 (m, 9H), 1.92~1.61 (m, 4H), 1.25~1.17 (m, 2H), 0.92 (s, 6H).

[0601] Step 7) Preparation of 3-((3-fluoro-4-(4-(2-(piperidin-4-yl)propan-2-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0602] 2.72 g (4.81 mmol) of the compound prepared in step 6) above was diluted in 40 mL of tetrahydrofuran:methanol = 1:1, 1.0 g of activated 10% Pd / C was added, and the mixture was degassed under hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen gas for 5 hours. Upon completion of the reaction, the mixture was washed with ethyl acetate through a Celite-filled filter and filtered under reduced pressure, and the resulting filtrate was distilled under reduced pressure. The obtained residue was stirred in ethyl acetate and filtered under reduced pressure to obtain 1.14 g (final yield: 55%) of the title compound.

[0603] 1 H-NMR (300 MHz, DMSO-d6): δ6.81~6.75 (m, 1H), 6.51~6.45 (m, 1H), 6.40~6.37 (m, 1H), 5.78~5.75 (m, 1H), 4.27~4.20 (m, 1H), 3.06~2.97 (m, 2H), 2.79~2.65 (m, 5H), 2.57~2.40 (m, 8H), 2.09~2.04 (m, 1H), 1.89~1.81 (m, 1H), 1.79~1.64 (m, 3H), 1.15 (m, 2H), 0.88 (s, 6H).

[0604] MS (ESI + ):m / z= 432.27.

[0605] Manufacturing Example 16: Manufacturing of 3-((3-fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0606]

[0607] Step 1) Preparation of (1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methanol

[0608] 20 g (123.2 mmol) of 1,2-difluoro-4-nitrobenzene and 15.36 g (129.36 mmol) of 4-piperidinemethanol were diluted in 200 mL of N,N-dimethylformamide, cooled to 0°C, and 25.67 g (184.8 mmol) of potassium carbonate were added. The reaction mixture was warmed to room temperature and stirred for 7 hours. When the reaction was complete, 2,000 mL of water was added to the reaction mixture and stirred at room temperature for 30 minutes. The resulting solid was washed with water and filtered under reduced pressure. The resulting solid was dried in a drying oven (at 50°C for 24 hours to obtain 31.32 g (yield: 99%) of the title compound.

[0609] 1 H-NMR (300 MHz, DMSO-d6): δ7.97~7.90 (m, 2H), 7.15~7.09 (m, 2H), 4.51~4.47 (m, 1H), 3.70~3.66 (m, 2H), 3.30~3.26 (m, 2H), 2.93~2.84 (m, 2H), 1.77~1.73 (m, 2H), 1.66~1.54 (m, 1H), 1.30 (m, 2H).

[0610] Step 2) Preparation of 1-(2-fluoro-4-nitrophenyl)piperidine-4-carbaldehyde

[0611] 31.32 g (123.18 mmol) of the compound prepared in the above step 1) was diluted in 310 mL of dichloromethane, and 53.86 g (123.18 mmol) of Dess-Martin periodinane was added. The reaction mixture was stirred at room temperature for 2 hours. When the reaction was complete, a saturated aqueous sodium sulfite solution was added to the reaction mixture to terminate the reaction, and the mixture was extracted twice with dichloromethane. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 5: 1 (volume ratio)) to obtain 12.62 g (yield: 41%) of the title compound.

[0612] Step 3) Preparation of tert-butyl 4-((1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0613] 5.61 g (29.53 mmol) of tert-butyl piperazine-1-carboxylate and 11.17 g (44.30 mmol) of the compound prepared in step 2) were diluted in 320 mL of N,N-dimethylacetamide, 4.15 mL (72.156 mmol) of acetic acid was added, and the mixture was stirred at room temperature for 30 minutes. 41.71 g (196.79 mmol) of sodium triacetoxyborohydride was added, and the mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (n-hexane: ethyl acetate = 1: 1 (volume ratio)) to obtain 6.98 g (yield: 56%) of the title compound.

[0614] 1 H-NMR (300 MHz, CDCl3): δ7.95~7.83 (m, 2H), 6.89~6.84 (t, 1H), 3.70~3.66 (m, 2H), 3.41~3.37 (m, 4H), 2.87~2.79 (m, 2H), 2.34~2.31 (m, 4H), 2.21~2.19 (m, 2H), 1.88~1.83 (m, 2H), 1.73~1.64 (m, 1H), 1.40 (s, 9H), 1.39~1.31 (m, 2H).

[0615] Step 4) Preparation of tert-butyl 4-((1-(4-amino-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0616] 6.98 g (16.52 mmol) of the compound prepared in the above step 3) was diluted in 140 mL of ethyl acetate:tetrahydrofuran = 1:1, 1.4 g of 10% Pd / C was added, and degassed under hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen gas for 9 hours. Upon completion of the reaction, the residue was washed with ethyl acetate through a Celite-filled filter and filtered under reduced pressure. The resulting filtrate was distilled under reduced pressure to obtain 6.24 g (yield: 96%) of the title compound.

[0617] Step 5) Preparation of tert-butyl 4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[0618] 6.24 g (15.90 mmol) of the compound prepared in the above step 4) and 7.63 g (39.74 mmol) of 3-bromopiperidine-2,6-dione were diluted in 70 mL of N,N-dimethylformamide, and 8.31 mL (47.69 mmol) of N,N-diethylisopropylamine was added. The reaction mixture was stirred at 80°C for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 2.8 g (yield: 34%) of the title compound.

[0619] Step 6) Preparation of 3-((3-fluoro-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)phenyl)amino)piperidine-2,6-dione; hydrochloride

[0620] 2.8 g (5.56 mmol) of the compound prepared in the above step 5) was diluted in 54 mL of dichloromethane, 14 mL (55.60 mmol) of 4N-hydrochloric acid was slowly added dropwise at room temperature, and the mixture was stirred for 16 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 2.44 g (final yield: 99%) of the title compound.

[0621] MS (ESI + ):m / z= 404.24 [M+H] + .

[0622] Manufacturing Example 17: Manufacturing of 2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0623]

[0624] Step 1) Preparation of ethyl 2-((4-cyanophenethyl)amino)-2-phenylacetate

[0625] 10 g (41.14 mmol) of ethyl 2-bromo-2-phenylacetate was diluted in 50 mL of N,N-dimethylformamide, and 9.7 g (53.48 mmol) of 4-(2-aminoethyl)benzonitrile hydrochloride and 17.2 mL (123.41 mmol) of triethylamine were sequentially added, and the mixture was stirred at 60°C for 3 hours. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 9.5 g (yield: 75%) of the title compound.

[0626] 1H-NMR (300 MHz, CDCl3): δ7.58 (m, 2H), 7.34~7.28 (m, 7H), 4.39 (m, 1H), 4.28~4.10 (q, 2H), 2.90~2.77 (m, 4H), 1.21 (t, 3H).

[0627] Step 2) Preparation of 2-((4-cyanophenethyl)amino)-N-(5-iodopyridin-2-yl)-2-phenylacetamide

[0628] 6 g (27.27 mmol) of 5-iodopyridin-2-amine and 8.4 g (27.27 mmol) of the compound prepared in step 1) above were diluted in 50 mL of N,N-dimethylformamide, and 36.3 mL (54.54 mmol) of a 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution was slowly added at 0°C, followed by stirring for 2 hours. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 9.0 g (yield: 68%) of the title compound.

[0629] 1 H-NMR (300 MHz, DMSO-d6): δ10.54 (s, 1H), 8.52 (s, 1H), 8.11 (m, 1H), 7.93 (m, 1H), 7.72 (m. 2H), 7.44 (m, 5H), 7.27 (m, 3H), 4.52 (m, 1H), 2.85 (m, 2H), 2.74 (m, 2H).

[0630] Step 3) Preparation of 2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0631] 9 g (18.66 mmol) of the compound prepared in the above step 2) was diluted in 90 mL of a mixed solution of water: 1,4-dioxane (1:5 (volume ratio)), and 7.8 g (27.99 mmol) of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate, 1.5 g (1.87 mmol) of (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, and 18.2 g (56.98 mmol) of cesium carbonate were sequentially added, and the mixture was stirred at 90°C for 16 hours. When the reaction was complete, the reaction mixture was cooled to room temperature and washed with ethyl acetate. 4N hydrochloric acid was slowly added to the resulting aqueous layer at 0°C, and the resulting solid was filtered under reduced pressure and dried under reduced pressure to obtain 6.5 g (yield: 72%) of the title compound.

[0632] 1 H-NMR (300 MHz, DMSO-d6): δ10.75 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.98 (m, 3H), 7.71 (m. 2H), 7.44~7.38 (m, 7H), 4.94 (m, 2H),4.78 (s, 1H), 2.94 (m, 4H).

[0633] MS (ESI + ):m / z= 481.19 [M+H] + .

[0634] Manufacturing Example 18: Preparation of 2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0635]

[0636] Except for using 2-(4-(trifluoromethyl)phenyl)ethan-1-amine instead of 4-(2-aminoethyl)benzonitrile hydrochloride in step 1) of the above Preparation Example 17, the same process as steps 1), 2), and 3) of the above Preparation Example 17 was performed sequentially to obtain 2.3 g of the title compound (final yield: 27%).

[0637] 1 H-NMR (300 MHz, DMSO-d6): δ10.52 (s, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.63 (d, 2H), 7.46 (d, 4H), 7.37-7.28 (m, 3H), 4.96 (s, 2H), 3,57 (s, 1H), 2.94 (m, 2H), 2.78 (m, 2H).

[0638] MS (ESI + ):m / z= 523.18 [M+H] + .

[0639] Manufacturing Example 19: Manufacturing of 2-(4-(6-(2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0640]

[0641] Step 1) Preparation of 1-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonitrile

[0642] 13.1 g (317.58 mmol) of sodium hydroxide was dissolved in 20 mL of distilled water, and then 10.0 g (52.93 mmol) of 2-(4-(trifluoromethyl)phenyl)acetonitrile, 6.7 mL (79.39 mmol) of 1-bromo-2-chloro-ethane, and 241 mg (1.06 mmol) of benzyltriethylammonium chloride were added. The resulting reaction mixture was stirred at 50°C for 16 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 11.2 g (yield: 99%) of the title compound.

[0643] 1 H-NMR (300 MHz, CDCl3): δ7.62 (d, 2H), 7.39 (d, 2H), 1.83 (t, 2H), 1.45 (t, 2H).

[0644] Step 2) Preparation of (1-(4-(trifluoromethyl)phenyl)cyclopropyl)methanamine

[0645] 9.2 g (43.46 mmol) of the compound prepared in the above step 1) was diluted in 180 mL of tetrahydrofuran, and 24 mL (56.50 mmol) of a 2.4 M tetrahydrofuran solution of lithium aluminum hydride was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. When the reaction was complete, 180 mL of tetrahydrofuran was added, and 30 mL of distilled water and a 2 M aqueous sodium hydroxide solution were slowly added at 0°C. Anhydrous sodium sulfate was added to the resulting reaction mixture and stirred for 10 minutes. The resulting reaction mixture was washed with ethyl acetate through a Celite-packed filter and filtered under reduced pressure. The resulting filtrate was washed with saturated brine and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 9.3 g (yield: 99%) of the title compound.

[0646] 1 H-NMR (300 MHz, CDCl3): δ7.56 (d, 2H), 7.43 (d, 2H), 2.83 (s, 2H), 0.83 (m, 4H).

[0647] Step 3) Preparation of ethyl 2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetate

[0648] 982 mg (4.56 mmol) of the compound prepared in the above step 2) and 1.1 g (4.56 mmol) of ethyl 2-bromo-2-phenylacetate were diluted in 10 mL of tetrahydrofuran, and 1.9 mL (13.69 mmol) of triethylamine was added. The resulting reaction mixture was stirred at 70°C for 3 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, washed with distilled water, and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 1.2 g (yield: 71%) of the title compound.

[0649] 1 H-NMR (300 MHz, CDCl3): δ7.53 (d, 2H), 7.43 (d, 2H), 7.29 (m, 5H), 4.33 (s, 1H), 4.18~4.06 (m, 2H), 2.74 (q, 2H), 1.17 (t, 3H), 0.83 (m, 4H).

[0650] Step 4) Preparation of N-(5-iodopyridin-2-yl)-2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide

[0651] 1.2 g (3.26 mmol) of the compound prepared in the above step 3) and 1.1 g (4.89 mmol) of 5-iodopyridin-2-amine were diluted in 10 mL of N,N-dimethylformamide, and 6.5 mL (6.52 mmol) of 1 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was washed with distilled water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 1.4 g (yield: 78%) of the title compound.

[0652] 1 H-NMR (300 MHz, CDCl3): δ9.48 (brs, 1H), 8.43 (s, 1H), 7.98 (d, 1H), 7.88 (d, 1H), 7.57 (d, 2H), 7.46 (d, 2H), 7.33 (m, 5H), 4.22 (s, 1H), 2.88 (s, 2H), 0.95~0.80 (m, 4H).

[0653] Step 5) Preparation of 2-(4-(6-(2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0654] 1.4 g (2.56 mmol) of the compound prepared in the above step 4), 1.7 g (6.64 mmol) of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate, 200 mg (0.26 mmol) of SPhos Pd G3, and 2.5 g (7.67 mmol) of cesium carbonate were diluted in 25 mL of a 1,4-dioxane : distilled water = 4 : 1 (volume ratio) mixed solution. The resulting reaction mixture was stirred at 120°C for 18 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and a 2 N hydrochloric acid aqueous solution was added dropwise until the pH became 3. The resulting mixture was washed with distilled water and filtered under reduced pressure. The resulting solid compound was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 916 mg of the title compound (final yield: 65%).

[0655] 1 H-NMR (300 MHz, CDCl3): δ8.23 (brs, 1H), 8.07 (d, 1H), 7.70 (m, 3H), 7.67~7.40 (m, 5H), 7.28 (m, 5H), 4.90 (d, 3H), 4.52 (brs, 1H), 2.88 (m, 2H), 0.97~0.80 (m, 5H).

[0656] MS (ESI + ):m / z= 550.20 [M+H] + .

[0657] Manufacturing Example 20: Manufacturing of 2-(4-(3-(2-((4-cyanophenethyl)amino)-2-phenylacetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetic acid

[0658]

[0659] Step 1) Preparation of 1-(6-iodo-1H-indol-3-yl)-2-phenylethan-1-one

[0660] 6-Iodo-1H-indole (10 g, 41.14 mmol) was diluted in 200 mL of dichloromethane, and 61 mL (61.72 mmol) of 1.0 M diethylaluminum chloride hexane solution was slowly added at 0°C, followed by stirring for 2 hours. 8.3 mL (61.72 mmol) of phenylacetyl chloride was added to the reaction mixture, and after the reaction was completed, the mixture was stirred for 4 hours at 0°C. Upon completion of the reaction, a saturated aqueous sodium bicarbonate solution was slowly added to the reaction mixture at 0°C, and the obtained solid was filtered under reduced pressure and dried under reduced pressure to obtain 14.5 g (yield: 98%) of the title compound.

[0661] 1 H-NMR (300 MHz, DMSO-d6): δ8.50 (m, 1H), 7.98 (m, 1H), 7.84 (s, 1H), 7.47 (m, 1H), 7.33~7.28 (m. 6H), 4.16 (s, 2H).

[0662] Step 2) Preparation of 2-bromo-1-(6-iodo-1H-indol-3-yl)-2-phenylethan-1-one

[0663] 7.0 g (19.38 mmol) of the compound prepared in the above step 1) was diluted in 210 mL of tetrahydrofuran, and a solution of 8.0 g (21.32 mmol) of trimethylphenylaluminum tribromide diluted in 70 mL of tetrahydrofuran was slowly added at 0°C, followed by stirring at room temperature for 4 hours. Upon completion of the reaction, the reaction mixture was diluted in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The resulting organic layer was dried over anhydrous sodium sulfate, and the resulting solid was washed with ethyl acetate, filtered under reduced pressure, and dried under reduced pressure to obtain 7.1 g (yield: 83%) of the title compound.

[0664] 1H-NMR (300 MHz, DMSO-d6): δ8.61 (m, 1H), 7.97 (m, 1H), 7.86 (s, 1H), 7.68 (m, 2H), 7.51 (m. 1H), 7.34 (m. 3H), 6.83 (s, 1H).

[0665] Step 3) Preparation of 2-(4-(3-(2-((4-cyanophenethyl)amino)-2-phenylacetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetic acid

[0666] Except for using the compound prepared in step 2) instead of 2-((4-cyanophenethyl)amino)-N-(5-iodopyridin-2-yl)-2-phenylacetamide in step 3) of the above Manufacturing Example 17, the same process as in steps 1) and 3) of the above Manufacturing Example 19 was sequentially performed to obtain 1.3 g of the title compound (final yield: 65%).

[0667] 1 H-NMR (300 MHz, DMSO-d6): δ12.26 (s, 1H), 8.51 (m, 1H), 8.16 (m, 2H), 7.90 (s, 1H), 7.79 (m. 2H), 7.66 (m, 3H), 7.44 (m, 5H), 4.96 (m, 3H), 3,12 (m, 4H).

[0668] MS (ESI + ):m / z= 504.20 [M+H] + .

[0669] Manufacturing Example 21: Manufacturing of 2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetic acid

[0670]

[0671] Except for using 2-(4-(trifluoromethyl)phenyl)ethan-1-amine instead of 4-(2-aminoethyl)benzonitrile hydrochloride in step 3) of the above Preparation Example 20, the same process as steps 3) and 4) of the above Preparation Example 20 was performed sequentially to obtain 1.5 g of the title compound (final yield: 37%).

[0672] 1 H-NMR (300 MHz, DMSO-d6): δ12.28 (s, 1H), 8.48 (d, 1H), 8.17 (s, 1H), 8.15 (d, 1H), 7.92 (s, 1H), 7.68 (m, 4H), 7.62 (s, 1H), 7.48 (m, 6H), 4.98 (s, 2H), 3,57 (s, 1H), 3.24-2.92 (m, 4H)

[0673] MS (ESI + ):m / z= 546.55 [M+H] + .

[0674] Manufacturing Example 22: Preparation of 2-(4-(6-(2-((3-(4-cyanophenyl)prop-2-yn-1-yl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0675]

[0676] Step 1) Preparation of tert-butyl (3-(4-cyanophenyl)prop-2-yn-1-yl)carbamate

[0677] 5.0 g (21.83 mmol) of 4-iodobenzonitrile and 5.3 g (21.83 mmol) of tert-butyl prop-2-yn-1-ylcarbamate were diluted in 50 mL of tetrahydrofuran, and 1.26 g (1.09 mmol) of tetrakis(triphenylphosphine)palladium, 208 mg (1.09 mmol) of cuprous iodide, and 4.26 mL (30.57 mmol) of triethylamine were added. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 19: 1 (volume ratio)) to obtain 5.4 g (yield: 72%) of the title compound.

[0678] 1 H-NMR (300 MHz, DMSO-d6): δ7.86 (m, 2H), 7.52 (m, 2H), 7.28 (s, 1H), 4.03 (d, 2H), 1.40 (s. 9H).

[0679] Step 2) Preparation of 2-(4-(6-(2-((3-(4-cyanophenyl)prop-2-yn-1-yl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0680] Except for using the compound prepared in step 1) instead of tert-butyl 4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazine-1-carboxylate in step 5) of the above Preparation Example 1, the same process as in step 5) of Preparation Example 1 and steps 1), 2), and 3) of Preparation Example 17 was performed sequentially to obtain 295 mg of the title compound (final yield: 65%).

[0681] MS (ESI + ):m / z= 491.18 [M+H] + .

[0682] Manufacturing Example 23: Manufacturing of (R)-2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0683]

[0684] Step 1) Preparation of 4-(2-oxoethyl)benzonitrile

[0685] 50.0 g (332.93 mmol) of 4-(2-hydroxyethyl)benzonitrile was diluted in 1 L of dichloromethane, and 172.9 g (399.51 mmol) of Dess-Martin periodinane was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. When the reaction was complete, a saturated aqueous sodium bicarbonate solution was slowly added at 0°C, and the resulting mixture was filtered under reduced pressure. The resulting filtrate was extracted with dichloromethane and washed with a saturated aqueous sodium sulfite solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 35.9 g (yield: 74%) of the title compound.

[0686] 1 H-NMR (300 MHz, CDCl3): δ9.79 (t, 1H), 7.66 (d, 2H), 7.33 (dd, 2H), 3.81 (m, 2H).

[0687] Step 2) Preparation of ethyl (R)-2-((4-cyanophenethyl)amino)-2-phenylacetate

[0688] 35.9 g (247.45 mmol) of the compound prepared in the above step 1) was diluted in 700 mL of methanol, and 82.5 g (371.18 mmol) of ethyl (2R)-2-amino-2-phenylacetate hydrochloride and 52.3 mL (371.18 mmol) of triethylamine were added, and the reaction mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was cooled to 0°C, and 57.3 g (866.08 mmol) of sodium cyanoborohydride was slowly added. The resulting reaction mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the reaction mixture was washed with distilled water and extracted with dichloromethane. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 54.8 g (yield: 72%) of the title compound.

[0689] 1 H-NMR (300 MHz, CDCl3): δ7.56 (d, 2H), 7.33 (m, 7H), 4.33 (d, 1H), 4.15 (q, 2H), 2.85 (m, 4H), 1.19 (t, 3H).

[0690] Step 3) Preparation of (R)-2-((4-cyanophenethyl)amino)-N-(5-iodopyridin-2-yl)-2-phenylacetamide

[0691] 12.0 g (38.91 mmol) of the compound prepared in the above step 1) and 17.5 g (77.83 mmol) of 5-iodopyridin-2-amine were diluted in 240 mL of toluene, and 78.0 mL (54.54 mmol) of a 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution was added dropwise at -78°C, followed by stirring for 20 hours. When the reaction was complete, a saturated aqueous ammonium chloride solution was added at the same temperature. The resulting mixture was extracted with ethyl acetate, and the separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 9.0 g (yield: 48%) of the title compound.

[0692] 1 H-NMR (300 MHz, DMSO-d6): δ10.54 (s, 1H), 8.52 (s, 1H), 8.11 (m, 1H), 7.93 (m, 1H), 7.72 (m. 2H), 7.44 (m, 4H), 7.27 (m, 3H), 4.52 (m, 1H), 2.85 (m, 2H), 2.74 (m, 2H).

[0693] Step 4) Preparation of (R)-2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0694] 9.0 g (18.66 mmol) of the compound prepared in the above step 2) was diluted in 180 mL of a mixed solution of water: 1,4-dioxane (1:5 (volume ratio)), and 9.9 g (33.59 mmol) of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate, 2.2 g (1.86 mmol) of tetrakis(triphenylphosphine)palladium(0), and 10.0 g (93.30 mmol) of sodium carbonate were added, and the mixture was stirred at 70°C for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 1 N aqueous hydrochloric acid solution was added, and then extracted with a dichloromethane: methanol = 4:1 (volume ratio) solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 1.2 g of the title compound (final yield: 13%).

[0695] 1 H-NMR (300 MHz, DMSO-d6): δ10.44 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.98 (m, 3H), 7.71 (m. 2H), 7.44~7.38 (m, 7H), 6.22 (m, 1H), 4.78 (m, 2H), 4.52 (s, 1H), 2.88 (m, 2H), 2.76 (m, 2H).

[0696] MS (ESI + ):m / z= 481.19 [M+H] + .

[0697] Manufacturing Example 24: Manufacturing of (R)-2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0698]

[0699] Except for using 2-(4-(trifluoromethyl)phenyl)ethan-1-ol instead of 4-(2-hydroxyethyl)benzonitrile in step 1) of the above Preparation Example 23, the same process as steps 1), 2), 3), and 4) of the above Preparation Example 23 was performed sequentially to obtain 702 mg of the title compound (final stage yield: 70%).

[0700] 1 H-NMR (300 MHz, DMSO-d6): δ10.52 (brs, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.63 (d, 2H), 7.46 (d, 4H), 7.37-7.28 (m, 3H), 4.96 (s, 2H), 3.57 (s, 1H), 2.94 (m, 2H), 2.78 (m, 2H).

[0701] MS (ESI + ):m / z= 524.18 [M+H] + .

[0702] Manufacturing Example 25: Manufacturing of (S)-2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0703]

[0704] The same process as steps 1), 2), 3), and 4) of the above Preparation Example 24 was sequentially performed, except that ethyl (2S)-2-amino-2-phenylacetate; hydrochloride was used instead of ethyl (2R)-2-amino-2-phenylacetate; hydrochloride in step 2) of the above Preparation Example 24, to obtain 381 mg of the title compound (final yield: 38%).

[0705] 1H-NMR (300 MHz, DMSO-d6): δ10.52 (brs, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 8.04 (d, 2H), 7.97 (s, 1H), 7.63 (d, 2H), 7.46 (d, 4H), 7.37-7.28 (m, 3H), 4.96 (s, 2H), 3.57 (s, 1H), 2.94 (m, 2H), 2.78 (m, 2H).

[0706] MS (ESI + ):m / z= 524.18 [M+H] + .

[0707] Manufacturing Example 26: Manufacturing of (R)-2-(4-(6-(2-((4-fluorophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0708]

[0709] Except for using 2-(4-fluorophenyl)ethan-1-ol instead of 4-(2-hydroxyethyl)benzonitrile in step 1) of the above Preparation Example 23, the same process as steps 1), 2), 3), and 4) of the above Preparation Example 23 was performed sequentially to obtain 4.2 g of the title compound (final yield: 60%).

[0710] 1 H-NMR (300 MHz, DMSO-d6): δ10.58 (brs, 1H), 8.58 (m, 1H), 8.21 (m, 1H), 8.05 (m, 2H), 7.92 (m, 2H), 7.45 (m, 2H), 7.35 (m, 5H), 7.25 (m, 3H), 4.92 (s, 2H), 4.62 (m, 1H), 2.79 (m, 2H), 2.52 (m, 2H).

[0711] MS (ESI + ):m / z= 474.19 [M+H] + .

[0712] Manufacturing Example 27: Preparation of 2-(4-(6-((R)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0713]

[0714] Step 1) Preparation of 2-(4-(trifluoromethyl)phenyl)acetyl chloride

[0715] 40.0 g (190.06 mmol) of 2-(4-(trifluoromethyl)phenyl)acetic acid was diluted in 84.4 mL (1162.3 mmol) of thionyl chloride and stirred at room temperature for 18 hours. Upon completion of the reaction, the residue was distilled under reduced pressure to obtain 30.4 g (yield: 99%) of the title compound.

[0716] Step 2) Preparation of (S)-4-benzyl-3-(2-(4-(trifluoromethyl)phenyl)acetyl)oxazolidin-2-one

[0717] (S)-(-)-4-Benzyl-2-oxazolidinone 27.4 g (150.23 mmol) was diluted in 450 mL of tetrahydrofuran, and 94 mL (150.23 mmol) of 1.6 M n-butyllithium hexane solution was added dropwise at -78°C. The resulting reaction mixture was stirred at the same temperature for 30 minutes. 30.4 g (136.57 mmol) of the compound prepared in step 1) was diluted in 180 mL of tetrahydrofuran, and added dropwise to the above reaction mixture at -78°C. Upon completion of the reaction, a saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, and then washed with saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 25.4 g (yield: 51%) of the title compound.

[0718] Step 3) Preparation of (S)-4-benzyl-3-((S)-2-(4-(trifluoromethyl)phenyl)propanoyl)oxazolidin-2-one

[0719] 46.0 g (126.6 mmol) of the compound prepared in the above step 2) was diluted in 200 mL of tetrahydrofuran, and 152 mL (151.92 mmol) of a 1 M sodium bis(trimethylsilyl)amide tetrahydrofuran solution was added dropwise at -78°C. The resulting reaction mixture was stirred at the same temperature for 1 hour. 9.5 mL (151.92 mmol) of methyl iodide was diluted in 30 mL of tetrahydrofuran, and added dropwise to the above reaction mixture at the same temperature. The resulting reaction mixture was stirred at the same temperature for 1 hour, and then at room temperature for 1 hour. Upon completion of the reaction, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, and washed with saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 25.7 g (yield: 54%) of the title compound.

[0720] 1 H-NMR (300 MHz, CDCl3): δ7.58 (d, 2H), 7.48 (d, 2H), 7.27 (m, 5H), 5.17 (t, 1H), 4.65 (m, 1H), 4.11 (m, 2H), 3.35 (dd, 1H), 2.81 (m, 1H), 1.59 (d, 3H).

[0721] Step 4) Preparation of (S)-2-(4-(trifluoromethyl)phenyl)propan-1-ol

[0722] 25.7 g (68.10 mmol) of the compound prepared in the above step 3) was diluted in 260 mL of diethyl ether, and 68 mL (136.21 mmol) of 2 M lithium borohydride was added dropwise at 0°C. The resulting reaction mixture was stirred at the same temperature for 1 hour. Upon completion of the reaction, 1 M aqueous sodium hydroxide solution was slowly added at the same temperature, and extracted twice with ethyl acetate. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 10.6 g (yield: 76%) of the title compound.

[0723] 1 H-NMR (300 MHz, CDCl3): δ7.58 (d, 2H), 7.36 (d, 2H), 3.74 (t, 2H), 3.03 (q, 1H), 1.30 (d, 3H).

[0724] Step 5) Preparation of (S)-2-(4-(trifluoromethyl)phenyl)propanol

[0725] 10.6 g (51.91 mmol) of the compound prepared in the above step 4) was diluted in 220 mL of dichloromethane, and 27.81 g (62.29 mmol) of Dess-Martin periodinane was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. When the reaction was complete, a saturated aqueous sodium bicarbonate solution was slowly added at 0°C, and the resulting mixture was filtered under reduced pressure. The resulting filtrate was extracted with ethyl acetate and washed with a saturated aqueous sodium sulfite solution. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 8.9 g (yield: 85%) of the title compound.

[0726] 1H-NMR (300 MHz, CDCl3): δ9.70 (d 1H), 7.64 (d, 2H), 7.34 (d, 2H), 3.73 (q, 1H), 1.48 (d, 3H).

[0727] Step 6) Preparation of ethyl (R)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetate

[0728] 8.9 g (44.02 mmol) of the compound prepared in the above step 5) was diluted in 180 mL of methanol, and 14.7 g (66.03 mmol) of ethyl (2R)-2-amino-2-phenylacetate hydrochloride and 9.3 mL (66.03 mmol) of triethylamine were added, and the reaction mixture was stirred at room temperature for 1 hour. The resulting reaction mixture was cooled to 0°C, and 9.9 g (154.07 mmol) of sodium cyanoborohydride was slowly added. The resulting reaction mixture was stirred at room temperature for 18 hours. Upon completion of the reaction, the reaction mixture was washed with distilled water and extracted with dichloromethane. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 6: 1 (volume ratio)) to obtain 6.6 g (yield: 41%) of the title compound.

[0729] 1 H-NMR (300 MHz, CDCl3): δ7.53 (d, 2H), 7.30 (m, 7H), 4.30 (s, 1H), 4.11 (q, 2H), 2.99 (m, 1H), 2.65 (m, 2H), 1.28 (d, 3H), 1.17 (t, 3H).

[0730] Step 7) Preparation of (R)-N-(5-iodopyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide

[0731] 6.6 g (18.03 mmol) of the compound prepared in the above step 6) and 5.9 g (27.05 mmol) of 5-iodopyridin-2-amine were diluted in 130 mL of toluene, and 36.0 mL (36.07 mmol) of 1 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution was added dropwise at -78°C, followed by stirring for 16 hours. When the reaction was complete, a saturated aqueous ammonium chloride solution was added at the same temperature. The resulting mixture was extracted with ethyl acetate, and the separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 20: 1 (volume ratio)) to obtain 6.7 g (yield: 68%) of the title compound.

[0732] 1 H-NMR (300 MHz, CDCl3): δ9.65 (s, 1H), 8.48 (s, 1H), 8.03 (d, 1H), 7.92 (dd, 1H), 7.55 (dd. 2H), 7.32 (m, 8H), 4.21 (s, 1H), 3.07 (q, 1H), 2.86 (m, 2H), 1.33 (d, 3H).

[0733] Step 8) Preparation of 2-(4-(6-((R)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0734] 6.7 g (12.35 mmol) of the compound prepared in the above step 7) was diluted in 120 mL of a mixed solution of water: 1,4-dioxane (1:5 (volume ratio)), and 6.6 g (22.22 mmol) of ethyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate, 1.5 g (1.23 mmol) of tetrakis(triphenylphosphine)palladium(0), and 6.6 g (67.74 mmol) of sodium carbonate were added, and the mixture was stirred at 70°C for 23 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, 1 M aqueous hydrochloric acid solution was added, and then extracted three times with a dichloromethane: methanol = 4:1 (volume ratio) solution. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 2.6 g of the title compound (final yield: 39%).

[0735] 1 H-NMR (300 MHz, DMSO-d6): δ10.49 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.98 (m, 3H), 7.65 (m. 2H), 7.55~7.28 (m, 7H), 6.21 (m, 1H), 4.88 (m, 2H), 3.11 (m, 1H), 2.57 (m, 2H), 1.26 (d, 3H).

[0736] MS (ESI + ):m / z= 538.20 [M+H] + .

[0737] Manufacturing Example 28: Manufacturing of 2-(4-(6-(2-(((S)-2-(4-cyanophenyl)propyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0738]

[0739] Except for using 2-(4-cyanophenyl)acetic acid instead of 2-(4-(trifluoromethyl)phenyl)acetic acid in step 1) of the above Preparation Example 27 and using ethyl 2-amino-2-phenylacetate; hydrochloride instead of ethyl (2R)-2-amino-2-phenylacetate; hydrochloride in step 6) of the above Preparation Example 27, the same process as steps 1), 2), 3), 4), 5), 6), 7), and 8) of the above Preparation Example 27 was performed sequentially to obtain 220 mg of the title compound (final yield: 60%).

[0740] MS (ESI + ):m / z= 495.21 [M+H] + .

[0741] Manufacturing Example 29: Preparation of 2-(4-(6-((S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid

[0742]

[0743] Except for separating the diastereoisomers in step 6) of the above Manufacturing Example 28, the same processes as steps 1), 2), 3), 4), 5), 6), 7), and 8) of the above Manufacturing Example 28 were performed sequentially to obtain 490 mg of the title compound (final stage yield: 74%).

[0744] 1 H-NMR (300 MHz, DMSO-d6): δ11.30 (s, 1H), 9.77 (brs, 1H), 9.37 (brs, 1H), 8.59 (s, 1H), 8.21 (s, 1H), 8.01 (m, 3H), 7.85 (d, 2H), 7.65 (m. 2H), 7.60~7.45 (m, 5H), 5.15 (m, 1H), 4.98 (S, 2H), 2.99 (m, 2H), 1.35 (m, 1H), 1.22 (d, 3H).

[0745] MS (ESI + ):m / z= 495.21 [M+H]+ .

[0746] Manufacturing Example 30: Preparation of 3-(3-methyl-2-oxo-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; hydrochloride

[0747]

[0748] Step 1) Preparation of 2,6-bis(benzyloxy)-3-nitropyridine

[0749] Benzyl alcohol (147.5 g, 1357.1 mmol) was diluted in 1 L of tetrahydrofuran, and 138.1 g (1206.3 mmol) of potassium tert-butoxide was slowly added at -15°C. The resulting reaction mixture was stirred at room temperature for 30 minutes. 2,6-dichloro-3-nitro-pyridine (100 g, 502.64 mmol) was diluted in 700 mL of tetrahydrofuran, and added dropwise to the reaction mixture at -15°C. The resulting reaction mixture was stirred at room temperature for 12 hours. When the reaction was complete, 2 L of ice water was added, and the mixture was stirred for 30 minutes. The resulting mixture was washed with distilled water and filtered. The resulting solid was dried in a drying oven (at 50°C for 24 hours to obtain 143.4 g (yield: 85%) of the title compound.

[0750] 1 H-NMR (300 MHz, DMSO-d6): δ8.45 (d, 1H), 7.40 (m, 10H), 6.61 (d, 1H), 5.56 (s, 2H), 5.46 (s, 2H).

[0751] Step 2) Preparation of 2,6-bis(benzyloxy)pyridin-3-amine

[0752] 35.63 g (142.7 mmol) of cupric sulfate pentahydrate was diluted in 800 mL of methanol, and 120.0 g (356.8 mmol) of the compound prepared in step 1) was added to the solution diluted in 800 mL of dichloromethane. The resulting reaction mixture was cooled to -15°C, and 81.0 g (2140.6 mmol) of sodium borohydride was slowly added. The resulting reaction mixture was stirred at -5°C for 1 hour. When the reaction was complete, 1 L of ice water was added. The resulting mixture was filtered under reduced pressure through a Celite-packed filter, and the resulting filtrate was extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 4:1 (volume ratio)) to obtain 82.3 g (yield: 75%) of the title compound.

[0753] 1 H-NMR (300 MHz, CDCl3): δ7.41 (m, 10H), 6.96 (d, 1H), 6.24 (d, 1H), 5.37 (s, 2H), 5.25 (s, 2H), 3.40 (brs, 2H).

[0754] Step 3) Preparation of 2,6-bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine

[0755] 82.3 g (268.8 mmol) of the compound prepared in the above step 2) was diluted in 500 mL of tetrahydrofuran, and 403 mL of a 1.0 M lithium bis(trimethylsilyl)amide tetrahydrofuran solution was added dropwise at -78°C. The resulting reaction mixture was stirred at the same temperature for 1 hour. 37.2 mL (295.7 mmol) of 4-bromo-1-fluoro-2-nitrobenzene was diluted in 300 mL of tetrahydrofuran, and then added to the above reaction mixture at -78°C. The resulting reaction mixture was stirred at the same temperature for 1 hour. Upon completion of the reaction, distilled water was added, extracted with ethyl acetate, and washed with saturated brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 10:1 (volume ratio)) to obtain 37.9 g (yield: 28%) of the title compound.

[0756] 1 H-NMR (300 MHz, CDCl3): δ9.14 (s, 1H), 8.31 (d, 1H), 7.51 (d, 1H), 7.38 (m, 11H), 6.72 (d, 1H), 6.43 (d, 1H), 5.38 (s, 2H), 5.36 (s, 2H).

[0757] Step 4)N 1 Preparation of -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine

[0758] 39.6 g (599.3 mmol) of zinc powder and 0.7 mL (7.5 mmol) of concentrated hydrochloric acid were added to 1 L of a methanol:tetrahydrofuran = 4:1 (volume ratio) solution. The resulting reaction mixture was stirred at room temperature for 1 hour, and then 37.9 g (74.9 mmol) of the compound prepared in step 3) and 23.6 g (374.5 mmol) of ammonium formate were added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Upon completion of the reaction, the resulting reaction mixture was filtered under reduced pressure, washed with 750 mL of methanol through a Celite-packed filter. The resulting filtrate was distilled under reduced pressure, and 400 mL of dichloromethane and 400 mL of ammonia water were added. The resulting mixture was stirred at room temperature for 30 minutes. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with ethyl acetate and methyl tert-butyl ether, filtered under reduced pressure, and dried in a drying oven (at 50°C) to obtain 35.6 g (yield: 99%) of the title compound.

[0759] Step 5) Preparation of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0760] 35.6 g (74.7 mmol) of the compound prepared in the above step 4) was diluted in 356 mL of N,N-dimethylformamide, and 38.3 g (224.2 mmol) of 1,1'-carbonyldiimidazole was added. The resulting reaction mixture was stirred at room temperature for 16 hours. When the reaction was complete, distilled water was added, and extraction was performed with ethyl acetate. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with methyl tert-butyl ether and hexane, filtered under reduced pressure, and dried under reduced pressure to obtain 30 g (yield: 80%) of the title compound.

[0761] 1H-NMR (300 MHz, DMSO-d6): δ7.78 (d, 1H), 7.39 (m, 6H), 7.22 (m, 5H), 7.15 (m, 1H), 6.59 (m, 2H), 5.36 (m, 4H).

[0762] Step 6) Preparation of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[0763] 30.0 g (59.7 mmol) of the compound prepared in the above step 5) was diluted in 300 mL of N,N-dimethylformamide, and 7.2 g (179.1 mmol) of sodium hydride was slowly added at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour, and then 3.7 mL (59.7 mmol) of methyl iodide was added. The resulting reaction mixture was stirred at room temperature for 1 hour. When the reaction was complete, ice water was added, and extraction was performed with ethyl acetate. The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with hexane, filtered under reduced pressure, and dried under reduced pressure to obtain 26.3 g (yield: 85%) of the title compound.

[0764] 1 H-NMR (300 MHz, DMSO-d6): δ7.79 (d, 1H), 7.40 (m, 6H), 7.22 (m, 5H), 7.15 (m, 1H), 6.61 (t, 2H), 5.36 (m, 4H), 3.37 (s, 3H).

[0765] Step 7) Preparation of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0766] 26.3 g (51.0 mmol) of the compound prepared in the above step 6) and 10.7 g (56.1 mmol) of tert-butyl piperazine-1-carboxylate were diluted in 250 mL of 1,4-dioxane and degassed under nitrogen gas for 15 minutes, and then 4.9 g (10.2 mmol) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and 4.8 g (5.10 mmol) of tris(dibenzylideneacetone)dipalladium(0) were added. The resulting reaction mixture was stirred at 90°C under nitrogen gas for 18 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, washed with ethyl acetate, and filtered under reduced pressure through a Celite-packed filter. The resulting filtrate was distilled under reduced pressure, and the resulting residue was separated by column chromatography (hexane: ethyl acetate = 1: 1 (volume ratio)) to obtain 26.0 g (yield: 82%) of the title compound.

[0767] 1 H-NMR (300 MHz, CDCl3): δ7.59 (d, 1H), 7.38 (m, 5H), 7.25 (m, 5H), 6.68 (m, 1H), 6.62 (m, 2H), 6.50 (d, 1H), 5.42 (m, 1H), 5.36 (m, 3H), 3.62 (m, 4H), 3.45 (s, 3H), 3.08 (m, 4H), 1.49 (s, 9H).

[0768] Step 8) Preparation of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0769] 26.0 g (41.8 mmol) of the compound prepared in the above step 7) was diluted in 260 mL of tetrahydrofuran, degassed under nitrogen gas for 10 minutes, and 8.9 g (8.4 mmol) of activated 10% Pd / C was added. The resulting reaction mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. Upon completion of the reaction, the resulting reaction mixture was filtered through a Celite-packed filter, washing with a solution of dichloromethane: methanol = 4: 1 (volume ratio). The resulting filtrate was distilled under reduced pressure, and the resulting solid was washed with ethyl acetate and filtered under reduced pressure to obtain 1.6 g (yield: 9%) of the title compound.

[0770] 1 H-NMR (300 MHz, DMSO-d6): δ6.96 (d, 1H), 6.87 (m, 1H), 6.65 (dd, 1H), 5.29 (m, 1H), 3.48 (m, 4H), 3.02 (m, 4H), 2.88 (m, 1H), 2.64 (m, 3H), 1.97 (m, 1H), 1.42 (s, 9H).

[0771]

[0772] Step 9) Preparation of 3-(3-methyl-2-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; hydrochloride

[0773] 1.6 g (3.72 mmol) of the compound prepared in the above step 8) was diluted in 35 mL of dichloromethane, and 9.5 mL (37.2 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the resulting reaction mixture was distilled under reduced pressure. The resulting solid was washed with ethyl acetate and filtered under reduced pressure to obtain 1.4 g (yield: 99%) of the title compound.

[0774] 1H-NMR (300 MHz, DMSO-d6): δ11.06 (s, 1H), 8.98 (brs, 2H), 7.00 (d, 1H), 6.90 (m, 1H), 6.69 (dd, 1H), 5.29 (m, 1H), 3.48 (m, 4H), 3.02 (m, 4H), 2.88 (m, 1H), 2.64 (m, 3H), 1.97 (m, 1H).

[0775] Step 10) Preparation of tert-butyl 4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

[0776] 1.4 g (3.71 mmol) of the compound prepared in the above step 9) and 2.9 g (13.0 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 40 mL of N,N-dimethylacetamide, and 0.47 mL (8.17 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 2 hours, and then 4.7 g (22.3 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mixture was stirred at room temperature for 4 hours. When the reaction was completed, distilled water was slowly added, washed with ethyl acetate, and extracted with distilled water. The resulting separated aqueous layer was basified with saturated sodium bicarbonate and extracted with a solution of dichloromethane: methanol = 4: 1 (volume ratio). The resulting separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with methanol and filtered under reduced pressure to obtain 1.5 g (yield: 75%) of the title compound.

[0777] 1H-NMR (300 MHz, DMSO-d6): δ11.05 (s, 1H), 6.93 (d, 1H), 6.82 (m, 1H), 6.62 (dd, 1H), 5.28 (m, 1H), 4.09 (q, 1H), 3.92 (m, 2H), 3.31 (m, 3H), 3.18 (d, 3H), 3.09 (m, 4H), 2.88 (m, 1H), 2.65 (m, 4H), 2.18 (m, 2H), 1.97 (m, 1H), 1.72 (m, 2H), 1.39 (s, 9H).

[0778] Step 11) Preparation of 3-(3-methyl-2-oxo-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; hydrochloride

[0779] 1.5 g (2.81 mmol) of the compound prepared in step 10) above was diluted in 30 mL of dichloromethane, and 7 mL (28.1 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was distilled under reduced pressure, diluted with ethyl acetate, and stirred at room temperature for 1 hour. The resulting mixture was filtered under reduced pressure and washed with ethyl acetate. The resulting solid was dried under reduced pressure to obtain 1.9 g (final yield: 99%) of the title compound.

[0780] 1 H-NMR (300 MHz, DMSO-d6): δ11.06 (s, 1H), 10.57 (brs, 1H), 8.71 (m, 1H), 7.00 (d, 1H), 6.96 (d, 1H), 6.68 (dd, 1H), 5.32 (m, 1H), 3.75 (m, 2H), 3.58 (m, 5H), 3.32 (m, 2H), 3.25 (m, 6H), 2.65 (m, 5H), 2.00 (m, 5H), 1.42 (m, 1H).

[0781] MS (ESI + ):m / z= 476.23 [M+H]+ .

[0782] Manufacturing Example 31: Preparation of 3-[4-[9-(4-piperidylmethyl)-3,9-diazaspiro[5,5]undecan-3-yl]phenyl]piperidine-2,6-dione; hydrochloride

[0783]

[0784] Step 1) Preparation of tert-butyl 9-[4-(2-methoxy-2-oxo-ethyl)phenyl]-3,9-diazaspiro[5,5]undecane-3-carboxylate

[0785] 10.6 g (46.27 mmol) of methyl 2-(4-bromophenyl)acetate and 23.5 g (92.55 mmol) of tert-butyl 3,9-diazaspiro[5,5]undecane-3-carboxylate were diluted in 250 mL of toluene, and 22.6 g (69.41 mmol) of cesium carbonate and 3.6 g (4.62 mmol) of dicyclohexylphosphino-2',6'-diisopropoxybiphenyl were added. The resulting reaction mixture was stirred at 110°C for 18 hours. Upon completion of the reaction, the mixture was filtered under reduced pressure through a Celite-packed filter, washed with ethyl acetate, and the resulting filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 5: 1 (volume ratio)) to obtain 16.8 g (yield: 86%) of the title compound.

[0786] 1 H-NMR (300 MHz, CDCl3): δ7.15 (d, 2H), 6.68 (d, 2H), 3.67 (s, 3H), 3.53 (s, 2H), 3.40 (m, 4H), 3.15 (m, 4H), 1.64 (m, 4H) 1.46 (m, 13H).

[0787] Step 2) Preparation of tert-butyl 9-[4-(2,6-dioxo-3-piperidyl)phenyl-3,9-diazaspiro[5,5]undecane-3-carboxylate

[0788] 16.8 g (41.73 mmol) of the compound prepared in the above step 1) was diluted in 170 mL of tetrahydrofuran, and 4.4 g (62.60 mmol) of acrylamide and 5.6 g (50.08 mmol) of potassium tert-butoxide were added at 0°C, followed by stirring at 50°C for 2 hours. When the reaction was complete, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 3: 1 (volume ratio)) to obtain 6.0 g (yield: 32%) of the title compound.

[0789] 1 H-NMR (300 MHz, CDCl3): δ7.96 (s, 1H), 7.07 (d, 2H), 6.91 (d, 2H), 3.74 (m, 1H), 3.41 (m, 4H), 3.17 (m, 4H), 2.66 (m, 2H), 2.25 (m, 2H), 1.63 (m, 4H) 1.49 (m, 13H).

[0790] Step 3) Preparation of 3-[4-(3,9-diazaspiro[5,5]undecan-3-yl)phenyl]piperidine-2,6-dione; hydrochloride

[0791] 3.0 g (6.79 mmol) of the compound prepared in step 2) above was diluted in 60 mL of dichloromethane, 10 mL (40.00 mmol) of 4N hydrochloric acid was slowly added dropwise at room temperature, and the mixture was stirred for 4 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 2.8 g (final yield: 99%) of the title compound.

[0792] 1H-NMR (300 MHz, DMSO-d6): δ7.73 (m. 2H), 7.53 (m, 2H), 4.02 (m, 1H), 3.66 (m, 4H), 3.31 (m, 4H), 2.63 (m, 2H), 2.27 (m, 2H), 2.11 (m, 4H) 1.97 (m, 4H).

[0793] Step 4) Preparation of tert-butyl 4-[[3-(4-(2,6-dioxo-3-piperidyl)phenyl]-3,9-diazaspiro[5,5]undecan-9-yl]methyl]piperidine-1-carboxylate

[0794] 1.0 g (2.41 mmol) of the compound prepared in the above step 3) and 1.8 g (8.44 mmol) of tert-butyl 4-formylpiperidine-1-carboxylate were diluted in 20 mL of N,N-dimethylacetamide, and 0.30 mL (5.31 mmol) of acetic acid was added. The resulting reaction mixture was stirred at room temperature for 2 hours, and 3.0 g (14.48 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mass was stirred at room temperature for 2 hours, and when the reaction was completed, a saturated aqueous sodium bicarbonate solution was slowly added, followed by stirring for 1 hour. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 1.1 g (yield: 87%) of the title compound.

[0795] 1 H-NMR (300 MHz, DMSO-d6): δ7.89 (s, 1H), 7.11 (d, 2H), 6.93 (d, 2H), 4.11 (m, 4H), 3.75 (m, 1H), 3.19 (m, 4H), 3.17 (m, 4H), 3.03 (s, 1H), 2.96 (s, 1H), 2.76 (m, 6H), 2.25-2.11 (m, 4H), 1.86-1.50 (m, 12H) 1.49 (m, 4H).

[0796] Step 5) Preparation of 3-[4-[9-(4-piperidylmethyl)-3,9-diazaspiro[5,5]undecan-3-yl]phenyl]piperidine-2,6-dione; hydrochloride

[0797] 0.8 g (1.49 mmol) of the compound prepared in the above step 4) was diluted in 20 mL of dichloromethane, 4 mL (16.00 mmol) of 4N-hydrochloric acid was slowly added dropwise at room temperature, and the mixture was stirred for 4 hours. Upon completion of the reaction, the resulting solid was washed with dichloromethane and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 0.7 g of the title compound (final yield: 92%).

[0798] 1 H-NMR (300 MHz, DMSO-d6): δ11.06 (s, 1H), 7. 7.11 (d, 2H), 6.93 (d, 2H), 3.76 (m, 4H), 3.73 (m, 1H), 3.21 (m, 4H), 3.09 (m, 4H), 2.96 (s, 1H), 2.76 (m, 6H), 2.25-2.11 (m, 4H), 2.07-1.90 (m, 5H) 1.49 (m, 4H).

[0799] MS (ESI + ):m / z= 438.62 [M+H] + .

[0800] Manufacturing Example 32: Manufacturing of 2-(5-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)thiophen-2-yl)acetic acid

[0801]

[0802] Step 1) Preparation of methyl 2-(5-bromothiophen-2-yl)acetate

[0803] 10.0 g (58.74 mmol) of methyl 2-(thiophen-2-yl) acetate was diluted in 800 mL of a 1:1 (volume) solution of chloroform: acetic acid, 10.6 g (59.33 mmol) of N-bromosuccinimide was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 18 hours. When the reaction was complete, a saturated aqueous sodium carbonate solution was added, and the resulting mixture was extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 10:1 (volume)) to obtain 10.5 g (yield: 69%) of the title compound.

[0804] 1 H-NMR (300 MHz, CDCl3): δ6.89 (d, 1H), 6.68 (d, 1H), 3.76 (s, 2H), 3.73 (s, 3H).

[0805] Step 2) Preparation of methyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate

[0806] 10.5 g (44.49 mmol) of the compound prepared in the above step 1) was diluted in 110 mL of 1,4-dioxane, 17.3 g (66.7 mmol) of bis(pinacolato)diboron and 13.5 g (133.48 mmol) of potassium acetate were added, and the mixture was degassed under nitrogen gas for 10 minutes. 3.7 g (4.45 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex was added, and the resulting reaction mixture was stirred at 85°C for 3 hours. Upon completion of the reaction, the resulting reaction mixture was filtered through a Celite-packed filter, and the resulting filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 10: 1 (volume ratio)) to obtain 8.9 g (yield: 71%) of the title compound.

[0807] 1 H-NMR (300 MHz, CDCl3): δ7.48 (m, 1H), 7.01 (m, 1H), 3.87 (s. 2H), 3.71 (s, 3H), 1.32 (s, 12H).

[0808] Step 3) Preparation of 2-(5-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)thiophen-2-yl)acetic acid

[0809] 827.3 mg (2.87 mmol) of the compound prepared in step 2) above was diluted in 18 mL of a 1,4-dioxane:distilled water = 5:1 (volume ratio) solution, and then 770.0 mg (1.60 mmol) of the compound prepared in step 2) of Preparation Example 17 above, 854.6 mg (7.98 mmol) of sodium carbonate, and 188.2 mg (0.16 mmol) of tetrakis(triphenylphosphine)palladium were added. The resulting reaction mixture was stirred at 90°C for 23 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature and acidified (pH~3) using a 1 N hydrochloric acid aqueous solution. The resulting mixture was washed with distilled water and filtered under reduced pressure. The resulting solid was diluted in a solution of dichloromethane: methanol = 4:1 (volume ratio), dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with ethyl acetate and filtered under reduced pressure to obtain 645.0 mg (final stage yield: 81%) of the title compound.

[0810] 1 H-NMR (300 MHz, DMSO-d6): δ10.92 (brs, 1H), 8.59 (s, 1H), 8.05 (q, 2H), 7.75 (d, 2H), 7.42 (m, 10H), 6.96 (d, 1H), 4.81 (m, 1H), 3.85 (s. 2H), 2.95 (m, 4H).

[0811] MS (ESI + ):m / z= 497.16 [M+H] + .

[0812] Manufacturing Example 33: Manufacturing of 2-(5-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)thiophen-2-yl)acetic acid

[0813]

[0814] 750.0 mg (1.55 mmol) of the compound prepared in step 2) of the above Preparation Example 17 was diluted in 18 mL of a 1,4-dioxane:distilled water = 5:1 (volume ratio) solution, and then 828.7 mg (2.80 mmol) of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate, 832.4 mg (7.77 mmol) of sodium carbonate, and 183.3 mg (0.16 mmol) of tetrakis(triphenylphosphine)palladium were added. The resulting reaction mixture was stirred at 90°C for 16 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature and acidified (pH~3) using a 1 N hydrochloric acid aqueous solution. The resulting mixture was washed with distilled water and filtered under reduced pressure. The resulting solid was diluted in a solution of dichloromethane: methanol = 4:1 (volume ratio), dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with ethyl acetate and filtered under reduced pressure to obtain 100.0 mg of the title compound (final yield: 13%).

[0815] 1 H-NMR (300 MHz, DMSO-d6): δ8.63 (s, 1H), 8.11 (s, 2H), 7.75 (d, 2H), 7.63 (d, 2H), 7.52 (m, 1H), 7.38 (m, 8H), 3.61 (s. 2H), 3.22 (m, 1H), 2.90 (m, 4H).

[0816] MS (ESI + ):m / z= 491.20 [M+H] + .

[0817] Manufacturing Example 34: Preparation of 3-(4-(2-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione; hydrochloride

[0818]

[0819] The same process as in Manufacturing Example 31 was sequentially performed, except that tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 3,9-diazaspiro[5,5]undecane-3-carboxylate in step 1) of Manufacturing Example 31, to obtain 1.33 g of the title compound (final yield: 99%).

[0820] MS (ESI + ):m / z= 411.27 [M+H] + .

[0821] Manufacturing Example 35: Preparation of 3-(4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione; hydrochloride

[0822]

[0823] The same process as in Manufacturing Example 31 was sequentially performed except that tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate was used instead of tert-butyl 3,9-diazaspiro[5,5]undecane-3-carboxylate in step 1) of Manufacturing Example 31, to obtain 1.04 g of the title compound (final yield: 99%).

[0824] MS (ESI + ):m / z= 411.27 [M+H] + .

[0825] Manufacturing Example 36: Manufacturing of 3-(4-(4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione hydrochloride

[0826]

[0827] Step 1) Preparation of (1-(4-bromophenyl)-4-piperidyl)methanol

[0828] 100 g (346.4 mmol) of 1-bromo-4-iodo-benzene and 53.47 g (450.3 mmol) of 4-piperidylmethanol were diluted in 500 mL of dimethyl sulfoxide, and 147.07 g (692.8 mmol) of potassium phosphate tribasic was added, followed by stirring for 20 minutes under a nitrogen atmosphere. 8.06 g (69.3 mmol) of L-proline and 13.2 g (69.3 mmol) of copper iodide were added, and the mixture was stirred at 80°C for 18.5 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, water was added to form a solid, and the mixture was stirred at room temperature for 1 hour. The formed solid was washed with water and filtered under reduced pressure. The resulting solid was stirred in ethyl acetate and then filtered under reduced pressure to obtain 54.9 g (yield: 58.7%) of the title compound.

[0829] 1 H-NMR (300 MHz, CDCl3): δ7.49~7.29 (m, 2H), 6.86~6.65 (m, 2H), 3.66 (dt, 2H), 3.55 (d, 2H), 2.71 (td, 2H), 1.91~1.79 (m, 2H), 1.73~1.61 (m, 1H), 1.45~1.35 (m, 2H), 1.32~1.25 (m, 1H);

[0830] MS (ESI + ):m / z= 270.04 [M+H] + .

[0831] Step 2) Preparation of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methanol

[0832] 20.0 g (47.9 mmol) of the compound prepared in the above step 1), 14.2 g (52.7 mmol) of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, and 32.2 g (95.8 mmol) of cesium carbonate were diluted in 900 mL of 1,4-dioxane and 90 mL of distilled water, and the mixture was degassed under nitrogen gas for 10 minutes. Then, 4.04 g (4.8 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex was added, and the reaction mixture was stirred at 100°C for 22 hours. Upon completion of the reaction, the mixture was filtered under reduced pressure, washed with ethyl acetate through a Celite-packed filter, and the resulting filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 8.5 g (yield: 36.9%) of the title compound.

[0833] 1 H-NMR (300 MHz, CDCl3): δ7.58 (d, 1H), 7.52~7.26 (m, 12H), 6.96 (d, 2H), 6.45 (d, 1H), 5.42 (s, 2H), 5.35 (s, 2H), 3.76 (d, 2H), 3.56 (t, 2H), 2.75 (td, 2H), 1.86 (d, 2H), 1.76~1.60 (m, 1H), 1.49~1.37 (m, 2H), 1.32 (t, 1H);

[0834] MS (ESI + ):m / z= 481.25 [M+H] + .

[0835] Step 3) Preparation of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-4-carbaldehyde

[0836] Dimethyl sulfoxide 3.5 mL (49.9 mmol) was diluted in 50 mL of dichloromethane, and oxalyl chloride 2.1 mL (25.0 mmol) was slowly added dropwise, and stirred for 30 minutes. 4.0 g (8.3 mmol) of the compound prepared in step 2) was diluted in 30 mL of dichloromethane, and slowly added dropwise, and stirred for 1 hour. Triethylamine 5.8 mL (41.6 mmol) was slowly added dropwise, and stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was diluted with dichloromethane and washed with distilled water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure to obtain 3.9 g (yield: 97.9%) of the title compound.

[0837] MS (ESI + ):m / z= 501.22 [M+Na] + .

[0838] Step 4) Preparation of tert-butyl 9-((1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0839] 4.0 g (8.36 mmol) of the compound prepared in the above step 3) and 5.3 g (20.89 mmol) of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate were diluted in 80 mL of N,N-dimethylacetamide, and 1.45 mL (25.07 mmol) of acetic acid was added. The reaction mixture was stirred at room temperature for 13 hours, and then 9.3 g (41.79 mmol) of sodium triacetoxyborohydride was added. The resulting reaction mixture was stirred at 25°C for 4 hours. Upon completion of the reaction, the reaction mixture was slowly added to a saturated aqueous sodium bicarbonate solution at 0°C and stirred for 2 hours. The resulting reaction mixture was filtered under reduced pressure and washed with distilled water. The resulting solid was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 2: 1 (volume ratio)) to obtain 3.6 g (yield: 60.1%) of the title compound.

[0840] 1 H-NMR (300 MHz, DMSO-d6): δ7.58 (d, 1H), 7.51~7.26 (m, 12H), 6.95 (d, 2H), 6.44 (d, 1H), 5.42 (s, 2H), 5.35 (s, 2H), 3.72 (d, 2H), 3.44~3.30 (m, 4H), 2.71 (t, 2H), 2.41~2.32 (m, 4H), 2.21 (d, 2H), 1.85 (d, 2H), 1.66 (s, 1H), 1.53~1.49 (m, 2H), 1.48~1.38 (m, 13H), 1.38~1.22 (m, 4H);

[0841] MS (ESI + ):m / z= 717.44 [M+H] + .

[0842] Step 5) Preparation of tert-butyl 9-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0843] 3.6 g (5.02 mmol) of the compound prepared in step 4) above was diluted in 36 mL of tetrahydrofuran. The resulting reaction mixture was degassed under nitrogen gas, and 1.07 g (1.00 mmol) of 10% Pd / C was added. The reaction mixture was stirred at 25°C for 70 hours under a hydrogen atmosphere. Upon completion of the reaction, the mixture was filtered under reduced pressure, washed with dichloromethane: methanol = 4: 1 (volume ratio) through a Celite-packed filter, and the filtrate was distilled under reduced pressure. The resulting residue was added to ethyl acetate, and stirred at room temperature for 1 hour. The resulting mixture was washed with ethyl acetate and filtered under reduced pressure. The resulting solid was dried under reduced pressure to obtain 2.02 g (yield: 74.7%) of the title compound.

[0844] 1 H-NMR (300 MHz, CDCl3): δ8.09 (s, 1H), 7.07 (d, 2H), 6.91 (d, 2H), 3.75~3.60 (m, 3H), 3.42~3.31 (m, 4H), 2.76~2.59 (m, 4H), 2.43~2.32 (m, 4H), 2.27~2.16 (m, 4H), 1.83 (d, 2H), 1.70~1.57 (m, 1H), 1.56~1.48 (m, 4H), 1.46~1.39 (m, 13H), 1.35~1.22 (m, 2H);

[0845] MS (ESI + ):m / z= 539.36 [M+H] + .

[0846] Step 6) Preparation of 3-(4-(4-((3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)phenyl)piperidine-2,6-dione hydrochloride

[0847] 2.02 g (3.75 mmol) of the compound prepared in step 5) above was diluted in 30 mL of dichloromethane, and 7 mL (28.0 mmol) of 4N hydrochloric acid was added dropwise. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the reaction mixture was filtered under reduced pressure and washed with dichloromethane to obtain 1.9 g (final yield: 99%) of the title compound.

[0848] 1 H-NMR (300 MHz, DMSO-d6): δ10.86 (s, 1H), 10.48~10.06 (m, 1H), 8.88 (s, 2H), 7.82~7.49 (m, 2H), 7.37 (s, 2H), 3.99~3.86 (m, 2H), 3.35 (d, 2H), 3.18~2.91 (m, 8H), 2.80~2.62 (m, 1H), 2.60~2.52 (m, 1H), 2.40~2.17 (m, 2H), 2.15~1.97 (m, 4H), 1.92~1.72 (m, 8H), 1.62~1.47 (m, 2H).

[0849] MS (ESI + ):m / z= 439.31 [M+H] + .

[0850] Manufacturing Example 37: Manufacturing of 2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)phenyl)-2,2-difluoroacetic acid

[0851]

[0852] Step 1) Preparation of ethyl 2-(4-bromophenyl)-2,2-difluoroacetate

[0853] 29.5 g (102.19 mmol) of 1-bromo-4-iodobenzene, 16.3 g (122.63 mmol) of ethyl 2-bromo-2,2-difluoroacetate, and 17.1 g (265.69 mmol) of copper were diluted in 150 mL of dimethyl sulfoxide and stirred at 60°C under a nitrogen atmosphere for 12 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and filtered under reduced pressure. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by column chromatography (hexane: ethyl acetate = 9: 1 (volume ratio)) to obtain 18.6 g (yield: 65.2%) of the title compound.

[0854] 1 H-NMR (300 MHz, CDCl3): δ7.60 (m, 2H), 7.48 (m, 2H), 4.30 (q, 2H), 1.30 (t, 3H);

[0855] MS (ESI + ):m / z= 300.97 [M+Na] +, 302.97 [M+Na] + .

[0856] Step 2) Preparation of ethyl 2,2-difluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[0857] 18.6 g (66.65 mmol) of the compound prepared in the above step 1), 25.4 g (99.97 mmol) of bis(pinacolato)diboron, and 19.6 g (199.94 mmol) of potassium acetate were diluted in 360 mL of 1,4-dioxane and degassed under nitrogen gas for 20 minutes, and then 3.0 g (3.67 mmol) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex was added. The resulting reaction mixture was stirred at 90°C under a nitrogen atmosphere for 4 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, filtered under reduced pressure through a Celite-packed filter, washed with ethyl acetate, and the filtrate was distilled under reduced pressure. The resulting residue was separated by column chromatography (hexane: ethyl acetate = 10: 1 (volume ratio)) to obtain 19.6 g of the title compound (yield: 90.2%).

[0858] 1 H-NMR (300 MHz, CDCl3): δ 7.88 (d, 2H), 7.59 (d, 2H), 4.27 (q, 2H), 1.33 (s, 12H), 1.27 (t, 3H).

[0859] Step 3) Preparation of 2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)phenyl)-2,2-difluoroacetic acid

[0860] 3.6 g (11.0 mmol) of the compound prepared in the above step 2) and 3.0 g (6.1 mmol) of 2-((4-cyanophenethyl)amino)-N-(5-iodopyridin-2-yl)-2-phenylacetamide were diluted in 100 mL of 1,4-dioxane and 20 mL of distilled water, and 718.8 mg (0.61 mmol) of tetrakis(triphenylphosphine)palladium and 3.3 g (30.5 mmol) of sodium carbonate were added, followed by stirring at 90°C for 20 hours. Upon completion of the reaction, the reaction mixture was diluted with dichloromethane: methanol = 4:1 (volume ratio) and washed with distilled water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was stirred with ethyl acetate for 1 hour and filtered under reduced pressure to obtain 1.87 g (yield: 58.3%) of the title compound.

[0861] 1 H-NMR (300 MHz, CDCl3): δ11.12 (s, 1H), 8.53~8.49 (m, 1H), 8.01~7.99 (m, 2H), 7.73~7.21 (m, 15H), 5.02~4.94 (m, 1H), 2.97 (d, 2H), 2.82~2.80 (m, 2H);

[0862] MS (ESI + ):m / z= 527.18 [M+H] + .

[0863] Manufacturing Example 38: Manufacturing of 2,2-difluoro-2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)phenyl)acetic acid

[0864]

[0865] Except for using N-(5-iodopyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide prepared as a result of step 2) of Manufacturing Example 18 instead of 2-((4-cyanophenethyl)amino)-N-(5-iodopyridin-2-yl)-2-phenylacetamide in step 3) of Manufacturing Example 37, the same processes as steps 1), 2), and 3) of Manufacturing Example 37 were performed sequentially to obtain 1.1 g of the title compound (final yield: 20.7%).

[0866] 1 H-NMR (300 MHz, DMSO-d6): δ11.04 (s, 1H), 8.56 (s, 1H), 8.02 (s, 2H), 7.63~7.37 (m, 15H), 4.98 (s, 1H), 3.00 (s, 2H), 2.84~2.79 (m, 2H);

[0867] MS (ESI + ):m / z= 570.17 [M+H] + .

[0868] Manufacturing Example 39: Manufacturing of (R)-2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)phenyl)-2,2-difluoroacetic acid

[0869]

[0870] 2.0 g (4.06 mmol) of the compound prepared in step 3) of the above Preparation Example 23 and 2.6 g (8.13 mmol) of the compound prepared in step 2) of the above Preparation Example 37 were diluted in 48 mL of a 1,4-dioxane:distilled water = 5:1 (volume ratio) solution, and then 1.1 g (10.16 mmol) of sodium carbonate and 479.2 mg (0.16 mmol) of tetrakis(triphenylphosphine)palladium were added. The resulting reaction mixture was stirred at 70°C for 18 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature and acidified (pH~3) using a 1 N hydrochloric acid aqueous solution. The resulting mixture was washed with distilled water and filtered under reduced pressure. The resulting solid was diluted in a solution of dichloromethane: methanol = 4:1 (volume ratio), dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting solid was washed with ethyl acetate and filtered under reduced pressure to obtain 1.3 g of the title compound (final yield: 63%).

[0871] 1 H-NMR (300 MHz, DMSO-d6): δ11.12 (s, 1H), 8.62 (m, 1H), 8.10 (m, 2H), 7.78~7.31 (m, 15H), 5.00 (m, 1H), 2.97 (m, 2H), 2.95 (m, 2H);

[0872] MS (ESI + ):m / z= 527.18 [M+H] + .

[0873] Manufacturing Example 40: Manufacturing of 2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)phenyl)acetic acid

[0874]

[0875] Except for using ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate instead of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate in step 3) of the above Preparation Example 18, the same process as steps 1), 2), and 3) of the above Preparation Example 18 was performed sequentially to obtain 1.1 g of the title compound (final stage yield: 21.7%).

[0876] 1 H-NMR (300 MHz, DMSO-d6): δ10.54 (s, 1H), 8.59~8.57 (m, 1H), 8.11~8.02 (m, 2H), 7.60 (d, 4H), 7.43~7.22 (m, 10H), 4.54 (s, 1H), 3.58 (s, 2H), 2.87~2.72 (m, 4H);

[0877] MS (ESI + ):m / z= 534.19 [M+H] + .

[0878] Manufacturing Example 41: Preparation of 3-((3-fluoro-4-(9-(piperidin-4-ylmethyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)piperidine-2,6-dione; hydrochloride

[0879]

[0880] Except for using tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate instead of tert-butyl piperazine-1-carboxylate in step 1) of the above manufacturing example 6, the same process as steps 1), 2), 3), 4), 5), and 6) of the above manufacturing example 6 was performed sequentially to obtain 1.5 g of the title compound (final stage yield: 99%).

[0881] MS (ESI + ):m / z= 506.28 [M+H] + .

[0882] [Example 1]

[0883] Preparation of 2-((4-cyanophenylethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0884]

[0885] 80 mg (0.20 mmol) of the compound of Preparation Example 1) and 141 mg (0.29 mmol) of the compound of Preparation Example 17) were diluted in 3 mL of N,N-dimethylformamide, and 75 mg (0.39 mmol) of EDCI, 40 mg (0.29 mmol) of HOBt, and 0.10 mL (0.59 mmol) of N,N-diethylisopropylamine were added. The reaction mixture was stirred at room temperature for 12 hours. When the reaction was complete, water was added to generate a solid, which was stirred at room temperature for 30 minutes. The resulting solid was washed with water, filtered under reduced pressure, and then separated by column chromatography (dichloromethane: methanol = 10:1 (volume ratio)) to obtain 26 mg (yield: 15%) of the title compound.

[0886] 1 H-NMR (300 MHz, DMSO-d6): δ10.44 (bs, 1H), 10.25 (bs, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.02 (m, 1H), 7.98~7.91 (m, 2H), 7.72 (m, 2H), 7.43 (m, 4H), 7.37~7.29 (m, 3H), 7.14 (m, 2H), 6.95 (m, 2H), 5.14 (m, 2H), 4.53 (s, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.72 (m, 2H), 3.14 (m, 6H), 2.87 (m, 3H), 2.74 (m, 2H), 2.69 (m, 4H), 2.33~2.21 (m, 3H), 2.18~2.15 (m, 2H), 1.87 (m, 4H);

[0887] MS (ESI+ ):m / z= 834.41 [M+H] + .

[0888] [Example 2]

[0889] Preparation of 2-((4-cyanophenethyl)amino)-N-(5-(1-(2-(((R)-5-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)amino)-3-methylpentyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0890]

[0891] The same process as Example 1 was performed except that the compound of Manufacturing Example 2) and the compound of Manufacturing Example 17) were used, thereby obtaining 14 mg (yield: 13%) of the title compound.

[0892] 1 H-NMR (300 MHz, DMSO-d6): δ10.45 (bs, 1H), 10.18 (bs, 1H), 8.59 (s, 1H), 8.18 (m, 1H), 8.13 (m, 1H), 7.98~7.91 (m, 2H), 7.75 (m, 2H), 7.46 (m, 4H), 7.34~7.27 (m, 3H), 7.00 (m, 2H), 6.56 (m, 2H), 5.54~5.10 (m, 1H), 4.78 (s, 2H), 4.53 (s, 1H), 3.63 (m, 3H), 3.15 (m, 3H), 3.02 (m, 2H), 2.87 (m, 3H), 2.77 (m, 4H), 1.57~1.48 (m, 6H), 0.97 (m, 3H);

[0893] MS (ESI + ):m / z= 767.37 [M+H] + .

[0894] [Example 3]

[0895] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0896]

[0897] The same process as Example 1 was performed except that the compound of Manufacturing Example 3) and the compound of Manufacturing Example 17) were used, thereby obtaining 23 mg (yield: 13%) of the title compound.

[0898] 1 H-NMR (300 MHz, DMSO-d6): δ10.76 (bs, 1H), 10.44 (bs, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 8.02 (m, 1H), 7.98~7.91 (m, 2H), 7.74 (m, 2H), 7.46 (m, 4H), 7.37~7.27 (m, 3H), 7.07 (m, 2H), 6.91 (m, 2H), 5.14 (s, 2H), 4.53 (s, 1H), 4.33 (m, 1H), 3.93 (m, 1H), 3.74 (m, 1H), 3.32 (m, 6H), 3.16 (m, 6H), 2.90~2.64 (m, 7H), 2.29~2.16 (m, 4H), 1.80 (m, 3H);

[0899] MS (ESI + ):m / z= 833.42 [M+H] + .

[0900] [Example 4]

[0901] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0902]

[0903] The same process as Example 1 was performed except that the compound of Manufacturing Example 4) and the compound of Manufacturing Example 17) were used, thereby obtaining 52 mg (yield: 23%) of the title compound.

[0904] 1 H-NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 10.58 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 8.03 (d, 1H), 7.95 (d, 1H), 7.92 (s, 1H), 7.73 (d, 2H), 7.45 (d, 4H), 7.37~7.28 (m, 3H), 7.03 (d, 2H), 6.88 (d, 2H), 5.16 (s, 2H), 4.53 (br, 1H), 3.73~3.64 (m, 5H), 3.54~3.45 (m, 8H), 2.90~2.87 (t, 2H), 2.79~2.72 (m, 2H), 2.67~2.60 (t, 2H), 2.45~2.34 (m, 4H), 2.21 (d, 1H), 1.81~1.71 (m, 2H), 1.69~1.60 (m, 1H), 1.23~1.18 (m, 2H);

[0905] MS (ESI + ):m / z= 833.42 [M+H] + .

[0906] [Example 5]

[0907] Preparation of N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[0908]

[0909] The same process as Example 1 was performed except that the compound of Manufacturing Example 3) and the compound of Manufacturing Example 18) were used, thereby obtaining 11 mg (yield: 5%) of the title compound.

[0910] 1 H-NMR (300 MHz, DMSO-d6): δ10.77 (s, 1H), 10.48 (s, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.91 (s, 1H), 7.63 (d, 2H), 7.46 (d, 4H), 7.37~7.28 (m, 3H), 7.07 (d, 2H), 6.89 (d, 2H), 5.14 (s, 2H), 4.55 (br, 1H), 4.39~4.31 (m, 1H), 3.94~3.89 (m, 1H), 3.80~3.77 (m, 1H), 3,18~3.11 (m, 4H), 2.91~2.87 (m, 2H), 2.80~2.75 (m, 2H), 2.70~2.61 (m, 2H), 2.23~2.19 (m, 3H), 2.12~2.05 (m, 1H), 1.80~1.71 (m, 3H), 1.35 (s, 1H), 1.26 (s 6H), 0.84~0.80 (m, 2H);

[0911] MS (ESI + ):m / z= 876.41 [M+H] + .

[0912] [Example 6]

[0913] Preparation of N-(5-(1-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[0914]

[0915] The same process as Example 1 was performed except that the compound of Manufacturing Example 4) and the compound of Manufacturing Example 18) were used, thereby obtaining 89 mg (yield: 41%) of the title compound.

[0916] 1H-NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 10.50 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 8.03 (d, 1H), 7.95 (d, 1H), 7.92 (s, 1H), 7.63 (d, 2H), 7.45 (d, 4H), 7.34~7.27 (m, 3H), 7.04 (d, 2H), 6.88 (d, 2H), 5.16 (s, 2H), 4.53 (br, 1H), 3.71~3.64 (m, 5H), 3.52~3.44 (m, 8H), 2.88~2.85 (t, 2H), 2.79~2.76 (m, 2H), 2.67~2.59 (t, 2H), 2.40~2.33 (m, 4H), 2.21 (d, 1H), 1.82~1.78 (m, 2H), 1.69~1.60 (m, 1H), 1.19~1.11 (m, 2H);

[0917] MS (ESI + ):m / z= 876.41 [M+H] + .

[0918] [Example 7]

[0919] Preparation of N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((1-(4-trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide

[0920]

[0921] The same process as Example 1 was performed except that the compound of Manufacturing Example 3) and the compound of Manufacturing Example 19) were used, to obtain 63 mg (yield: 38%) of the title compound.

[0922] 1H-NMR (300 MHz, DMSO-d6): δ10.76 (s, 1H), 10.44 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 8.02 (m, 1H), 7.95 (m, 1H), 7.90 (s, 1H), 7.56 (m, 2H), 7.55 (m, 2H), 7.45 (m, 2H), 7.35 (m, 3H), 7.06 (d, 2H), 6.87 (d, 2H), 5.13 (m, 2H), 4.54 (m, 1H), 4.35 (m, 1H), 3.75 (m, 1H), 3.70 (m, 1H), 3.11 (m, 5H), 2.75~2.59 (m, 5H), 2.20 (m, 2H), 2.10 (m, 1H), 1.95~1.70 (m, 4H), 1.24 (m, 2H), 1.23~0.95 (m, 2H), 0.85 (d, 6H);

[0923] MS (ESI + ):m / z= 902.43 [M+H] + .

[0924] [Example 8]

[0925] Preparation of 4-(2-((2-(6-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[0926]

[0927] The same process as Example 1 was performed except that the compound of Manufacturing Example 3) and the compound of Manufacturing Example 20) were used, to obtain 25 mg (yield: 13%) of the title compound.

[0928] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.76 (s, 1H), 8.53 (m, 1H), 8.12 (m, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.74 (m, 2H), 7.55 (s, 1H), 7.47 (m, 5H), 7.26 (m, 2H), 7.18 (m, 1H), 7.04 (m, 2H), 6.90 (m, 2H), 5.28 (bs, 1H), 5.12 (m, 2H), 4.34 (m, 1H), 3.93 (m, 1H), 3.76 (m, 2H), 3.45 (m, 6H), 3.18 (m, 4H), 2.84 (m, 3H), 2.55 (m, 5H), 2.12 (m, 4H), 1.80~1.76 (m, 3H);

[0929] MS (ESI + ):m / z= 856.42 [M+H] + .

[0930] [Example 9]

[0931] Preparation of 3-(4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0932]

[0933] The same process as Example 1 was performed except that the compound of Manufacturing Example 3) and the compound of Manufacturing Example 21) were used, to obtain 30 mg (yield: 15%) of the title compound.

[0934] 1H-NMR (300 MHz, DMSO-d6): δ12.05 (s, 1H), 10.82 (s, 1H), 8.56 (s, 1H), 8.12 (d, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.62 (d, 2H), 7.56 (s, 1H), 7.48~7.42 (m, 5H), 7.31~7.26 (m, 2H), 7.25~7.18 (m, 1H), 7.05 (d, 2H), 6.88 (d, 2H), 5.32 (br, 1H), 5.12 (s, 2H), 4.23~4.21 (m, 1H), 3.93~3.81 (m, 2H), 3.76~3.66 (m, 2H), 3.52~3.45 (m, 2H), 3.28~3.22 (m, 5H), 2.86~2.85 (t, 2H), 2.73~2.60 (m, 6H), 2.27~2.20 (m, 2H), 2.18~2.10 (m, 2H), 1.88~1.78 (m, 3H), 1.25~1.18 (m, 2H);

[0935] MS (ESI + ):m / z= 899.41 [M+H] + .

[0936] [Example 10]

[0937] Preparation of 4-(4-((1-(2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

[0938]

[0939] The same process as Example 1 was performed except that the compound of Manufacturing Example 5) and the compound of Manufacturing Example 17) were used, thereby obtaining 51 mg (yield: 32%) of the title compound.

[0940] 1H-NMR (300 MHz, DMSO-d6): δ10.84 (bs, 1H), 10.44 (bs, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.05 (m, 2H), 7.98 (m, 2H), 7.75 (m, 2H), 7.64 (m, 1H), 7.37 (m, 4H), 7.30 (m, 3H), 6.84 (m, 2H), 5.14 (s, 2H), 4.77 (m, 1H), 4.53 (m, 1H), 4.34 (m. 1H), 3.94 (m, 1H), 3.46 (m, 4H), 3.34 (m, 5H), 3.08 (m, 2H), 2.90 (m, 4H), 2.82 (m, 4H), 2.65 (m, 1H), 2.21 (m, 5H), 1.78 (m, 4H);

[0941] MS (ESI + ):m / z= 894.41 [M+H] + .

[0942] [Example 11]

[0943] Preparation of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl))phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide

[0944]

[0945] The same process as Example 1 was performed except that the compound of Manufacturing Example 5) and the compound of Manufacturing Example 18) were used, to obtain 76 mg (yield: 28%) of the title compound.

[0946] 1H-NMR (300 MHz, DMSO-d6): δ10.82 (bs, 1H), 10.46 (bs, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 8.03~8.00 (m, 2H), 7.95~7.91 (m, 1H), 7.89 (s, 1H), 7.61~7.58 (m, 3H), 7.44~7.41 (m, 4H), 7.34~7.25 (m, 3H), 6.81~6.78 (m, 2H), 5.12 (m, 2H), 4.70 (m, 1H), 4.52 (m, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.28 (m, 5H), 3.05 (m, 1H), 2.87~2.71 (m, 6H), 2.60 (m, 1H), 2.45 (m, 4H), 2.18 (m, 2H), 2.06 (m, 2H), 1.78 (m, 3H), 1.26 (m, 1H), 0.95 (m, 1H);

[0947] MS (ESI + ):m / z= 937.41 [M+H] + .

[0948] [Example 12]

[0949] Preparation of 4-(4-((1-(2-(4-(3-(2-((4-cyanophenethyl)amino)-2-phenylacetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

[0950]

[0951] The same process as Example 1 was performed except that the compound of Manufacturing Example 5) and the compound of Manufacturing Example 20) were used, to obtain 50 mg (yield: 20%) of the title compound.

[0952] 1H-NMR (300 MHz, DMSO-d6): δ11.98 (bs, 1H), 10.83 (bs, 1H), 8.53 (m, 1H), 8.11~8.03 (m, 3H), 7.84 (s, 1H), 7.72~7.69 (m, 2H), 7.61~7.55 (m, 1H), 7.45 (s, 1H), 7.7.41~7.37 (m, 5H), 7.28~7.23 (m, 2H), 7.19~7.17 (m, 1H), 6.81~6.73 (m, 2H), 5.26 (bs, 1H), 5.10 (m, 2H), 4.75 (m, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.27 (m, 5H), 3.05 (m, 1H), 2.84~2.45 (m, 7H), 2.45 (m, 3H), 2.16 (m, 3H), 2.12 (m, 1H), 1.78 (m, 3H), 1.15 (m, 2H), 0.95 (m, 1H);

[0953] MS (ESI + ):m / z= 917.42 [M+H] + .

[0954] [Example 13]

[0955] Preparation of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl))phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide

[0956]

[0957] The same process as Example 1 was performed except that the compound of Manufacturing Example 5) and the compound of Manufacturing Example 21) were used, thereby obtaining 51 mg (yield: 21%) of the title compound.

[0958] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.83 (s, 1H), 8.54 (m, 1H), 8.11~8.01 (m, 3H), 7.84 (s, 1H), 7.64~7.55 (m, 4H), 7.46~7.37 (m, 5H), 7.28~7.24 (m, 2H), 7.19~7.17 (m, 1H), 6.82~6.73 (m, 2H), 5.28 (bs, 1H), 5.10 (m, 2H), 4.71 (m, 1H), 4.35 (m, 1H), 3.90 (m, 1H), 3.06 (m, 2H), 2.87~2.62 (m, 10H), 2.45 (m, 5H), 2.18 (m, 3H), 1.97 (m, 1H), 1.78 (m, 3H), 1.07 (m, 1H), 0.94 (m, 1H);

[0959] MS (ESI + ):m / z= 960.41 [M+H] + .

[0960] [Example 14]

[0961] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0962]

[0963] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 17) were used, to obtain 28 mg (yield: 16%) of the title compound.

[0964] 1H-NMR (300 MHz, DMSO-d6): δ10.77 (bs, 1H), 10.44 (bs, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.05 (m, 2H), 7.97 (m, 2H), 7.75 (m, 2H), 7.50 (m, 4H), 7.37 (m, 3H), 6.87 (m, 1H), 6.54~6.44 (m, 2H), 5.79 (m, 1H), 5.14 (s, 2H), 4.53 (m, 1H), 4.26 (m, 2H), 3.94 (m, 2H), 3.46 (m, 4H), 3.34 (m, 5H), 3.08 (m, 2H), 2.87 (m, 7H), 2.74 (m, 4H), 2.56 (m, 2H), 2.23 (m, 4H), 1.86 (m, 4H);

[0965] MS (ESI + ):m / z= 866.42 [M+H] + .

[0966] [Example 15]

[0967] Preparation of N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[0968]

[0969] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 18) were used, thereby obtaining 5 mg (yield: 2%) of the title compound.

[0970] 1H-NMR (300 MHz, DMSO-d6): δ10.77 (s, 1H), 10.47 (s, 1H), 8.56 (s, 1H), 8.13 (s, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.91 (s, 1H), 7.62 (d, 2H), 7.47 (d, 3H), 7.33~7.27 (m, 3H), 6.83 (t, 1H), 6.53 (d, 2H), 6.48 (d, 2H), 5.78 (d, 1H), 5.14 (s, 2H), 4.55 (br, 1H), 4.37~4.28 (m, 2H), 3.93~3.80 (m, 1H), 2.79~2.70 (m, 10H), 2.18~2.10 (m, 3H), 1.92~1.83 (m, 5H), 1.60~1.48 (m, 3H), 1.19~1.11 (m, 2H), 0.94~0.83 (m, 2H);

[0971] MS (ESI + ):m / z= 909.41 [M+H] + .

[0972] [Example 16]

[0973] Preparation of N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide

[0974]

[0975] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 19) were used, thereby obtaining 29 mg (yield: 17%) of the title compound.

[0976] 1H-NMR (300 MHz, DMSO-d6): δ10.76 (s, 1H), 10.44 (s, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 8.02~7.90 (m, 3H), 7.54 (m, 4H), 7.45 (m, 2H), 7.35~7.20 (m, 3H), 6.83 (t, 1H), 6.60~6.45 (m, 2H), 5.80 (m, 1H), 5.13 (m, 2H), 4.54 (m, 1H), 4.35 (m, 2H), 3.95 (m, 1H), 3.05 (m, 1H), 2.95~2.59 (m, 7H), 2.20 (m, 2H), 2.10 (m, 1H), 1.95~1.65 (m, 4H), 1.24 (m, 3H), 1.22 (m, 2H), 0.85 (d, 6H);

[0977] MS (ESI + ):m / z= 935.43 [M+H] + .

[0978] [Example 17]

[0979] Preparation of 4-(2-((2-(6-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[0980]

[0981] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 20) were used, to obtain 32 mg (yield: 16%) of the title compound.

[0982] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.77 (s, 1H), 8.51 (m, 1H), 8.13 (m, 2H), 7.86 (s, 1H), 7.75 (m, 2H), 7.57 (s, 1H), 7.45 (m, 5H), 7.28 (m, 2H), 7.19 (m, 1H), 6.86 (m, 1H), 6.53 (m, 2H), 5.81 (m, 1H), 5.78 (s, 1H), 5.28 (m, 1H), 5.12 (m, 2H), 4.29 (m, 2H), 3.76 (m, 2H), 3.45 (m, 6H), 3.92 (m, 1H), 2.86 (m, 6H), 2.74 (m, 6H), 2.18 (m, 3H), 1.79 (m, 4H);

[0983] MS (ESI + ):m / z= 889.42 [M+H] + .

[0984] [Example 18]

[0985] 3-((3-Fluoro-4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phe

[0986] Preparation of (methyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[0987]

[0988] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 21) were used, thereby obtaining 12 mg (yield: 4%) of the title compound.

[0989] 1H-NMR (300 MHz, DMSO-d6): δ12.06 (s, 1H), 10.81 (s, 1H), 8.56 (s, 1H), 8.10 (d, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.63 (d, 2H), 7.57 (s, 1H), 7.48~7.42 (m, 3H), 7.31~7.26 (m, 2H), 7.24~7.18 (m, 1H), 7.05 (d, 2H), 6.90~6.81 (m, 1H), 6.53 (d, 1H), 6.48 (d, 1H), 5.78 (d, 1H), 5.32 (br, 1H), 5.12 (s, 2H), 4.29~4.25 (m, 1H), 3.93~3.81 (m, 2H), 3.76~3.66 (m, 2H), 3.52~3.45 (m, 2H), 3.28~3.22 (m, 5H), 2.86~2.85 (m, 2H), 2.73~2.60 (m, 6H), 2.27~2.20 (m, 2H), 2.18~2.10 (m, 2H), 1.88~1.78 (m, 3H), 1.25~1.18 (m, 2H);

[0990] MS (ESI + ):m / z= 932.42 [M+H] + .

[0991] [Example 19]

[0992] Preparation of 2-((3-(4-cyanophenyl)prop-2-yn-1-yl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6)-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0993]

[0994] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 22) were used, thereby obtaining 7 mg (yield: 4%) of the title compound.

[0995] 1H-NMR (300 MHz, DMSO-d6): δ9.54 (bs, 1H), 8.45 (s, 1H), 8.26 (m, 1H), 7.82 (m, 3H), 7.63 (m, 2H), 7.52 (m, 5H), 7.41 (m, 3H), 6.89 (m, 1H), 6.47 (m, 1H), 5.06 (m, 2H), 4.62 (m, 3H), 4.06 (m, 2H), 3.80 (m, 2H), 3.01 (m, 4H), 2.64 (m, 6H), 2.26 (m, 2H), 1.94 (m, 3H);

[0996] MS (ESI + ):m / z= 876.40 [M+H] + .

[0997] [Example 20]

[0998] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-)indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[0999]

[1000] The same process as Example 1 was performed except that the compound of Manufacturing Example 7) and the compound of Manufacturing Example 17) were used, thereby obtaining 42 mg (yield: 22%) of the title compound.

[1001] 1H-NMR (300 MHz, DMSO-d6): δ10.84 (s, 1H), 10.44 (s, 1H), 8.57 (m, 1H), 8.12 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.90 (s, 1H), 7.75 (m, 2H), 7.52~7.41 (m, 5H), 7.39~7.23 (m, 3H), 6.91 (d, 1H), 6.84 (m, 1H), 5.15 (m, 2H), 4.54 (m, 1H), 4.40~4.20 (m, 2H), 3.95 (m, 1H), 3.89 (s, 3H), 3.22 (m, 4H), 3.09 (m, 1H), 2.88 (m, 2H), 2.76 (m, 2H), 2.65 (m, 2H), 2.52 (m, 2H), 2.42~2.10 (m, 4H), 1.98~1.70 (m, 3H), 1.24 (m, 3H), 1.22~0.81 (m, 2H);

[1002] MS (ESI + ):m / z= 887.44 [M+H] + .

[1003] [Example 21]

[1004] Preparation of N-(5-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1005]

[1006] The same process as Example 1 was performed except that the compounds of Manufacturing Example 7) and Manufacturing Example 18) were used, to obtain 34 mg (yield: 19%) of the title compound.

[1007] 1H-NMR (300 MHz, DMSO-d6): δ10.84 (s, 1H), 10.44 (s, 1H), 8.56 (d, 1H), 8.12 (s, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.91 (s, 1H), 7.62 (m, 2H), 7.51~7.43 (m, 5H), 7.36~7.24 (m, 3H), 6.92 (d, 1H), 6.84 (m, 1H), 5.13 (m, 2H), 4.54 (m, 1H), 4.40~4.20 (m, 2H), 3.95 (m, 1H), 3.89 (s, 3H), 3.21 (m, 4H), 3.07 (m, 1H), 2.88 (m, 2H), 2.76 (m, 2H), 2.63 (m, 2H), 2.52 (m, 2H), 2.42~2.10 (m, 4H), 1.98~1.75 (m, 3H), 1.24 (m, 3H), 1.22~0.81 (m, 2H);

[1008] MS (ESI + ):m / z= 930.43 [M+H] + .

[1009] [Example 22]

[1010] Preparation of 4-(2-((2-(6-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1011]

[1012] The same process as Example 1 was performed except that the compound of Manufacturing Example 7) and the compound of Manufacturing Example 20) were used, to obtain 35 mg (yield: 18%) of the title compound.

[1013] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.83 (s, 1H), 8.53~8.52 (m, 1H), 8.11~8.08 (m, 1H), 8.05 (s, 1H), 7.84 (s, 1H), 7.72~7.69 (m, 2H), 7.55 (s, 1H), 7.50~7.37 (m, 6H), 7.28~7.23 (m, 1H), 7.19~7.17 (m, 1H), 6.92~689 (m, 1H), 6.83 (s, 1H), 5.26 (bs, 1H), 5.11 (m, 2H), 4.26~4.22 (m, 2H), 3.87 (m, 4H), 3.22~3.20 (m, 4H), 3.06 (m, 1H), 2.84~2.82 (m, 2H), 2.71~2.50 (m, 9H), 2.30~213 (m, 4H), 1.80~1.76 (m, 3H), 1.20~0.90 (m, 3H);

[1014] MS (ESI + ):m / z= 910.44 [M+H] + .

[1015] [Example 23]

[1016] Preparation of 3-(1-methyl-6-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione

[1017]

[1018] The same process as Example 1 was performed except that the compound of Manufacturing Example 7) and the compound of Manufacturing Example 21) were used, thereby obtaining 21 mg (yield: 9%) of the title compound.

[1019] 1H-NMR (300 MHz, DMSO-d6): δ12.16 (s, 1H), 10.86 (s, 1H), 8.56 (s, 1H), 8.13 (d, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.61 (d, 2H), 7.57 (s, 1H), 7.48~7.41 (m, 6H), 7.31~7.27 (m, 2H), 7.25~7.19 (m, 1H), 6.95 (d, 1H), 6.87 (s, 1H), 5.87 (s, 1H), 5.30 (br, 1H), 5.12 (s, 2H), 4.35~4.28 (m, 2H), 4.12~4.05 (m, 1H), 3.93~3.90 (m, 1H), 3.89 (s, 3H), 3.76~3.66 (m, 2H), 3.50~3.42 (m, 2H), 3.31~3.25 (m, 5H), 2.86~2.85 (m, 2H), 2.71~2.61 (m, 4H), 2.30~2.21 (m, 4H), 1.90~1.78 (m, 2H);

[1020] MS (ESI + ):m / z= 953.44 [M+H] + .

[1021] [Example 24]

[1022] Preparation of 2-((4-cyanophenethyl)amino)-N-(5-(1-(2-(((3R)-5-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)-3-methylpentyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1023]

[1024] The same process as Example 1 was performed except that the compound of Manufacturing Example 8) and the compound of Manufacturing Example 17) were used, thereby obtaining 79 mg (yield: 34%) of the title compound.

[1025] 1H-NMR (300 MHz, DMSO-d6): δ10.72 (bs, 1H), 10.45 (bs, 1H), 8.58 (s, 1H), 8.18 (m, 1H), 8.11 (m, 1H), 7.98 (m, 2H), 7.75 (m, 2H), 7.46 (m, 4H), 7.34 (m, 3H), 3.61 (m, 1H), 3.54 (m, 2H), 3.23 (m, 4H), 3.01 (m, 2H), 2.87 (m, 3H), 2.77 (m, 4H), 1.59 (m, 4H), 1.42 (m, 2H), 0.97 (m, 3H);

[1026] MS (ESI + ):m / z= 766.38 [M+H] + .

[1027] [Example 25]

[1028] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1029]

[1030] The same process as Example 1 was performed except that the compound of Manufacturing Example 9) and the compound of Manufacturing Example 17) were used, thereby obtaining 42 mg (yield: 24%) of the title compound.

[1031] 1H-NMR (300 MHz, DMSO-d6): δ10.77 (s, 1H), 10.44 (s, 1H), 8.57 (d, 1H), 8.14 (s, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.43 (m, 4H), 7.40~7.27 (m, 3H), 7.10 (d, 2H), 6.93 (d, 2H), 5.16 (m, 2H), 4.52 (m, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.77~3.55 (m, 5H), 3.25~2.90 (m, 5H), 2.85 (m, 2H), 2.77 (m, 2H), 2.66 (m, 1H), 2.26~1.98 (m, 2H), 1.79~1.25 (m, 5H), 0.86 (m, 2H);

[1032] MS (ESI + ):m / z= 847.40 [M+H] + .

[1033] [Example 26]

[1034] Preparation of 4-(2-((2-(6-(1-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1035]

[1036] The same process as Example 1 was performed except that the compounds of Manufacturing Example 9) and Manufacturing Example 20) were used, to obtain 34 mg (yield: 16%) of the title compound.

[1037] 1H-NMR (300 MHz, DMSO-d6): δ11.98 (bs, 1H), 10.79 (bs, 1H), 8.54 (d, 1H), 8.12~8.08 (m, 2H), 7.87 (s, 1H), 7.74~7.70 (m, 2H), 7.56 (s, 1H), 7.47~7.38 (m, 5H), 7.28 (2H), 7.18 (m, 1H), 7.07 (d, 2H), 6.92 (d, 2H), 5.28 (bs, 1H), 5.14 (m, 2H), 4.35 (m, 1H), 3.97 (m, 1H), 3.77~3.60 (m, 5H), 3.19~2.92 (m, 6H), 2.88 (m, 2H), 2.79~2.62 (m, 4H), 2.21~1.91 (m, 2H), 1.79~1.52 (m, 3H), 1.45 (m, 1H), 0.88 (m, 1H);

[1038] MS (ESI + ):m / z= 870.40 [M+H] + .

[1039] [Example 27]

[1040] 3-(4-(4-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)a

[1041] Preparation of (cetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[1042]

[1043] The same process as Example 1 was performed except that the compound of Manufacturing Example 9) and the compound of Manufacturing Example 21) were used, to obtain 90 mg (yield: 36%) of the title compound.

[1044] 1H-NMR (300 MHz, DMSO-d6): δ11.98 (bs, 1H), 10.77 (s, 1H), 8.54 (m, 1H), 8.13~8.06 (m, 2H), 7.90 (s, 1H), 7.61~7.55 (m, 3H), 7.46~7.37 (m, 5H), 7.28~7.24 (m, 2H), 7.19~7.17 (m, 1H), 7.08~7.05 (m, 2H), 6.93~6.90 (m, 2H), 5.29 (bs, 1H), 5.14 (m, 2H), 4.30 (m, 1H), 3.95 (m, 1H), 3.75~3.59 (m, 6H), 3.14 (m, 6H), 2.98 (m, 1H), 2.85 (m, 2H), 2.72 (m, 3H), 2.62 (m, 1H), 2.02 (m, 2H), 1.66 (m, 3H), 1.45 (m, 1H);

[1045] MS (ESI + ):m / z= 913.39 [M+H] + .

[1046] [Example 28]

[1047] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1048]

[1049] The same process as Example 1 was performed except that the compound of Manufacturing Example 10) and the compound of Manufacturing Example 17) were used, thereby obtaining 30 mg (yield: 17%) of the title compound.

[1050] 1H-NMR (300 MHz, DMSO-d6): δ10.77 (s, 1H), 10.49 (s, 1H), 8.56 (d, 1H), 8.11 (s, 1H), 8.03 (m, 1H), 7.96 (m, 1H), 7.90 (s, 1H), 7.72 (m, 2H), 7.43 (m, 4H), 7.38~7.27 (m, 3H), 7.03 (d, 2H), 6.86 (d, 2H), 5.16 (m, 2H), 4.52 (m, 1H), 4.34 (m, 1H), 3.94 (m, 1H), 3.73 (m, 1H), 3.48 (m, 2H), 3.11 (m, 1H), 2.88 (m, 2H), 2.77 (m, 2H), 2.66 (m, 3H), 2.49~2.30 (m, 5H), 2.22~1.95 (m, 2H), 1.86 (m, 1H), 1.65 (m, 1H), 1.25 (m, 2H), 1.18 (d, 6H), 0.84 (m, 2H);

[1051] MS (ESI + ):m / z= 861.45 [M+H] + .

[1052] [Example 29]

[1053] Preparation of N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1054]

[1055] The same process as Example 1 was performed except that the compound of Manufacturing Example 10) and the compound of Manufacturing Example 18) were used, thereby obtaining 37 mg (yield: 18%) of the title compound.

[1056] 1H-NMR (300 MHz, DMSO-d6): δ10.75 (s, 1H), 10.47 (s, 1H), 8.56 (d, 1H), 8.12 (s, 1H), 8.03 (m, 1H), 7.96 (m, 1H), 7.90 (s, 1H), 7.62 (m, 2H), 7.45 (m, 4H), 7.38~7.27 (m, 3H), 7.03 (d, 2H), 6.86 (d, 2H), 5.12 (m, 2H), 4.54 (m, 1H), 4.35 (m, 1H), 3.94 (m, 1H), 3.72 (m, 1H), 3.48 (m, 2H), 3.11 (m, 1H), 2.86 (m, 2H), 2.77 (m, 2H), 2.62 (m, 3H), 2.49~2.30 (m, 5H), 2.22~1.95 (m, 2H), 1.78 (m, 1H), 1.65 (m, 1H), 1.25 (m, 2H), 1.06 (d, 6H), 0.84 (m, 2H);

[1057] MS (ESI + ):m / z= 904.44 [M+H] + .

[1058] [Example 30]

[1059] Preparation of N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1060]

[1061] The same process as Example 1 was performed except that the compounds of Manufacturing Example 11) and Manufacturing Example 18) were used, to obtain 29 mg (yield: 13%) of the title compound.

[1062] 1H-NMR (300 MHz, DMSO-d6): δ10.72 (s, 1H), 10.48 (s, 1H), 8.57 (d, 1H), 8.12 (s, 1H), 8.02 (dd, 2H), 7.91 (s, 1H), 7.61 (d, 2H), 7.45 (d, 4H), 7.40~7.30 (m, 3H), 7.03 (d, 1H), 6.91 (d, 2H), 5.15~5.10 (m, 2H), 4.54 (s, 1H), 4.35~4.28 (m, 1H), 3.94~3.90 (m, 1H), 3.73~3.68 (m, 1H), 3.47~3.40 (m, 2H), 3.10~3.05 (m, 1H), 2.90~2.85 (m, 2H), 2.78~2.74 (m, 2H), 2.67~2.62 (m, 3H), 2.49~2.30 (m, 5H), 2.04~1.99 (m, 2H), 1.82~1.75 (m, 1H), 1.68~1.64 (m, 1H), 1.25 (d, 1H), 1.06 (s, 3H), 1.04 (s. 3H), 0.88~0.84 (m, 2H);

[1063] MS (ESI + ):m / z= 922.43 [M+H] + .

[1064] [Example 31]

[1065] 4-(2-((2-(6-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2-flu

[1066] Preparation of (orophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1067]

[1068] The same process as Example 1 was performed except that the compounds of Manufacturing Example 11) and Manufacturing Example 20) were used, to obtain 22 mg (yield: 8%) of the title compound.

[1069] 1 H-NMR (300 MHz, DMSO-d6): δ12.06 (s, 1H), 10.81 (s, 1H), 8.55 (s, 1H), 8.11 (d, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.72 (d, 2H), 7.56 (s, 1H), 7.48~7.42 (m, 4H), 7.32~7.28 (m, 2H), 7.25~7.20 (m, 1H), 7.05 (d, 1H), 6.94~6.88 (m, 2H), 5.32 (s, 1H), 5.11 (d, 2H), 4.28~4.12 (m, 4H), 3.97~3.94 (m, 1H), 3.45~3.41 (m, 2H), 3.20~3.15 (m, 1H), 2.90~2.85 (m, 2H), 2.83~2.78 (m, 2H), 2.72~2.30 (m, 8H), 2.10~1.99 (m, 2H), 1.87~1.79 (m, 1H), 1.69~1.65 (m, 1H), 1.24 (s, 1H), 1.07 (s, 3H), 1.04 (s. 3H);

[1070] MS (ESI + ):m / z= 902.44 [M+H] + .

[1071] [Example 32]

[1072] Preparation of 3-(4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)piperidine-2,6-dione

[1073]

[1074] The same process as Example 1 was performed except that the compounds of Manufacturing Example 11) and Manufacturing Example 21) were used, to obtain 32 mg (yield: 12%) of the title compound.

[1075] 1H-NMR (300 MHz, DMSO-d6): δ12.05 (s, 1H), 10.82 (s, 1H), 8.56 (s, 1H), 8.12 (d, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7.62 (d, 2H), 7.56 (s, 1H), 7.48~7.43 (m, 5H), 7.31~7.26 (m, 2H), 7.24~7.19 (m, 1H), 7.05 (d, 1H), 6.90~6.81 (m, 2H), 5.32 (br, 1H), 5.12 (d, 2H), 4.54 (s, 1H), 4.38~4.32 (m, 1H), 3.93~3.87 (m, 1H), 3.79~3.74 (m, 1H), 3.47~3.40 (m, 2H), 3.19~3.14 (m, 1H), 2.90~2.84 (m, 2H), 2.78~2.72 (m, 2H), 2.69~2.65 (m, 3H), 2.49~2.30 (m, 5H), 2.27~2.23 (m, 2H), 2.03~1.99 (m, 1H), 1.84~1.78 (m, 1H), 1.69~1.65 (m, 1H), 1.24 (s, 1H), 1.06 (s, 3H), 1.04 (s. 3H);

[1076] MS (ESI + ):m / z= 945.44 [M+H] + .

[1077] [Example 33]

[1078] Preparation of N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1079]

[1080] The same process as Example 1 was performed except that the compounds of Manufacturing Example 12) and Manufacturing Example 18) were used, to obtain 26 mg (yield: 14%) of the title compound.

[1081] 1 H-NMR (300 MHz, DMSO-d6): δ10.85 (bs, 1H), 10.49 (bs, 1H), 8.55 (d, 1H), 8.12 (s, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.90 (s, 1H), 7.63 (m, 2H), 7.44 (m, 4H), 7.36~7.26 (m, 4H), 6.93 (d, 2H), 5.14 (m, 2H), 4.54 (bs, 1H), 4.35 (m, 1H), 3.83 (m, 1H), 3.82 (m, 1H), 3.05 (m, 4H), 2.99~2.70 (m, 7H), 2.68~2.51 (m, 4H), 2.36 (m, 2H), 2.24 (m, 1H), 1.97 (m, 1H), 1.82 (m, 2H), 1.63 (m, 1H), 1.08 (d, 6H), 0.84 (m, 1H);

[1082] MS (ESI + ):m / z= 940.42 [M+H] + .

[1083] [Example 34]

[1084] Preparation of 4-(2-((2-(6-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1085]

[1086] The same process as Example 1 was performed except that the compounds of Manufacturing Example 12) and Manufacturing Example 20) were used, to obtain 38 mg (yield: 19%) of the title compound.

[1087] 1 H-NMR (300 MHz, DMSO-d6): δ11.98 (d, 1H), 10.85 (bs, 1H), 8.55 (d, 1H), 8.10 (d, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.72 (m, 2H), 7.56 (s, 1H), 7.47~7.37 (m, 5H), 7.32 (m, 2H), 7.25 (m, 1H), 6.93 (d, 2H), 5.28 (bs, 1H), 5.11 (m, 2H), 4.45 (m, 1H), 3.93 (m, 1H), 3.82 (m, 1H), 3.05 (m, 3H), 2.89~2.51 (m, 11H), 2.39 (m, 2H), 2.24 (m, 1H), 1.97 (m, 1H), 1.85 (m, 2H), 1.65 (m, 1H), 1.25 (m, 2H), 1.01 (d, 6H), 0.85 (m, 1H);

[1088] MS (ESI + ):m / z= 920.43 [M+H] + .

[1089] [Example 35]

[1090] Preparation of 3-(4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3,5-difluorophenyl)piperidine-2,6-dione

[1091]

[1092] The same process as Example 1 was performed except that the compounds of Manufacturing Example 12) and Manufacturing Example 21) were used, to obtain 26 mg (yield: 15%) of the title compound.

[1093] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.83 (s, 1H), 8.54 (m, 1H), 8.11~8.08 (m, 1H), 8.04 (s, 1H), 7.83 (s, 1H), 7.61~7.54 (m, 3H), 7.46~7.36 (m, 5H), 7.28~7.23 (m, 2H), 7.19~7.16 (m, 1H), 6.94~6.90 (m, 2H), 5.28 (bs, 1H), 5.10~5.09 (m, 2H), 4.40 (m, 1H), 3.95 (m, 1H), 3.82~3.78 (m, 1H), 3.01~2.97 (m, 3H), 2.79 (m, 7H), 2.69~2.57 (m, 5H), 2.35 (m, 2H), 2.20 (m, 1H), 1.97 (m, 1H), 1.78~1.75 (m, 2H), 1.65 (m, 1H), 1.06~0.93 (m, 8H);

[1094] MS (ESI + ):m / z= 963.43 [M+H] + .

[1095] [Example 36]

[1096] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1097]

[1098] The same process as Example 1 was performed except that the compounds of Manufacturing Example 13) and Manufacturing Example 17) were used, to obtain 71 mg (yield: 33%) of the title compound.

[1099] 1H-NMR (300 MHz, DMSO-d6): δ10.75 (s, 1H), 10.42 (bs, 1H), 8.55 (s, 1H), 8.12 (s, 1H), 8.03~8.00 (m, 1H), 7.95~7.89 (m, 2H), 7.72~7.69 (m, 2H), 7.43~7.41 (m, 4H),7.34~7.25 (m, 3H), 6.86~6.80 (t, 1H), 6.54~6.48 (m, 1H), 6.43~6.39 (m, 1H), 5.85~5.83 (m, 1H), 5.16~5.13 (m, 2H),4.51 (bs, 1H), 4.29~4.25 (m, 2H), 3.95 (m, 1H), 3.64~3.57 (m, 4H), 3.14 (m, 1H), 2.87~2.66 (m, 12H), 2.58~2.56 (m, 1H), 2.06 (m, 1H), 1.85 (m, 1H), 1.65 (m, 3H), 1.50 (m, 1H);

[1100] MS (ESI + ):m / z= 880.40 [M+H] + .

[1101] [Example 37]

[1102] Preparation of N-(5-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1103]

[1104] The same process as Example 1 was performed except that the compounds of Manufacturing Example 13) and Manufacturing Example 18) were used, to obtain 89 mg (yield: 42%) of the title compound.

[1105] 1H-NMR (300 MHz, DMSO-d6): δ10.75 (s, 1H), 10.42 (bs, 1H), 8.55 (s, 1H), 8.12 (s, 1H), 8.03~8.00 (m, 1H), 7.95~7.89 (m, 2H), 7.72~7.69 (m, 2H), 7.43~7.41 (m, 4H),7.34~7.25 (m, 3H), 6.86~6.80 (t, 1H), 6.54~6.48 (m, 1H), 6.43~6.39 (m, 1H), 5.85~5.83 (m, 1H), 5.16~5.13 (m, 2H),4.51 (bs, 1H), 4.29~4.25 (m, 2H), 3.95 (m, 1H), 3.64~3.57 (m, 4H), 3.14 (m, 1H), 2.87~2.66 (m, 12H), 2.58~2.56 (m, 1H), 2.06 (m, 1H), 1.85 (m, 1H), 1.65 (m, 3H), 1.50 (m, 1H);

[1106] MS (ESI + ):m / z= 923.39 [M+H] + .

[1107] [Example 38]

[1108] Preparation of 4-(2-((2-(6-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1109]

[1110] The same process as Example 1 was performed except that the compounds of Manufacturing Example 13) and Manufacturing Example 20) were used, to obtain 54 mg (yield: 27%) of the title compound.

[1111] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.76 (bs, 1H), 8.53~8.52 (m, 1H), 8.11~8.06 (m, 2H), 7.84 (s, 1H), 7.71~7.69 (m, 2H), 7.69 (s, 1H), 7.54~7.37 (m, 5H), 7.28~7.23 (2H), 7.19~7.16 (m, 1H), 6.83~6.80 (m, 1H), 6.54~6.48 (m, 1H), 6.43~6.40 (m, 1H), 5.86~5.84 (m, 1H), 5.26 (bs, 1H), 5.14~5.11 (m, 2H), 4.29~4.27 (m, 4H), 3.95 (m, 1H), 3.65~3.57 (m, 4H), 3.14 (m, 1H), 2.95~2.58 (11H), 2.05 (m, 1H), 1.85 (m, 1H), 1.66 (m, 3H), 1.50 (m, 1H);

[1112] MS (ESI + ):m / z= 903.40 [M+H] + .

[1113] [Example 39]

[1114] Preparation of 3-((3-fluoro-4-(4-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[1115]

[1116] The same process as Example 1 was performed except that the compounds of Manufacturing Example 13) and Manufacturing Example 21) were used, to obtain 9 mg (yield: 4%) of the title compound.

[1117] 1H-NMR (300 MHz, DMSO-d6): δ11.98 (bs, 1H), 10.77 (s, 1H), 8.55 (s, 1H), 8.12~8.07 (m, 2H), 7.85 (s,1 H), 7.61~7.55 (m, 3H), 7.46~7.37 (m, 5H), 7.28~7.24 (m, 2H), 7.19~7.17 (m, 1H), 6.86~6.80 (t, 1H), 6.55~6.49 (m, 1H), 6.43~6.40 (m, 1H), 5.87~5.84 (m, 1H), 5.28 (bs, 1H), 5.14 (m, 2H), 4.29~4.26 (m, 2H), 3.95 (m, 1H), 3.65~3.57 (m, 4H), 3.16 (m, 1H), 2.96~2.58 (m, 12H), 2.10 (m, 1H), 1.85 (m, 1H), 1.66 (m, 3H), 1.40 (m, 1H);

[1118] MS (ESI + ):m / z= 946.39 [M+H] + .

[1119] [Example 40]

[1120] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1121]

[1122] The same process as Example 1 was performed except that the compounds of Manufacturing Example 14) and Manufacturing Example 17) were used, to obtain 38 mg (yield: 19%) of the title compound.

[1123] 1H-NMR (300 MHz, DMSO-d6): δ10.81 (s, 1H), 10.46 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.02 (d, 1H), 7.97 (d, 1H), 7.91 (s, 1H), 7.73 (d, 2H), 7.45 (d, 4H), 7.37~7.27 (m, 3H), 6.81 (t, 1H), 6.50 (d, 1H), 6.46 (d, 1H) 5.76 (d, 1H), 5.15 (s, 2H), 4.54 (s, 1H), 4.29~4.23 (m, 2H), 3.92~3.88 (m, 2H), 3.01~2.90 (m, 5H), 2.88~2.82 (m, 2H), 2.81~2.73 (m, 3H), 2.23~2.20 (m, 4H), 2.12~2.09 (m, 1H), 1.87~1.77 (m, 3H), 1.69~1.63 (m, 1H), 1.03 (s 3H), 1.02 (s,3H), 1.16~1.13 (m, 2H);

[1124] MS (ESI + ):m / z= 894.45 [M+H] + .

[1125] [Example 41]

[1126] Preparation of N-(5-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1127]

[1128] The same process as Example 1 was performed except that the compounds of Manufacturing Example 14) and Manufacturing Example 18) were used, to obtain 32 mg (yield: 12%) of the title compound.

[1129] 1H-NMR (300 MHz, DMSO-d6): δ10.78 (s, 1H), 10.50 (s, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 7.99 (d, 1H), 7.97 (d, 1H), 7.91 (s, 1H), 7.63 (d, 2H), 7.45 (d, 4H), 7.36~7.27 (m, 3H), 6.79 (t, 1H), 6.51 (d, 1H), 6.45 (d, 1H) 5.79 (d, 1H), 5.13 (d, 2H), 4.54 (s, 1H), 4.39~4.32 (m, 1H), 4.30~4.22 (m, 1H), 3.92~3.88 (m, 1H), 3.01~2.82 (m, 5H), 2.81~2.73 (m, 3H), 2.68~2.52 (m, 3H), 2.40~2.31 (m, 4H), 2.13~2.04 (m, 1H), 1.87~1.77 (m, 3H), 1.69~1.63 (m, 2H), 1.09 (s 3H), 1.07 (s,3H), 1.01~1.87 (m, 1H);

[1130] MS (ESI + ):m / z= 937.44 [M+H] + .

[1131] [Example 42]

[1132] Preparation of 4-(2-((2-(6-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1133]

[1134] The same process as Example 1 was performed except that the compounds of Manufacturing Example 14) and Manufacturing Example 20) were used, to obtain 36 mg (yield: 17%) of the title compound.

[1135] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.76 (bs, 1H), 8.53~8.52 (m, 1H), 8.11~8.05 (m, 2H), 7.84 (s, 1H), 7.72~7.69 (m, 2H), 7.69 (s, 1H), 7.54~7.36 (m, 5H), 7.28~7.24 (2H), 7.19~7.17 (m, 1H), 6.77 (m, 1H), 6.46 (m, 1H), 6.41~6.38 (m, 1H), 5.80~5.74 (m, 1H), 5.27 (bs, 1H), 5.10~5.09 (m, 2H), 4.40 (m, 1H), 4.25 (m, 1H), 3.95 (m, 1H), 2.95~2.53 (m, 13H), 2.37~2.30 (m, 4H), 2.07 (m, 1H), 1.84~1.80 (m, 3H), 1.65 (m, 1H), 1.02~0.84 (m, 8H);

[1136] MS (ESI + ):m / z= 917.45 [M+H] + .

[1137] [Example 43]

[1138] Preparation of 3-((4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione

[1139]

[1140] The same process as Example 1 was performed except that the compound of Manufacturing Example 14) and the compound of Manufacturing Example 21) were used, thereby obtaining 46 mg (yield: 22%) of the title compound.

[1141] 1H-NMR (300 MHz, DMSO-d6): δ11.99 (bs, 1H), 10.78 (bs, 1H), 8.55 (m, 1H), 8.13~8.06 (m, 2H), 7.85 (s, 1H), 7.62 (m, 2H), 7.60 (s, 1H), 7.56~7.38 (m, 5H), 7.30~7.24 (2H), 7.18 (m, 1H), 6.78 (m, 1H), 6.52 (m, 1H), 6.48 (m, 1H), 5.79 (m, 1H), 5.31 (bs, 1H), 5.11 (m, 2H), 4.43 (m, 1H), 4.22 (m, 1H), 3.95 (m, 1H), 3.01~2.53 (m, 13H), 2.35 (m, 4H), 2.07 (m, 1H), 1.85~1.80 (m, 3H), 1.65 (m, 1H), 1.02 (d, 6H);

[1142] MS (ESI + ):m / z= 960.45 [M+H] + .

[1143] [Example 44]

[1144] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1145]

[1146] The same process as Example 1 was performed except that the compounds of Manufacturing Example 15) and Manufacturing Example 17) were used, to obtain 34 mg (yield: 17%) of the title compound.

[1147] 1H-NMR (300 MHz, DMSO-d6): δ10.76 (bs, 1H), 10.44 (bs, 1H), 8.56~8.56 (m, 1H), 8.11 (s, 1H), 8.03~8.00 (m, 1H), 7.95~7.92 (m, 1H), 7.89 (s, 1H), 7.73~7.70 (m, 2H), 7.43~7.34 (m, 4H), 7.32~7.25 (m, 3H), 6.79 (m, 1H), 6.52~6.46 (m, 1H), 6.41~6.37 (m, 1H), 5.79~5.76 (m, 1H), 5.13~5.11 (m, 2H), 4.51 (bs, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 3.96 (m, 1H), 3.00~2.71 (m, 11H), 2.59~2.47 (m, 6H), 2.05 (m, 1H), 1.84~1.75 (m, 4H), 1.20~1.00 (m, 2H), 0.87 (s, 6H);

[1148] MS (ESI + ):m / z= 894.45 [M+H] + .

[1149] [Example 45]

[1150] Preparation of N-(5-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide

[1151]

[1152] The same process as Example 1 was performed except that the compounds of Manufacturing Example 15) and Manufacturing Example 18) were used, to obtain 46 mg (yield: 25%) of the title compound.

[1153] 1H-NMR (300 MHz, DMSO-d6): δ10.76 (bs, 1H), 10.47 (bs, 1H), 8.54 (m, 1H), 8.11 (s, 1H), 8.03~8.00 (m, 1H), 7.95~7.92 (m, 1H), 7.89 (s, 1H), 7.62~7.59 (m, 2H), 7.45~7.42 (m, 4H), 7.34~7.7.25 (m, 3H), 6.82~6.76 (m, 1H), 6.52~6.46 (m, 1H), 6.41~6.38 (m, 1H), 5.78~5.76 (m, 1H), 5.13~5.11 (m, 2H), 4.53 (bs, 1H), 4.40 (m, 1H), 4.23 (m, 1H), 3.96 (m, 1H), 2.98~2.70 (m, 11H), 2.67~2.58 (m, 6H), 2.07~2.05 (m, 1H), 1.85~1.76 (m, 4H), 1.03 (m, 2H), 0.87 (s, 6H);

[1154] MS (ESI + ):m / z= 937.44 [M+H] + .

[1155] [Example 46]

[1156] Preparation of 4-(2-((2-(6-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile

[1157]

[1158] The same process as Example 1 was performed except that the compounds of Manufacturing Example 15) and Manufacturing Example 20) were used, to obtain 25 mg (yield: 11%) of the title compound.

[1159] 1H-NMR (300 MHz, DMSO-d6): δ11.97 (bs, 1H), 10.76 (s, 1H), 8.53~8.52 (m, 1H), 8.11~8.08 (m, 1H), 8.06 (s, 1H), 7.84 (s, 1H),7.72~7.69 (m, 2H), 7.55 (s, 1H), 7.46~7.37 (m, 5H), 7.29~7.24 (m, 2H), 7.19~7.17 (m, 1H), 6.80 (m, 1H), 6.52~6.47 (m, 1H), 6.46~6.41 (m, 1H), 5.78~5.74 (m, 1H), 5.27 (bs, 1H), 5.11~5.09 (m, 2H), 4.45 (m, 1H), 4.25 (m, 1H), 3.95 (m, 1H), 3.00 (m, 1H), 2.86~2.82 (m, 7H), 2.73~2.66 (m, 3H), 2.59~2.52 (m, 6H), 2.05 (m, 1H), 1.89~1.76 (m, 4H), 1.15 (m, 2H), 0.87 (s, 6H);

[1160] MS (ESI + ):m / z= 917.45 [M+H] + .

[1161] [Example 47]

[1162] Preparation of 3-((3-fluoro-4-(4-(2-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)propan-2-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione

[1163]

[1164] The same process as Example 1 was performed except that the compounds of Manufacturing Example 15) and Manufacturing Example 21) were used, to obtain 65 mg (yield: 31%) of the title compound.

[1165] 1H-NMR (300 MHz, DMSO-d6): δ11.98 (bs, 1H), 10.77 (s, 1H), 8.55 (s, 1H), 8.12~8.09 (m, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.62~7.59 (m, 2H), 7.55 (s, 1H), 7.47~7.37 (m, 5H), 7.29~7.24 (m, 2H), 7.20~7.17 (m, 1H), 6.83~6.77 (m, 1H), 6.53~6.47 (m, 1H), 6.42~6.38 (m, 1H), 5.79~5.77 (m, 1H), 5.29 (bs, 1H), 5.12~5.10 (m, 2H), 4.45 (m, 1H), 4.24 (m, 1H), 3.95 (m, 1H), 3.00 (m, 1H), 2.85~2.83 (m, 7H), 2.76~2.67 (m, 3H), 2.59~2.52 (m, 6H), 2.07 (m, 1H), 1.86~1.76 (m, 4H), 1.15 (m, 2H), 0.87 (s, 6H);

[1166] MS (ESI + ):m / z= 960.45 [M+H] + .

[1167] [Example 48]

[1168] Preparation of 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1169]

[1170] The same process as Example 1 was performed except that the compounds of Manufacturing Example 16) and Manufacturing Example 17) were used, to obtain 58 mg (yield: 29%) of the title compound.

[1171] 1H-NMR (300 MHz, DMSO-d6): δ10.75 (bs, 1H), 10.43 (bs, 1H), 8.56~8.55 (m, 1H), 8.12 (s, 1H), 8.03~8.01 (m, 1H), 7.96~7.92 (m, 1H), 7.90 (s, 1H), 7.73~7.70 (m, 2H), 7.44~7.41 (m, 4H), 7.35~7.25 (m, 3H), 6.81 (m, 1H), 6.51 (m, 1H), 6.46~6.42 (m, 1H), 5.77~5.74 (m, 1H), 5.14 (s, 2H), 4.51 (bs, 1H), 4.25 (m, 1H), 3.50~3.44 (m, 4H), 3.12~3.08 (m, 2H), 2.88~2.83 (m, 3H), 2.76~2.72 (m, 3H), 2.58~2.54 (m, 3H), 2.39~2.32 (m, 4H), 2.20~2.18 (m, 2H), 2.07 (m, 1H), 1.78~1.74 (m, 3H), 1.55 (m, 1H), 1.25~1.22 (m, 2H);

[1172] MS (ESI + ):m / z= 866.42 [M+H] + .

[1173] [Example 49]

[1174] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1175]

[1176] The same process as Example 1 was performed except that the compound of Manufacturing Example 3) and the compound of Manufacturing Example 23) were used, to obtain 53 mg (yield: 20%) of the title compound.

[1177] 1H-NMR (300 MHz, DMSO-d6): δ10.76 (bs, 1H), 10.44 (bs, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 8.02 (m, 1H), 7.98~7.91 (m, 2H), 7.74 (m, 2H), 7.46 (m, 4H), 7.37~7.27 (m, 3H), 7.07 (m, 2H), 6.91 (m, 2H), 5.14 (s, 2H), 4.53 (s, 1H), 4.33 (m, 1H), 3.93 (m, 1H), 3.74 (m, 1H), 3.32 (m, 6H), 3.16 (m, 6H), 2.90~2.64 (m, 7H), 2.29~2.16 (m, 4H), 1.80 (m, 3H);

[1178] MS (ESI + ):m / z= 833.42 [M+H] + .

[1179] [Example 50]

[1180] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1181]

[1182] The same process as Example 1 was performed except that the compound of Manufacturing Example 10) and the compound of Manufacturing Example 23) were used, to obtain 62 mg (yield: 23%) of the title compound.

[1183] 1H-NMR (300 MHz, DMSO-d6): δ10.74 (bs, 1H), 10.42 (bs, 1H), 8.56~8.55 (m, 1H), 8.10 (s, 1H), 8.03~8.00 (m, 1H), 7.95~7.92 (m, 1H), 7.89 (s, 1H), 7.73~7.70 (d, 2H), 7.44~7.41 (m, 4H), 7.35~7.25 (m, 3H), 7.04~7.01 (m, 2H), 6.87~6.84 (m, 2H), 5.12~5.10 (m, 2H), 4.51 (bs, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.71~6.37 (m, 1H), 3.48~3.44 (m, 1H), 2.93 (m, 1H), 2.87~2.54 (m, 9H), 2.41~2.32 (m, 5H), 2.01~2.00 (m, 2H), 1.79 (m, 2H), 1.65 (m, 2H), 1.07 (d, 6H), 0.95 (m, 1H);

[1184] MS (ESI + ):m / z= 861.45 [M+H] + .

[1185] [Example 51]

[1186] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1187]

[1188] The same process as Example 1 was performed except that the compounds of Manufacturing Example 11) and Manufacturing Example 23) were used, to obtain 40 mg (yield: 15%) of the title compound.

[1189] 1H-NMR (300 MHz, DMSO-d6): δ10.79 (s, 1H), 10.42 (s, 1H), 8.56 (d, 1H), 8.11 (s, 1H), 8.01 (m, 1H), 7.96 (m, 1H), 7.91 (s, 1H), 7.75 (d, 2H), 7.42 (m, 4H), 7.38~7.25 (m, 3H), 6.96 (m, 3H), 5.12 (m, 2H), 4.52 (s, 1H), 4.33 (m, 1H), 3.94 (m, 1H), 3.82 (q, 1H), 3.18 (m, 2H), 3.01 (m, 2H), 2.86 (m, 2H), 2.75 (m, 2H), 2.61 (m, 4H), 2.46~2.30 (m, 3H), 2.25~1.91 (m, 2H), 1.90~1.60 (m, 3H), 1.25 (m, 2H), 1.06 (d, 6H);

[1190] MS (ESI + ):m / z= 879.44 [M+H] + .

[1191] [Example 52]

[1192] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1193]

[1194] The same process as Example 1 was performed except that the compound of Manufacturing Example 6) and the compound of Manufacturing Example 23) were used, to obtain 34 mg (yield: 12%) of the title compound.

[1195] 1H-NMR (300 MHz, DMSO-d6): δ10.77 (bs, 1H), 10.44 (bs, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 8.05 (m, 2H), 7.97 (m, 2H), 7.75 (m, 2H), 7.50 (m, 4H), 7.37 (m, 3H), 6.87 (m, 1H), 6.54~6.44 (m, 2H), 5.79 (m, 1H), 5.14 (s, 2H), 4.53 (m, 1H), 4.26 (m, 2H), 3.94 (m, 2H), 3.46 (m, 4H), 3.34 (m, 5H), 3.08 (m, 2H), 2.87 (m, 7H), 2.74 (m, 4H), 2.56 (m, 2H), 2.23 (m, 4H), 1.86 (m, 4H);

[1196] MS (ESI + ):m / z= 866.42 [M+H] + .

[1197] [Example 53]

[1198] 4-(4-((1-(2-(4-(6-((R)-2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

[1199]

[1200] The same process as Example 1 was performed except that the compound of Manufacturing Example 5) and the compound of Manufacturing Example 23) were used, thereby obtaining 42 mg (yield: 15%) of the title compound.

[1201] 1H-NMR (300 MHz, DMSO-d6): δ10.81 (bs, 1H), 10.42 (bs, 1H), 8.56~8.55 (m, 1H), 8.11 (s, 1H), 8.00~7.89 (m, 4H), 7.73~7.70 (m, 2H), 7.64~7.58 (t, 1H), 7.44~7.41 (m, 4H), 7.34~7.23 (m, 3H), 6.82~6.73 (m, 2H), 5.12 (m, 2H), 4.73~4.69 (m, 1H), 4.51 (bs, 1H), 4.31~4.27 (m, 1H), 3.92~3.88 (m, 1H), 2.85~2.80 (m, 1H), 2.76~2.58 (m, 8H), 2.48 (m, 5H), 2.18~1.99 (m, 4H), 1.78~1.76 (m, 3H), 1.23 (m, 2H), 1.11 (m, 2H), 0.97~0.93 (m, 1H);

[1202] MS (ESI + ):m / z= 894.41 [M+H] + .

[1203] [Example 54]

[1204] (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide

[1205]

[1206] The same process as Example 1 was performed except that the compound of Manufacturing Example 30) and the compound of Manufacturing Example 23) were used, thereby obtaining 36 mg (yield: 20%) of the title compound.

[1207] 1H-NM...

Claims

1. A compound of chemical formula 1 or a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In chemical formula 1, m is an integer from 0 to 5, R 1 In each case, halogen, C 1~3 Alkyl, C 3~6 Cycloalkyl, CN and CF3 are substituents selected independently from each other in m order; Q 1 Silver CR 4 R 5 , CR 6 , Geminal C 3~5 Cycloalkylene, geminal haloC 3~5 Cycloalkylene, C 3~5 Cycloalkylene, haloC 3~5 Cycloalkylene, or C≡C, where R 4 , R 5 Wow R 6 are H and C respectively 1~5 Alkyl, C 3~5 Cycloalkyl and haloC 3~5 A functional group independently selected from the group consisting of cycloalkyl; Q 2 is CR 7 R 8 , CR 9 , Geminal C 3~5 Cycloalkylene or C 3~5 Cycloalkylene, where R 7 , R 8 and R 9 are H and C respectively 2~5 Alkyl and C 3~5 A functional group independently selected from the group consisting of cycloalkyl, provided that Q 1 This CR 6 When Q 2 Go CR 9 It should be, Q 2 Go CR 9 Q on the other side 1 This CR 6 It must be, Q 1 and Q 2 In between The sign is Q 1 and Q 2 Each CR 6 and CR 9 When Q 1 and Q 2 Indicates that it is directly connected by a double bond, otherwise Q 1 and Q 2 It indicates that they are directly connected by a single bond; R 2 is a substituted or unsubstituted C 6~10 Aryl, substituted or unsubstituted 5-6 membered heteroaryl; R 3 , X and Is a) R 3 This X and with one substituted or unsubstituted C 8~14 Forming a fused bicyclic heteroarylene together, or b) X is CH or N, and R 3 This H, C 1~3 Alkyl, C 1~2 alkyleneNHR 10 , NH2, NHR 10 or NR 10 R 11 and, is any one ring selected from the group consisting of substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene, wherein R 10 and R 11 C are chosen independently from each other 1~3 It is alkyl; is selected from substituted or unsubstituted phenylene and substituted or unsubstituted 5-6 membered heteroarylene; E 1 and E 2 are each independently hydrogen or halogen. L is a linker, Z is an E3 ligase binding functional group, The above substitution C 6~10 Aryl, substituted 5-6 membered heteroaryl, substituted C 8~14 Fused bicyclic heteroarylene, substituted phenylene or substituted 5-6 membered heteroarylene is a fused bicyclic heteroarylene in which at least one ring hydrogen is C 1~6 A ring substituted with a functional group independently selected from the group consisting of alkyl, halogen, CN, NO2, and CF3.

2. A compound according to claim 1, wherein the E3 ligase is a von Hippel-Lindau tumor suppressor protein or cereblon.

3. In the first paragraph, a compound characterized in that L has a structure of chemical formula 2: [Chemical Formula 2] L in chemical formula 2 1 Silver NHC 1~3 A functional group independently selected from the group consisting of alkylene, 5-6 membered heterocyclylene, substituted 5-6 membered heterocyclylene and 8-12 membered spiroheterocycloalkylene, L 1 This NHC 1~3 When it is alkylene, NHC 1~3 C of alkylene 1~3 L on alkylene carbon 2 is connected, and the substituted 5-6 membered heterocyclylene has at least one ring hydrogen as C 1~2 A functional group independently substituted with alkyl, L 2 is C 1~3 Alkylene or substituted C 1~3 Alkylene, wherein the above-mentioned substituted C 1~3 Alkylene is a group in which one or more hydrogens are C 1~3 A functional group substituted with a substituent independently selected from the group consisting of alkyl and oxo, L 3 NHC, which is connected to Z 1~3 A functional group independently selected from the group consisting of alkylene, 5-6 membered heterocyclylene, 8-12 membered spiroheterocycloalkylene and substituted 5-6 membered heterocyclylene, wherein the substituted 5-6 membered heterocyclylene has at least one ring hydrogen atom of C 1~2 These are functional groups independently substituted with alkyl.

4. In the first paragraph, a compound characterized in that Z has a structure of chemical formula 3: [Chemical Formula 3] is any one selected from the group consisting of substituted or unsubstituted phenylene, substituted or unsubstituted fused bicyclic heteroarylene, and 2,3-dihydro-3-methyl-2-oxo-1H-benzo[d]imidazolylene, wherein the substituted phenylene or the substituted fused bicyclic heteroarylene has at least one ring hydrogen atom as C 1~6 A ring substituted with a functional group each independently selected from the group consisting of alkyl, halogen, CN, NO2 and CF3; Q 3 is NH, CONH or a chemical bond; Q 4 is CH or N; Is It indicates that L is chemically bonded to A.

5. In the first paragraph, the compound is characterized by having a structure of chemical formula 4: [Chemical Formula 4] Q in chemical formula 4 3 is NH, CONH or a chemical bond; Q 4 is CH or N; m is an integer from 0 to 4, and each Q 5 are halogens that are independently selected from each other; J 1 is CN or CF3; J 2 J 4 Wow n is If n is 0, then J 2 Ga CH, J 3 and J 4 is N, or J 2 is S, and J 3 This C, J 4 is CH or, If n is 1, J 2 Wow J 4 is CH, and J 3 This is C; class Is this And, go This or that, this And, go , and here ★ is or The ring of -C(G 2 )(G 3 ) points to the location connected to, and ■ or refers to the position where the ring is connected to the carbonyl group or phenyl group of chemical formula 4; G 1 and G 2 are each independently hydrogen or methyl, or G 1 and G 2 Together they form an oxo substituent.

6. In the first paragraph, the compound is characterized by having a structure of chemical formula 5: [Chemical Formula 5] Q in chemical formula 5 3 is NH, CONH or a chemical bond; J 1 CN, halogen or CF3; Is and here * is indicates the position where it is connected to the carbonyl group, and ** It points to the position where it is connected to the 1H-pyrazolyl group; G 1 and G 2 are each independently hydrogen or methyl, or G 1 and G 2 together form an oxo substituent; G 3 and G 4 are each independently hydrogen or methyl; Is , and here † is ‡ indicates the position where the piperazine group is connected to the piperazine group. Go Q 3 Points to the location connected to; m is a natural number from 1 to 4, and each Q 5 are independently selected halogens, and Q 6 is hydrogen or methyl.

7. Any one compound selected from the group consisting of the following compounds, a stereoisomer, a tautomer, a solvate or a pharmaceutically acceptable salt thereof: 2-((4-cyanophenylethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanophenethyl)amino)-N-(5-(1-(2-(((R)-5-((4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)amino)-3-methylpentyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, N-(5-(1-(2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-(4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione, 4-(4-((1-(2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-(2-phenyl-2-((4-(trifluoromethyl))phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide, 4-(4-((1-(2-(4-(3-(2-((4-cyanophenethyl)amino)-2-phenylacetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl))phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((1-(4-(trifluoromethyl)phenyl)cyclopropyl)methyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-((3-fluoro-4-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 2-((3-(4-cyanophenyl)prop-2-yn-1-yl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6)-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-)indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-)yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-(1-methyl-6-(4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione, 2-((4-cyanophenethyl)amino)-N-(5-(1-(2-(((3R)-5-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)-3-methylpentyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 4-(2-((2-(6-(1-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-(4-(4-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)a (cetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)piperidine-2,6-dione, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl )amino)ethyl)benzonitrile, 3-(4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)piperidine-2,6-dione, N-(5-(1-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)-2,6-difluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-(4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3,5-difluorophenyl)piperidine-2,6-dione, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazine-1-carbonyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-((3-fluoro-4-(4-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidine-4-carbonyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-(((2S,6R)-4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-((4-((3S,5R)-3,5-dimethyl-4-((1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, N-(5-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 4-(2-((2-(6-(1-(2-(4-(2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)propan-2-yl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-oxo-1-phenylethyl)amino)ethyl)benzonitrile, 3-((3-fluoro-4-(4-(2-(1-(2-(4-(3-(2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetyl)-1H-indol-6-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)propan-2-yl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 4-(4-((1-(2-(4-(6-((R)-2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide, (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2R)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, (2R)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-((R)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide, (2R)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, (2S)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, (2R)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide, (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide, (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide, (2R)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-((R)-2-((4-fluorophenethyl)amino)-2-phenylacetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide, (2R)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-((4-fluorophenethyl)amino)-2-phenylacetamide, (2R)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide, (2R)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide, (2R)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-((1-(2-(4-(6-((R)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamido)pyridin-3-yl)-1H-pyrazol-1-yl)acetyl)piperidin-4-yl)methyl)piperazin-1-yl)benzamide, (2R)-N-(5-(1-(2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-(((S)-2-(4-(trifluoromethyl)phenyl)propyl)amino)acetamide, 2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-(((2R,6S)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, (2S)-2-(((S)-2-(4-cyanophenyl)propyl)amino)-N-(5-(1-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(4-((2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-(((2S,6R)-4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(5-(2-(9-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethyl)thiophen-2-yl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(9-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide, 2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide, (2R)-2-((4-cyanopheneethyl)amino)-N-(5-(4-(2-(4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1,1-difluoro-2-oxoethyl)phenyl)pyridin-2-yl)-2-phenylacetamide and (2R)-N-(5-(1-(2-(4-((9-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-phenyl-2-((4-(trifluoromethyl)phenethyl)amino)acetamide.

8. A pharmaceutical composition for the treatment or prevention of cancer comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient.

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