Helios, a piperidinil low molecular weight degrading agent, and its method of use.

Abstract

Disclosed are compounds and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers that can cause degradation of various proteins, such as IKZF2 (Helios). Also disclosed are pharmaceutical compositions containing the same, and methods of making and using the compounds to treat diseases and disorders that are related to Helios and that can benefit from Helios degradation.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of priority under 35 U.S.C § 119(e) to U.S. Provisional Patent Application No. 63 / 092,610 filed on 16 October 2020 and U.S. Provisional Patent Application No. 63 / 153,599 filed on 25 February 2021, which are incorporated herein by reference in their entirety. [Background technology]

[0002] Imide molecules such as thalidomide and its analogs bind to cereblon (CRBN), a substrate adapter for the ubiquitously expressed kalin ring ligase 4(CUL4)-RBX1-DDB1-CRBN(CUL4 CRBN)E3 ligase (Kronke et al., Science 343:301-305 (2014); Ito et al., Science 327:1345-1350 (2010)). This results in the recruitment, ubiquitination, and subsequent proteasomal degradation of neosubstrates, namely Ikaros (IKZF1) and Aiolos (IKZF3), but not of other members of the IKZF zinc finger transcription factor family. The imide analog CC-885 is predicted to have some activity in inducing Helios degradation, but it also induces the degradation of GSPT1, an important translation termination factor (Matyskiela et al., Nature 535:252-257 (2016)).

[0003] Helios (IKZF2), a member of the IKZF family, is a key regulator of T cell activity and function. Gene deletion of Helios resulted in enhanced antitumor immune responses (Kim et al., Science 350:334-339 (2015)). In particular, Helios is highly expressed in regulatory T cells, a subpopulation of T cells that limit the activity of effector T cells (Elkord et al., Expert Opin. Biol. Ther. 12:1423-1425 (2012)). Selective deletion of Helios in regulatory T cells resulted in both loss of inhibitory activity and acquisition of effector T cell function (Najagawa et al., Proc.Natl.Acad.Sci.USA113:6248-6253(2016); Yates et al., Proc.Natl.Acad.Sci.USA115:2162-2167(2018). Therefore, Helios is a key factor limiting T cell effector function in Tregs.

[0004] Helios expression is associated with chronic viral infections (Crawford et al., Immunity 40:289-302 (2014), Doering et al., Immunity 371130-1144 (2012); Scott-Browne et al., Immunity 45:1327-1340 (2016)) and tumors (Martinez et al., Immunity 42:265-278 (2015); Mognol et al., Proc.Natl.Acad.Sci.USA 114:E2776-E2785 (2017); Pereira et al., J.Leukoc.Biol.102:601-615 (2017); Singer et al., Cell 166:1500-1511 (2016); Schietinger et al. Helios has been reported to be upregulated in “exhausted” T cells in both situations (Long et al., Immunity 45:389-401 (2016)) and in dysfunctional chimeric antigen receptor (CAR) T cells (Long et al., Nat. Med. 21:581-590 (2015)). Overexpression or abnormal expression of Helios and various splice isoforms has been reported in several hematological malignancies, including T-cell leukemias and lymphomas (Nakase et al., Exp. Hematol. 30:313-317 (2002); Tabayashi et al., Cancer Sci. 98:182-188 (2007); Asanuma et al., Cancer Sci. 104:1097-1106 (2013)). Furthermore, knockdown of Helios in a model of mixed-phenotype leukemia (MLL)-driven myeloid leukemia strongly suppressed proliferation and increased cell death (Park et al., J. Clin. Invest. 125:1286-1298 (2015); Park et al., Cell Stem Cell 24:153-165 (2019)). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Kronke et al.,Science 343:301-305(2014) [Non-licensed document 2] Ito et al.,Science 327:1345-1350(2010) [Non-licensed document 3] Matyskiela et al.,Nature 535:252-257(2016)

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[0006] A first aspect of the present invention is formula (I): [ka] (In the formula, R 1a , R 1b , R 1a ', R 1b ' 、 R2, R3, R4, R4' 、A compound having a structure represented by (where R5, R5’, R6 and n1 are as defined herein), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0007] A second aspect of the present invention is a compound of formula (II):

Chemical formula

[0008] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a co-crystal of a compound of formula (I) or (II).

[0009] A further aspect of the present invention relates to a method of treating a disease or disorder that benefits from IKZF2 (Helios) degradation.

[0010] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is T cell leukemia, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, or carcinoid.

[0011] As demonstrated in the examples, the compounds of the present invention exhibit potent degradation of IKZF2(Helios).

[0012] While not intended to be bound by any particular operating theory, the compounds of the present invention are thought to enhance the antitumor immune response by converting regulatory T cells into effector T cells and rescuing effector T cell function in exhausted T cells or CAR-T cells. [Modes for carrying out the invention]

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this specification belongs. Where used herein and in the appended claims, unless otherwise specified, the following terms have the meanings provided for the convenience of understanding the invention.

[0014] As used in the description and appended claims, the singular forms "a," "an," and "the" include plural referents unless the context explicitly indicates otherwise. Thus, for example, a reference to "composition" includes mixtures of two or more such compositions, a reference to "inhibitor" includes mixtures of two or more such inhibitors, and so on.

[0015] Unless otherwise specified, the term "approximately" means within 10% (e.g., within 5%, 2%, or 1%) of the specific value modified by the term "approximately".

[0016] The transitional phrase “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is comprehensive or open-ended, and does not exclude additional unlisted elements or process steps. When used in relation to the number of heteroatoms in a heterocyclic structure, it means the heterocyclic group of the minimum number of heteroatoms. In contrast, the transitional phrase “consisting of” excludes elements, processes, or components not specified in the claims. The transitional phrase “consisting essentially of” limits the claims to a particular material or process “that does not substantially affect the basic and novel features of the claimed invention.”

[0017] With respect to the compounds of the present invention, and to the extent to which the following terms are used herein to further describe them, the following definitions apply.

[0018] As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical. In one embodiment, the alkyl radical is C1-C 18 It is a group. In other embodiments, the alkyl radicals are C0-C6, C0-C5, C-0-C3, C1-C 12These are C1-C8, C1-C6, C1-C5, C1-C4, or C1-C3 groups (wherein C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group or a methyl group.

[0019] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain having 1 to 12 carbon atoms, consisting only of carbon and hydrogen, without unsaturation, and linking the rest of the molecule to a radical group, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may be bonded to the rest of the molecule via single bonds, or to the radical group via single bonds. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains one carbon atom (C1 alkylene).

[0020] As used herein, the term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyls include radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. For example, an alkenyl radical is C2-C 18 It is a group. In other embodiments, the alkenyl radical is C2-C 12 , C2-C 10 , C2-C 8、 These are C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0021] As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. For example, an alkynyl radical is C2-C 18 It is a group. In other examples, the alkynyl radical is C2-C 12 , C2-C 10 , C2-C 8、 These are C2-C6 or C2-C3 groups. Examples include ethinylpropa-1-inyl, propa-2-inyl, buta-1-inyl, buta-2-inyl, and buta-3-inyl.

[0022] As used herein, the terms "alkoxyl" or "alkoxy" refer to the alkyl group defined above, which has an oxygen radical bonded to it and is the bonding site. Typical alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. An "ether" is two hydrocarbyl groups covalently bonded by oxygen. Therefore, the substituents of an alkyl group that make an alkyl group an ether are alkoxyl or alkoxy-like, which can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl groups.

[0023] As used herein, the term "halogen" (or "halo" or "halogenated") refers to fluorine, chlorine, bromine, or iodine.

[0024] As used herein, the term “ring group” is used alone or as part of a larger part and broadly refers to any group including saturated, partially saturated, or aromatic ring systems, e.g., carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl groups. A ring group may have one or more (e.g., condensed) ring systems. Thus, for example, a ring group may contain one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0025] As used herein, the term “carbocyclic” (or “carbocyclyl”) refers to a group, either alone or as part of a larger part, that includes saturated, partially unsaturated, or aromatic ring systems having 3 to 20 carbon atoms (e.g., alkcarbocyclic group). The term carbocyclyl includes monocyclic, dicyclic, tricyclic, fused, bridging, and spirocyclic systems, as well as combinations thereof. In one embodiment, a carbocyclyl contains 3 to 15 carbon atoms (C3- 15 In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C3-C3). 12). In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5-C 10 In other embodiments, the carbocyclyl comprises C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl as a bicycle comprises C7-C 12 Includes. In some embodiments, the carbocyclyl as a spirocycle system is C5-C 12 Includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, Examples include cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl. Bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocycyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, di-, or spiro-carbon rings). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) different ring groups (e.g., aryl rings or heterocycles), where the bond radicals or dots are located on the carbocyclic ring.

[0026] Therefore, when the term "carbon ring" is used herein, R c Formula -R is an alkylene chain. c-This also includes carbocyclylalkyl groups, which refer to the carbocyclyl group. When the term carbocyclyl is used herein, R c Formula where is an alkylene chain --O--R c -This also includes carbocyrylalkoxy groups, which refer to groups bonded via the oxygen atom of a carbocyryl molecule.

[0027] As used herein, the terms “aryl” (e.g., “aralkyl” where the terminal carbon atom on an alkyl group is the bond site, e.g., a benzyl group, “aralkoxy” where the oxygen atom is the bond site, or “aloxyalkyl” where the bond site is on an aryl group), used alone or as part of a larger part, refer to groups comprising monocyclic, bicyclic, or tricyclic carbocyclic systems, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, the aralkoxy group is a benzoxy group. The term “aryl” may be used interchangeably with the term “aryl ring.” In one embodiment, aryl includes groups having 6 to 18 carbon atoms. In one embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthrasyl, biphenyl, phenantrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthilidinyl, and others, which may be substituted or independently substituted with one or more substituents described herein. A particular aryl is phenyl. In some embodiments, the aryl group comprises an aryl ring fused to one or more (e.g., 1, 2, or 3) different ring groups (e.g., a carbocyclic or heterocyclic ring), with the bond radical or dot located on the aryl ring. Any structure of an aryl group that may have double bonds at different positions is considered to encompass any and all such resonance structures.

[0028] Therefore, the term aryl, which includes the aralkyl group (e.g., benzyl) disclosed above, is R c Formula -R is an alkylene chain such as methylene or ethylene. c- Refers to an aryl group. In some embodiments, the aralkyl group is a benzyl group which may be substituted. The term aryl is used herein as R c The formula is such that methylene or ethylene is an alkylene chain --OR c --This also includes aryl alkoxy groups, which refer to groups bonded via the oxygen atom of an aryl group.

[0029] As used herein, the term “heterocyclyl” is used alone or as part of a larger part to refer to a “carbocyclyl” that includes saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes monocyclic, dicyclic, tricyclic, fused, bridging, and spirocyclic systems, as well as combinations thereof. In some embodiments, heterocyclyl refers to 3- to 15-membered heterocyclyl ring systems. In some embodiments, heterocyclyl refers to 3- to 12-membered heterocyclyl ring systems. In some embodiments, heterocyclyl refers to saturated ring systems such as 3- to 12-membered saturated heterocyclyl ring systems. In some embodiments, heterocyclyl refers to heteroaryl ring systems such as 5- to 14-membered heteroaryl ring systems. The term heterocyclyl also includes C3-C8 heterocycloalkyls, which are saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic systems containing 3 to 8 carbon atoms and one or more (1, 2, 3, or 4) heteroatoms.

[0030] In some embodiments, the heterocyclyl group includes monocyclic, dicyclic, tricyclic, and spirocyclic systems, comprising 3 to 12 ring atoms, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl comprises a 3 to 7-membered monocycle having one or more heteroatoms selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocyclyl comprises a 4 to 6-membered monocycle having one or more heteroatoms selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocyclyl comprises a 3-membered monocycle. In some embodiments, the heterocyclyl comprises a 4-membered monocycle. In some embodiments, the heterocyclyl comprises a 5 to 6-membered monocycle. In some embodiments, the heterocyclyl group comprises 0 to 3 double bonds. In any of the embodiments described above, the heterocyclyl comprises 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be quaternized (e.g., [NR4]). + Cl - [NR4] + OH -). Representative examples of heterocyclyls include oxyranil, azilidinil, thiranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, pyrrolidinil, dihydro-1H-pyrrolyl, dihydrofuranil, tetrahydropyranil, dihydrothienyl, tetrahydrothienyl, imidazolidinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholinil, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexahydropyrimidinil, oxadina Nyl, thiadinyl, thioxanil, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanil, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranil, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinol, oxazolidinol, imidazolidinol, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[ [d]Imidazolyl, 1,6-dihydroimidazole [4,5-d]pyrrolo [2,3-b]pyridinyl, thiadinyl, thiophenyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, py Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1] Octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azabicyclo[4.5]decane-2-only, azaspiro[5.5] Examples include undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranil. Examples of five-membered heterocyclyls containing a sulfur atom or an oxygen atom and 1 to 3 nitrogen atoms are thiazolyls containing thiazole-2-yl and thiazole-2-yl N-oxide, thiadiazolyls containing 1,3,4-thiadiazole-5-yl and 1,2,4-thiadiazole-5-yl, oxazolyl, e.g., oxazol-2-yl, and oxadiazolyls such as 1,3,4-oxadiazole-5-yl and 1,2,4-oxadiazole-5-yl. Examples of five-membered heterocyclyl rings containing 2 to 4 nitrogen atoms include imidazolyls such as imidazole-2-yl; triazolyls such as 1,3,4-triazole-5-yl, 1,2,3-triazole-5-yl, and 1,2,4-triazole-5-yl; and tetrazolyls such as 1H-tetrazole-5-yl. Representative examples of benzo-condensed five-membered heterocyclyls are benzoxazole-2-yl, benzthiazole-2-yl, and benzimidazole-2-yl. Examples of six-membered heterocyclyls include pyridyls such as pyrido-2-yl, pyrido-3-yl, and pyrido-4-yl; pyrimidyls such as pyrimido-2-yl and pyrimido-4-yl; triazinyls such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; and pyridazinyls, particularly pyridazin-3-yl and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide, as well as pyridyl, pyrimido-2-yl, pyrimido-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl groups, are yet another example of heterocyclyl groups. In some embodiments, the heterocyclic group comprises a heterocycle fused to one or more (e.g., 1, 2, or 3) different ring groups (e.g., a carbocyclic or heterocyclic ring), where the bonding radical or point is located on the heterocycle, and in some embodiments, the bonding point is a heteroatom contained within the heterocycle.

[0031] Therefore, as used herein, the term heterocycle also includes N-heterocyclyl groups, which refer to heterocyclyl groups containing at least one nitrogen atom, where the bond between the heterocyclyl group and the rest of the molecule is via a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. As used herein, the term heterocycle also includes C-heterocyclyl groups, which refer to heterocyclyl groups containing at least one heteroatom, where the bond between the heterocyclyl group and the rest of the molecule is via a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. As disclosed above, the term heterocycle also includes R c Formula -R is an alkylene chain. c -This also includes heterocyclylalkyl groups that refer to the heterocyclyl group. The term heterocycle, as used herein, is R c Formula where is an alkylene chain --O--R c -This also includes heterocyclylalkoxy groups, which refer to radicals bonded via the oxygen atom of a heterocyclyl.

[0032] As used herein, the term "heteroaryl," used alone or as part of a larger phrase (e.g., "heteroarylalkyl" or "heteroarylalkoxy"), refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, with at least one ring being aromatic and containing at least one heteroatom. In one embodiment, a heteroaryl comprises a 5-6 membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, Examples include pyrazinyl, pyridadinyl, triazinyl, tetradinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazole-2-yl, 1,3,4-triazole-5-yl, 1,3-oxazole-2-yl, 1,3,4-oxadiazole-5-yl, 1,2,4-oxadiazole-5-yl, 1,3,4-thiadiazolyl-5-yl, 1H-tetrazole-5-yl, 1,2,3-triazole-5-yl, and pyrido-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl is condensed on one or more cyclic rings (e.g., carbocyclyl or heterocyclyl) and the radical or dot of the bond lies on the heteroaryl ring.Non-limiting examples include indolyl, indolidinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different ring groups (e.g., a carbocyclic or heterocyclic ring), where the bonding radical or dot is on the heteroaryl ring, and in some embodiments, the bonding dot is a heteroatom contained in the heterocyclic ring. Any structure of a heteroaryl group that may have double bonds at different positions is considered to encompass any and all of such resonance structures.

[0033] Therefore, as used herein, the term heteroaryl also includes N-heteroaryl groups, which refer to heteroaryl groups containing at least one nitrogen atom, where the bond between the heteroaryl group and the rest of the molecule is via a nitrogen atom in the heteroaryl group. As used herein, the term heteroaryl also includes C-heteroaryl groups, which refer to heteroaryl groups where the bond between the heteroaryl group and the rest of the molecule is via a carbon atom in the heteroaryl group, as defined above. c Formula -R is an alkylene chain. c -This also includes heteroarylalkyl groups disclosed above, which refer to heteroaryl groups. When used herein, the term heteroaryl is defined as R c Formula where is an alkylene chain --O--R c-This also includes heteroaralkoxy (heteroarylalkoxy) groups, which refer to groups bonded via the oxygen atom of a heteroaryl group.

[0034] Unless otherwise specified, any group described herein may be substituted or unsubstituted to the extent not further defined for any particular group (one or more). As used herein, the term “substituted” broadly refers to all permissible substituents, implicitly provided that such substitution follows the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. Representative substituents include halogens, hydroxyl groups, and any other organic groups that contain any number of carbon atoms, e.g., 1 to 14 carbon atoms, and may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms such as oxygen, sulfur, and nitrogen arranged on the group in a linear, branched, or cyclic structural form.

[0035] Unless otherwise disclosed for any particular group, typical examples of substituents include alkyl, substituted alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), halo Lukyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5-C6), substitution ring formulas (e.g., C3-C 12 , C5-C6), carbocyclic (e.g., C3-C 12 , C5-C6), substituted carbocyclic formulas (e.g., C3-C 12 , C5-C6), complex rings (e.g., C3-C 12, C5-C6), substitutional complex rings (e.g., C3-C 12 C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C6) 12 , C6), substituted aryloxy (e.g., C6-C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C) 12 , C6), substitution arylthio (e.g., C6-C 12 Examples include C6, cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acids, and peptide groups.

[0036] In one embodiment, the compound of the present invention is of formula (I): [ka] It is represented by, or by, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof. (In the formula, Each R 1a , R 1b , R 1a 'and R 1b ' is independently hydrogen or (C1-C6) alkyl, or R 1a and R 1a ', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R1a and R 1a ', when on different carbon atoms, together with the atom they are bonded to, form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, or R 1b and R 1b ' forms a spiro(C3-C7)cycloalkyl group or a 4-7 member heterocycloalkyl group, and the alkyl, cycloalkyl or heterocycloalkyl group consists of one or more identical or different R 15 It may be further independently substituted by the base; Each R2 is independently selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halo, (C1-C6)alkyl, and (C1-C6)haloalkyl; R3 is selected from the group consisting of hydrogen, amino, hydroxyl, cyano, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl, and the alkyl is one or more identical or different R 15 It may be further independently substituted by the base, or R3 and R4, together with the carbon atoms to which they are bonded, form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R2 and R3, together with the atoms to which they are bonded, form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group consists of one or more identical or different R2s. 15 It may be further independently substituted by the base; Each R4 and R4' independently consists of hydrogen, hydroxyl, amino, amide, carbonyl, cyano, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10) Selected from the group consisting of aryl, monocyclic and bicyclic 5-10 member heteroaryl, (C2-C6) alkenyl, and (C2-C6) alkynyl, wherein the alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base, or R4 and R4', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R4 and R4', together with the same carbon atom they are bonded to, either form C=(O) or If R4 and R4' are on different carbon atoms, they can form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group together with the atom they are bonded to, or R4 and R4', together with the carbon atom they are bonded to, form (C6-C 10 ) form an aryl or a 5 or 6-membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; R5 and R5' are independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; R6 is an R7-substituted aryl or R7-substituted heteroaryl, and the aryl or heteroaryl is one or more identical or different R 15It may be further independently substituted by the base, or The R6 is [ka] [ka] And, R7 is [ka] Selected from the group consisting of; The R8 is (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each R9 independently consists of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, and (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each R 11 and R 11 ' is independently hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 ) Selected from the group consisting of aryl, monocyclic and bicyclic 5-10 member heteroaryl, halo, cyano, -N(R9)2, -OR9, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R 15may be further independently substituted by a radical, or R 11 and R 11 ’ together with the same carbon atom to which they are attached form a spiro(C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 11 and R 11 ’ together with the same carbon atom to which they are attached form C=(O), or R 11 and R 11 ’ when on different carbon atoms, together with the atoms to which they are attached form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, said cycloalkyl or heterocycloalkyl being optionally further independently substituted by one or more identical or different R 15 groups; R 12 and R 13 together with the carbon atom to which they are attached form a (C6-C 10 )aryl, or a monocyclic or bicyclic 5- to 10-membered heteroaryl, said aryl or heteroaryl being optionally further independently substituted by one or more identical or different R 15 groups; each R 14 and R 14 ’ is independently selected from the group consisting of hydrogen, (C 1- C6)alkyl, (C 1- C6)haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 )aryl, monocyclic and bicyclic 5- to 10-membered heteroaryl, halo, cyano, -N(R9)2, -OR9, (C 1- C6)alkoxy, (C 1- C6)haloalkoxy, (C 2- C6)alkenyl and (C 2- C6)alkynyl, said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl being optionally further independently substituted by one or more identical or different R15 It may be further independently substituted by the base, or R 14 and R 14 ', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 14 and R 14 ' either together with the same carbon atom they are bonded to, to form C=(O), or R 14 and R 14 When ' is on different carbon atoms, it combines with the atom to which it is bonded to form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group consists of one or more identical or different R 15 It may be further independently substituted by the base, However, at least one R 14 and at least one R 14 ', together with the same carbon atom to which they are bonded, form C=(O); Each R 15These are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl , containing formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, at least one nitrogen atom,Selected from the group consisting of 4- to 7 member heterocycloalkyl, aryl, and heteroaryl groups linked via a nitrogen atom, and also two adjacent R groups, 15 These, together with the individual atoms to which they are bonded, form aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl groups; R 16 Hydrogen, (C 1- C6) Alkyl, (C 1- C6) Haloalkyl, (C3-C7) Cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 )aryl, monocyclic and bicyclic 5-10 member heteroaryl, halo, cyano, -N(R9)2, -OR9, (C 1- C6) alkyl, (C 1- C6) Haloalkoxy, (C 2- C6) Alkenil, (C 2- C6) Selected from the group consisting of alkynyls and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each G is independent of C(R 11 )(R 11 '), NR 11 and selected from O, however at least one G is NR 11 or O; W1 is selected from the group consisting of -O-, -S-, and -NR9-; W2 is selected from the group consisting of -O-, -S-, -SO2-, -C=(O)-, and -NR9-; Each W3 contains either nitrogen or CR 16 and; Y is -SO2- or -C=(O)-; Each Q is independent of C, C(R) 16 ), C=(O), O, S, N and NR 16 Selected from; n1 is 0, 1, or 2; n3 is independently 1, 2, or 3; n4 is independently 1 or 2; and n5 is independently either 0 or 1.

[0037] In some embodiments, the compound is represented by formula I, where: Each R 1a , R 1b , R 1a 'and R 1b ' is hydrogen; Each R2 is independently selected from the group consisting of hydrogen, halo, and (C1-C6)alkyl; R3 is selected from the group consisting of hydrogen, amino, hydroxyl, cyano, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl, and the alkyl is one or more identical or different R 15 It may be further independently substituted by the base; Each R4 and R4' is independently selected from the group consisting of hydrogen, hydroxyl, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C1-C6)hydroxyalkyl, wherein the alkyl is one or more identical or different R 15 It may be further substituted independently by the base, or R4 and R4', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or If R4 and R4' are on different carbon atoms, they combine with the atoms they are bonded to to form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; R5 and R5' are independently hydrogen or (C1-C6) alkyl, and the alkyl is one or more identical or different R 15 It may be further independently substituted by the base; R6 is an R7-substituted aryl or R7-substituted heteroaryl, and the aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base, or The R6 is [ka] And, R7 is [ka] Selected from the group consisting of; The R8 is (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each R9 independently consists of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, and (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each R 11 and R 11 ' is independently hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 ) Selected from the group consisting of aryl, monocyclic and bicyclic 5-10 member heteroaryl, halo, cyano, -N(R9)2, -OR9, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base, or R 11 and R 11', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, or R 11 and R 11 ' either together with the same carbon atom they are bonded to, to form C=(O), or R 11 and R 11 When ' is on different carbon atoms, it combines with the atom to which it is bonded to form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group consists of one or more identical or different R 15 It may be further independently substituted by the base; R 12 and R 13 These, together with the carbon atoms to which they are bonded, (C6-C 10 ) form an aryl, or a monocyclic or bicyclic 5-10 member heteroaryl, wherein the aryl or heteroaryl comprises one or more identical or different R 15 It may be further independently substituted by the base; Each R 14 and R 14 ' is independently of hydrogen, (C 1- C6) Alkyl, (C 1- C6) Haloalkyl, (C3-C7) Cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 )aryl, monocyclic and bicyclic 5-10 member heteroaryl, halo, cyano, -N(R9)2, -OR9, (C 1- C6) alkyl, (C 1- C6) Haloalkoxy, (C 2- C6) Alkenyl and (C 2- C6) Selected from the group consisting of alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base, or R 14 and R14 ', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 14 and R 14 ' either together with the same carbon atom they are bonded to, to form C=(O), or R 14 and R 14 When ' is on different carbon atoms, it combines with the atom to which it is bonded to form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group consists of one or more identical or different R 15 It may be further independently substituted by the base, However, at least one R 14 and at least one R 14 ', together with the same carbon atom to which they are bonded, form C=(O); Each R 15These are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl , containing formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, at least one nitrogen atom,Selected from the group consisting of 4- to 7 member heterocycloalkyl, aryl, and heteroaryl groups linked via a nitrogen atom, and also two adjacent R groups, 15 These, together with the individual atoms to which they are bonded, form aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl groups; R 16 Hydrogen, (C 1- C6) Alkyl, (C 1- C6) Haloalkyl, (C3-C7) Cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 )aryl, monocyclic and bicyclic 5-10 member heteroaryl, halo, cyano, -N(R9)2, -OR9, (C 1- C6) alkyl, (C 1- C6) Haloalkoxy, (C 2- C6) Alkenil, (C 2- C6) Selected from the group consisting of alkynyls and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each G is independent of C(R 11 )(R 11 '), NR 11 and selected from O, however at least one G is NR 11 or O; W1 is selected from the group consisting of -O-, -S-, and -NR9-; W2 is selected from the group consisting of -O-, -S-, -SO2-, -C=(O)-, and -NR9-; Each W3 contains either nitrogen or CR 16 and; Y is -SO2- or -C=(O)-; Each Q is independent of C, C(R) 16 ), C=(O), O, S, N and NR 16 Selected from; n1 is 0, 1, or 2; n3 is independently 1, 2, or 3; n4 is independently 1 or 2; and n5 is independently either 0 or 1.

[0038] In some embodiments, the compound is represented by formula I, where, Each R2 is a hydrogen atom; R3 is either hydrogen or hydroxyl; Each R4 and R4' is independently hydrogen or a (C1-C6) alkyl group; R5 and R5' are independently selected from hydrogen or (C1-C6) alkyl groups; The R6 is [ka] and; Each R 11 and R 11 ' is independently hydrogen or (C1-C6) alkyl, wherein the alkyl is one or more identical or different R 15 It may be further independently substituted by the base, or R 11 and R 11 ', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 11 and R 11 ' either together with the same carbon atom they are bonded to, to form C=(O), or R 11 and R 11 When ' is on different carbon atoms, it combines with the atom to which it is bonded to form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group consists of one or more identical or different R 15 It may be further independently substituted by the base; R 16The radicals are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, halo, cyano, -N(R9)2, -OR9, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and radicals involved in the formation of single bonds, wherein the alkyl is one or more identical or different R 15 It may be further independently substituted by the base; and n1 is 1.

[0039] In some embodiments, the compound is represented by formula I, where R6 is [ka] And R6 is (C 1- C6) May be further independently substituted with one or more groups selected from alkyl, halo, and cyano; and Each R 11 and R 11 ' is independently of hydrogen or (C 1- C6) It is an alkyl group.

[0040] In some embodiments, the compound is represented by formula I, where R8 is [ka] Selected from, R8 is one or more R 15 It may be further independently substituted.

[0041] In some embodiments, the compound is represented by formula I, where R8 is [ka] Selected from, R8 is one or more R 15 It may be further independently substituted.

[0042] A second aspect of the present invention is formula (II): [ka] This relates to compounds having the structure represented by, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. (In the formula: Each R 1a , R 1b , R 1a 'and R 1b ' is independently hydrogen or (C1-C6) alkyl, or R 1a and R 1a ', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 1a and R 1a ', when on different carbon atoms, together with the atom they are bonded to, form a (C3-C7) cycloalkyl group or a 4-7 member heterocycloalkyl group, or R 1b and R 1b ' forms a spiro(C3-C7)cycloalkyl group or a 4-7 member heterocycloalkyl group, and the alkyl, cycloalkyl or heterocycloalkyl group consists of one or more identical or different R 15 It may be further independently substituted by the base; Each R2 is independently selected from the group consisting of hydrogen, hydroxyl, amino, cyano, halo, (C1-C6)alkyl, and (C1-C6)haloalkyl; Each R4 and R4' independently consists of hydrogen, hydroxyl, amino, amide, carbonyl, cyano, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 ) Selected from the group consisting of aryl, monocyclic and bicyclic 5-10 membered heteroaryls, (C2-C6) alkenyls, and (C2-C6) alkynyls, wherein the alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R15 It may be further independently substituted by the base, or R4 and R4', together with the same carbon atom to which they are bonded, form a spiro(C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R4 and R4', together with the same carbon atom they are bonded to, either form C=(O) or If R4 and R4' are on different carbon atoms, they may, together with the atoms they are bonded to, form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or; R4 and R4', together with the carbon atom they are bonded to, form (C6-C 10 ) form an aryl or a 5- or 6-membered heteroaryl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; R5 and R5' are independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each R 15These are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl , containing formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, at least one nitrogen atom,Selected from the group consisting of 4- to 7 member heterocycloalkyl, aryl, and heteroaryl groups linked via a nitrogen atom, and also two adjacent R groups, 15 These, together with the individual atoms to which they are bonded, form aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl groups; R 21 is a substituted C6-aryl, wherein the aryl is at least two R 15 It is substituted with, however, if it is on an adjacent carbon atom, R 15 The two of these are at least one (C6-C 10 ) Forms a 5 or 6-membered heteroaryl substituted with an aryl, or a monocyclic or bicyclic 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl are one or more R 15 It may be further independently substituted by the base, or R 21 is a substituted 5- or 6-membered heteroaryl, wherein the heteroaryl has at least two R 15 It is substituted with, however, if it is on an adjacent atom, R 15 The two are C6-aryl or at least one (C6-C 10 ) Forms a 5 or 6-membered heteroaryl substituted with an aryl, or a monocyclic or bicyclic 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl are one or more R 15 It may be further independently substituted by the base, or R 21 teeth [ka] and; The R8 is (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; W1 is selected from the group consisting of -O-, -S-, and -NR9-; Each R9 independently consists of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4-7 member heterocycloalkyl, and (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Y is -SO2- or -C=(O)-; Each Q is independent of C, C(R) 16 ), C=(O), O, S, N and NR 16 Selected from; R 16 Hydrogen, (C 1- C6) Alkyl, (C 1- C6) Haloalkyl, (C3-C7) Cycloalkyl, 4-7 member heterocycloalkyl, (C6-C 10 )aryl, monocyclic and bicyclic 5-10 member heteroaryl, halo, cyano, -N(R9)2, -OR9, (C 1- C6) alkyl, (C 1- C6) Haloalkoxy, (C 2- C6) Alkenil, (C 2- C6) Selected from the group consisting of alkynyls and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; n1 is 0, 1 or 2; and n5 is independently either 0 or 1.

[0043] In some embodiments, the compound is represented by formula II, where, Each R 1a , R 1b , R 1a 'and R 1b' is hydrogen; Each R2 is a hydrogen atom; Each R4 and R4' is independently hydrogen or a (C1-C6) alkyl group; R5 and R5' are hydrogen or (C1-C6) alkyl, respectively; R 21 teeth, [ka] and; Each Q1 independently controls C, C(R) 16 ), C=(O), O, S, N, and NR 16 Selected from, however at least one Q1 is N; R 16 The radicals are independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, halo, cyano, -N(R9)2, -OR9, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are one or more identical or different R 15 It may be further independently substituted by the base; and n1 is 1.

[0044] In some embodiments, the compound is represented by formula II, In the formula, R 21 teeth, [ka] [ka] Selected from, R 21 is one or more (C 1- C6) May be independently substituted with alkyl, halo, and cyano compounds.

[0045] In some embodiments, the compound is represented by formula II, where R8 is [ka] Selected from, R8 is one or more R 15 It may be further independently substituted.

[0046] In some embodiments, the compound is represented by formula II, where R8 is [ka] Selected from, R8 is one or more R 15 It may be further independently substituted.

[0047] In some embodiments, the compounds of the present invention are represented by formulas IIa, IIb, IIc, IId, or IIe, or are pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof: [ka] (In the formula, Each R2 is independently selected from the group consisting of hydrogen and halos; The R8 is (C6-C 10 ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R 15 It may be further independently substituted by the base; Each R 15Alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl Formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, containing at least one nitrogen atom,Selected from the group consisting of 4-7 member heterocycloalkyl, aryl, and heteroaryl groups bonded via a nitrogen atom, and also two adjacent R groups, 15 These, together with the individual atoms to which they are bonded, form aryl, heteroaryl, 5-8 membered cycloalkyl or 5-8 membered heterocycloalkyl groups; and Each R 16 (These are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, and halo).

[0048] In some embodiments, R8 is [ka] Selected from, R8 is one or more R 15 It may be further independently substituted.

[0049] In some embodiments, R8 is [ka] Selected from, R8 is one or more (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, cyano, halo, and R 15 It may be further independently substituted by one or more groups selected from; and R 16 ' is selected from the group consisting of hydrogen and (C1-C6) alkyl groups.

[0050] A representative compound of the present invention has the following structure: [ka] [ka] [ka] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] <好 [Chemistry] [Chemistry] [Chemistry] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0051] Compounds 1-26, 32-34, and 45-52 are included in Formula I. Compounds 27-31, 35-44, and 53-99 are included in Formula II.

[0052] The compounds of the present invention (compounds of formulas (I) and (II)) may be in the form of free acids or free bases, or pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable” in the context of salts means a salt of a compound that does not negate the biological activity or properties of the compound and is relatively non-toxic; that is, the salt form of the compound can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or without interacting in a harmful manner with any other components of the composition containing it. The term “pharmaceutically acceptable salt” means a product obtained by the reaction of the compound of the present invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids, such as hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, bitartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucarones, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, 4-methylbenzenesulfons, or p-toluenesulfons. Certain compounds of the present invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin. Suitable base salts include salts of aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc.

[0053] The compounds of the present invention may have at least one chiral center and therefore may be in the form of stereoisomers, which, as used herein, encompass all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes enantiomers (enantiomers containing the (R-) or (S-) configuration of a compound), mixtures of enantiomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound having multiple chiral centers that are not mirror images of each other (diastereoisomers). The chiral centers of a compound can undergo epimerization in vivo; therefore, for these compounds, a dose of the compound in its (R-) form is considered equivalent to a dose of the compound in its (S-) form. Accordingly, the compounds of the present invention may be produced and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0054] In some embodiments, the compound is an isotopic derivative having at least one desired isotopic substitution of an atom in an amount exceeding the natural abundance of the isotope, i.e., a concentrated amount. In one embodiment, the compound comprises deuterium or a plurality of deuterium atoms. Deuterium, i.e. 2 Substitution with heavier isotopes, such as 1H, may result in certain therapeutic benefits stemming from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose, and therefore may be advantageous in some situations.

[0055] The compounds of the present invention may also be in the form of N-oxides, crystalline forms (also known as polymorphs), active metabolites of compounds having the same type of activity, prodrugs, tautomers, and non-solvated forms as well as solvated (e.g., hydrated) forms of the compounds with pharmaceutically acceptable solvents such as water and ethanol.

[0056] The compounds of the present invention may be prepared by crystallization under different conditions and may exist as one or a combination of polymorphisms of the compound. For example, different polymorphisms may be identified and / or prepared by crystallization at different temperatures using different solvents or mixtures of different solvents for recrystallization, or by using various cooling modes ranging from very rapid to very slow cooling during crystallization. Polymorphisms may also be obtained by heating or melting the compound and then cooling it gradually or rapidly. The presence of polymorphisms may be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and / or other known techniques.

[0057] In some embodiments, the pharmaceutical composition includes a cocrystal of the compound of the present invention. As used herein, the term "cocrystal" refers to a stoichiometric multicomponent system comprising the compound of the present invention and a cocrystal-forming agent, wherein the compound of the present invention and the cocrystal-forming agent are connected by non-covalent interactions. As used herein, the term "cocrystal-forming agent" refers to a compound that can form intermolecular interactions with the compound of the present invention and cocrystallize with it. Typical examples of cocrystal-forming agents include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine-p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoic acid, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0058] Synthesis method In another aspect, the present invention relates to methods for producing the compounds of the present invention or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. Generally, the compounds of the present invention or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof may be prepared by any steps known to be applicable to the preparation of chemically related compounds. The compounds of the present invention are described in various examples and are likely to be better understood in relation to synthetic schemes illustrating non-limiting methods by which the compounds of the present invention can be prepared.

[0059] Pharmaceutical composition Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” known in the art refers to a pharmaceutically acceptable material, composition or vehicle suitable for administering the compound of the present invention to a mammal. Suitable carriers include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semi-solids), and gases that function to transport or deliver the compound from one organ or part of the body to another organ or part of the body. The carrier is “acceptable” in the sense that it is physiologically inert to the subject or patient, compatible with other components of the formulation, and not harmful to the subject or patient. Depending on the type of formulation, the composition may also contain one or more pharmaceutically acceptable excipients.

[0060] In general, the compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers can be formulated into a given type of composition according to conventional pharmaceutical practices such as mixing, dissolution, granulation, sugar-coated tablet preparation, polishing, emulsification, encapsulation, sealing, and compression steps (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. ARGennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im)), and intrasternal injection or infusion techniques, intraocular, intra-arterial, intramedullary, intrathecal, intraventricular, percutaneous, interdermal, vaginal, intraperitoneal, mucosal, nasal, endotracheal, bronchial, and inhalation), and topical (e.g., perdermal). Generally, the most appropriate route of administration depends on various factors, including, for example, the properties of the drug (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound can be administered relatively quickly, such as in single-dose treatments and / or acute conditions.

[0061] In some embodiments, the compound is formulated for oral administration or intravenous administration (e.g., systemic intravenous injection).

[0062] Accordingly, the compounds of the present invention can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions containing the compound, suspensions containing dispersed solid particles of the compound, emulsions, and solutions, syrups, and elixirs containing liposomes, micelles, or nanoparticles); semi-solid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid release, intermediate release, or sustained release.

[0063] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with carriers such as sodium citrate or dicalcium phosphate and additional carriers or excipients, for example, a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) water retention agents such as glycerol, d) disintegrants such as cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), e) solution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. Solid compositions of the same type can also use excipients such as lactose or milk sugar and high molecular weight polyethylene glycol as fillers in soft and hard filled gelatin capsules. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings. They may further contain opacifying agents.

[0064] In some embodiments, the compounds of the present invention can be formulated into hard or soft gelatin capsules. Typical excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and sodium croscarmellose. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and a coloring agent.

[0065] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to compounds, liquid dosage forms may contain aqueous or non-aqueous carriers (depending on the solubility of the compound) commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof. Oral compositions may also contain excipients, such as wetting agents, suspending agents, colorants, sweeteners, flavoring agents, and fragrances.

[0066] Preparations for parenteral administration may include sterile aqueous solutions or oily suspensions. They can be formulated according to standard techniques using appropriate dispersants or wetting and suspending agents. Sterile preparations for parenteral administration may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Furthermore, sterile fixatives have been conventionally used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration with a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use. The effect of a compound can be sustained by delaying its absorption, which can be achieved by using a liquid suspension or crystalline or amorphous material with low water solubility. Sustained absorption of compounds from parenteral formulations can also be achieved by suspending the compounds in an oily vehicle.

[0067] In certain embodiments, the compounds of the present invention may be administered topically rather than systemically, often in the form of depot preparations or sustained-release formulations, for example, by direct injection of a conjugate into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Injectable depot formulations are prepared by forming a microcapsule matrix of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). The release rate of the compound can be controlled by changing the compound-to-polymer ratio and the properties of the specific polymer used. Depot injection formulations are also prepared by encapsulating the compound in liposomes or microemulsions that conform to body tissues. Furthermore, in other embodiments, the compounds are delivered by targeted drug delivery systems, such as liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ.

[0068] The composition may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0069] The compounds of the present invention can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists, or powders. The pharmaceutical composition may be delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve for delivering a measured amount. In some embodiments, capsules and cartridges containing gelatin for use in, for example, in inhalers or blowers may be formulated containing a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0070] The compounds of the present invention, when used herein, can be formulated for topical administration, referring to intradermal administration of the formulations according to the present invention. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0071] Typical examples of carriers useful for formulating compounds for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, bandages, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). For example, creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants such as polyoxy-40-stearate.

[0072] In some embodiments, topical formulations may also include excipients, examples of which are penetration enhancers. These agents can deliver pharmacologically active compounds through the stratum corneum to the epidermis or dermis, preferably with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in improving the rate of drug penetration through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995) (which outlines the use and testing of various skin penetration enhancers), and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Typical examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octriphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate and propylene glycol monooleate), and N-methylpyrrolidone.

[0073] Representative examples of other excipients that may be included in topical formulations and other types of formulations (as far as they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citrate. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citrate buffer, hydrochloric acid buffer, and lactate buffer. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0074] Transdermal formulations typically utilize transdermal delivery devices and transdermal delivery patches, where compounds are formulated in lipophilic emulsions or buffered aqueous solutions and dissolved and / or dispersed in polymers or adhesives. Patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoresis patches. Transdermal patches may offer controlled delivery of compounds, where the absorption rate is slowed by using a rate-controlled membrane or by trapping the compound within a polymer matrix or gel. Absorption can be increased using absorption enhancers, examples of which include absorbable, pharmaceutically acceptable solvents that help pass through the skin.

[0075] Ophthalmic preparations include eye drops.

[0076] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retained enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectal or vaginal cavity, releasing the compound.

[0077] Dosage As used herein, the term “therapeutic dose” means the amount of the compound of the present invention or any pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer that is effective in producing a desired therapeutic response in a patient suffering from a disease or disorder involving IKZF2 (Helios) and is expected to benefit from IKZF2 degradation. Accordingly, the term “therapeutic dose” includes the amount of the compound of the present invention or any pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer that, when administered, induces a positive modification of the disease or disorder being treated, prevents the onset or progression of the disease or disorder, alleviates to some extent one or more symptoms of the disease or disorder being treated in a subject, or simply kills or inhibits the proliferation of diseased cells, or reduces the amount of IKZF2 in diseased cells.

[0078] The total daily dose and dosage of a compound can be determined according to standard medical practice, for example, by the attending physician using sound medical judgment. The specific therapeutically effective dose for any particular subject depends on a variety of factors, including: the disease or disorder being treated and its severity (e.g., its current condition); the activity of the compound used; the specific composition used; the subject's age, weight, overall health, sex, and diet; the timing of administration, route of administration, and rate of excretion of the compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field (see, for example, Hardman et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, McGraw-Hill Press, 155-173, 2001).

[0079] The compounds of the present invention may be effective over a wide range of dosages. In some embodiments, the total daily dose (e.g., for adults) may range from about 0.001 to about 1600 mg, 0.01 to about 1000 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100 to 400 mg per day, about 1 to about 50 mg per day, about 5 to about 40 mg per day, and in yet other embodiments, about 10 to about 30 mg per day. Individual doses may be formulated to contain the desired dose depending on the number of times the compound is administered per day. For example, capsules may be formulated with about 1 to about 200 mg of the compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the compound may be administered in doses ranging from about 0.01 mg to about 200 mg / kg body weight / day. In some embodiments, doses of 0.1 to 100 mg / kg per day, for example, 1 to 30 mg / kg, may be effective with one or more doses per day. For example, suitable doses for oral administration may range from 1 to 30 mg / kg body weight per day, and suitable doses for intravenous administration may range from 1 to 10 mg / kg body weight per day.

[0080] How to use In some embodiments, the present invention relates to a method for treating a disease or disorder involving IKZF2, comprising administering a therapeutically effective amount of a compound of formula (I) and / or (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, to a subject in need.

[0081] Generally, diseases or disorders suitable for treatment with the compounds of the present invention are those involving IKZF2 activity or functionally abnormal IKZF2 activity compared to a non-pathological state. A “disease” is generally considered a health condition of a subject in which the subject is unable to maintain homeostasis and, if the disease does not improve, the subject’s health continues to deteriorate. In contrast, a “disorder” in a subject is a health condition in which the subject is able to maintain homeostasis, but the subject’s health condition is less desirable than that in the absence of the disorder. Leaving it untreated does not necessarily lead to a further deterioration of the subject’s health condition. In some embodiments, the compounds of formulas (I) and (II) may be useful in treating cytoproliferative diseases and disorders (e.g., cancer or benign neoplasms). As used herein, the term “cytoproliferative disease or disorder” refers to a condition characterized by unregulated or abnormal cell proliferation, or both, including non-cancerous conditions such as neoplasms, precancerous conditions, benign tumors, and cancer.

[0082] As used herein, the term “subject” (or “patient”) includes all members of the animal kingdom who are susceptible to or suffering from the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, livestock such as cattle, horses, sheep, goats, and pigs, and other livestock and wild animals. A subject “in need” treatment according to the present invention is one who is thought to “suffer from or suspected of suffering from” a particular disease or disorder, or who has been positively diagnosed with or can present with a sufficient number of risk factors or a sufficient number of signs or symptoms or combinations thereof, so that a medical professional may diagnose or suspect that the subject has the disease or disorder. Subjects who are suffering from or suspected of suffering from a particular disease or disorder are not necessarily two separate groups.

[0083] Exemplary types of non-cancerous (e.g., proliferative) diseases or disorders that may be suitable for treatment with the compounds of the present invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, and allergic and genetic diseases.

[0084] Specific examples of non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative states, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, euerythrocytic anemia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndromes (CAPS), endotoxin shock, endometritis, Gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, and adult respiratory distress. Obstructive pulmonary disease, chronic obstructive pulmonary disease, chronic pneumonia, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behçet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile-onset diabetes, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, Hashimoto's disease, Sjögren's syndrome, vitiligo, Wegener's granulomatosis, granulomatous orchitis, autoimmune oophoritis, sa Lucoidosis, rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, herpetiform dermatitis, ulcerative colitis, pancreatic fibrosis, hepatitis, hepatic fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, fever (pyresis), restenosis, cervicitis, stroke and ischemic injury, neurological trauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria , leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, hernia, ruptured or herniated disc syndrome, osteopetrosis, sinusitis, thrombosis, silicosis, pulmonary sarcoidosis, bone resorption disorders such as osteoporosis, fibromyalgia, AIDS, and other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus and cytomegalovirus, type I and type II diabetes mellitus, obesity, insulin resistance and diabetic retinopathy, 22q11.These include 2-deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, color blindness, Cri-de-Chat syndrome, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefleter's syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sickle cell anemia, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, atherosclerosis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, varicose veins, vaginitis, depression, and sudden infant death syndrome.

[0085] In other embodiments, the method relates to treating subjects having cancer. Generally, the compounds of the present invention may be effective in treating carcinomas (solid tumors including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers such as leukemia, lymphoma, and multiple myeloma (cancers affecting the blood, including lymphocytes, bone marrow, and / or lymph nodes). This includes adult tumors / cancers and pediatric tumors / cancers. Cancers may be angiogenic, or not yet substantially angiogenic, or non-angiogenic tumors.

[0086] Representative examples of cancer include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's and AIDS-related lymphoma), appendiceal cancer, childhood cancers (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, brain cancer (e.g., glioma and glioblastoma, e.g., brainstem glioma, gestational chorioblastoma, cerebellar astrocytoma) Cystoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectoderm tumor, optic tract and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), polycythemia vera, lymphoid neoplasms, mycosis fungoidesFungoids), Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic cholangiocarcinoma, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., stomach cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), germ cell tumors, ovarian germ cell tumors, head and neck cancer, Hodgkin lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumors (pancreatic endocrine part), kidney cancer (e.g., Wilms' tumor, clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenström macroglobulinemia, melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of unknown primary origin, multiple endocrine neoplasms (MEN), myelodysplastic syndrome, essential thrombocythemia, myelodysplastic / myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer (e.g., oral cancer, lip cancer, tongue cancer, oropharyngeal cancer, pharyngeal cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, low-grade ovarian tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus cancer and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (endometrial uterine cancer, uterine sarcoma, endometrial cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other parts of the urinary tract, urethral cancer, gestational trophoblastoma, vaginal cancer and vulvar cancer.

[0087] Sarcomas that may be treatable with the compounds of the present invention include cancers of both soft tissue and bone, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesosarcoma or mesothelioma (inner membrane layer of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), and mesenchymal tumors or mixed mesodermal tumors (mixed connective tissue type).

[0088] In some embodiments, the methods of the present invention involve the treatment of subjects having proliferative disorders or disorders of the blood system, liver, brain, lungs, colon, pancreas, prostate, ovaries, breasts, skin, and endometrium.

[0089] As used herein, “cytoproliferative disorders or disorders of the hematological system” includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammaglobulinemia, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, idiopathic myeloid metaplasia, and essential thrombocythemia. Therefore, representative examples of blood cancers include multiple myeloma, lymphoma (T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., diffuse large B-cell lymphoma (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma)), Burkitt lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / w Examples of leukemias include Rudenström macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B-cell non-Hodgkin lymphoma, and relapsed B-cell non-Hodgkin lymphoma, pediatric lymphoma, and lymphomas of lymphocytic and cutaneous origin (e.g., B-cell non-Hodgkin lymphoma selected from small lymphocytic lymphoma), leukemia, pediatric leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, and mast cell leukemia, as well as myeloid neoplasms and mast cell neoplasms.

[0090] As used herein, “proliferative disorders or disorders of the liver” include all forms of proliferative disorders affecting the liver. Examples of proliferative disorders of the liver include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), precancerous or precancerous conditions of the liver, benign proliferations or lesions of the liver, and malignant proliferations or lesions of the liver, as well as metastatic lesions in other tissues and organs of the body. Examples of proliferative disorders of the brain include hyperplasia, metaplasia, hepatic dysplasia, hepatocellular carcinoma, intrahepatic cholangiocarcinoma (cholangiocarcinoma), angiosarcoma, hemangiosarcoma, hepatoblastoma, and secondary liver cancer (metastatic liver cancer).

[0091] As used herein, “cytoproliferative disorders or disorders of the brain” includes all forms of cytoproliferative disorders affecting the brain. Examples of cytoproliferative disorders of the brain include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and primitive neuroectoderm tumors (medulloblastoma)), precancerous or precancerous conditions of the brain, benign proliferation or lesions of the brain, as well as malignant proliferation or lesions of the brain, and metastatic lesions in tissues and organs of the body other than the brain. Examples of cytoproliferative disorders of the brain include brain hyperplasia, metaplasia, and dysplasia.

[0092] As used herein, “cellular proliferative disorders or disorders of the lung” include all forms of cellular proliferative disorders affecting lung cells. Cellular proliferative disorders of the lung include lung cancer, precancerous and precancerous conditions of the lung, benign proliferation or lesions of the lung, lung hyperplasia, metaplasia, and dysplasia, as well as metastatic lesions in other tissues and organs of the body. Lung cancer includes all forms of lung cancer, such as malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer includes small cell lung cancer ("SLCL"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma. Other lung cancers may include “scar carcinoma,” bronchoalveolar cell carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell type). In some embodiments, the compounds of the present invention can be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC with ROS 1 rearrangement, lung adenocarcinoma, and squamous cell lung cancer).

[0093] As used herein, “cytoproliferative disorders or disorders of the colon” ​​include all forms of cytoproliferative disorders affecting colonic cells, including colon cancer, precancerous or precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colonic neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer may be associated with hereditary non-polypoid colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner syndrome, Peutz-Jegers syndrome, Turcott syndrome, and juvenile polyposis. Cytoproliferative disorders of the colon may also be characterized by colonic hyperplasia, metaplasia, or dysplasia.

[0094] As used herein, “cytoproliferative disorders or disorders of the pancreas” includes all forms of cytoproliferative disorders affecting pancreatic cells. Examples of pancreatic cytoproliferative disorders include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign proliferation or lesions of the pancreas, as well as malignant proliferation or lesions of the pancreas, and metastatic lesions in other tissues and organs of the body. Pancreatic cancer includes all forms of pancreatic cancer, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclastoid giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreaticblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, as well as pancreatic neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0095] As used herein, “proliferative disorders or conditions of the prostate” include all forms of proliferative disorders affecting the prostate. Examples of proliferative disorders of the prostate include prostate cancer, precancerous or precancerous conditions of the prostate, benign proliferative disorders or lesions of the prostate, malignant proliferative disorders or lesions of the prostate, and metastatic lesions in other tissues and organs of the body. Examples of proliferative disorders of the prostate include prostatic hyperplasia, metaplasia, and dysplasia.

[0096] As used herein, “ovarian proliferative disorders or disorders” include all forms of cytoproliferative disorders affecting ovarian cells. Ovarian proliferative disorders may include ovarian precancerous or precancerous conditions, benign ovarian proliferation or lesions, ovarian cancer, and metastatic lesions in other tissues and organs of the body. Examples of ovarian proliferative disorders include ovarian hyperplasia, metaplasia, and dysplasia.

[0097] As used herein, “cytoproliferative disorders or disorders of the breast” include all forms of cytoproliferative disorders affecting breast cells. Examples of cytoproliferative disorders of the breast include breast cancer, precancerous or precancerous conditions of the breast, benign proliferations or lesions of the breast, and metastatic lesions in other tissues and organs of the body. Examples of cytoproliferative disorders of the breast include breast hyperplasia, metaplasia, and dysplasia.

[0098] As used herein, “proliferative disorders or conditions of the skin” include all forms of proliferative disorders affecting skin cells. Examples of proliferative disorders of the skin include precancerous or precancerous conditions of the skin, benign proliferations or lesions of the skin, melanoma, malignant melanoma or other malignant proliferations or lesions of the skin, and metastatic lesions in tissues and organs of the body other than the skin. Examples of proliferative disorders of the skin include cutaneous hyperplasia, metaplasia, and dysplasia.

[0099] As used herein, “endometrial proliferative disorders or disorders” include all forms of cytoproliferative disorders affecting endometrial cells. Examples of endometrial proliferative disorders include endometrial precancerous or precancerous conditions, benign endometrial proliferation or lesions, endometrial cancer, and metastatic lesions in other tissues and organs of the body. Examples of endometrial proliferative disorders include endometrial hyperplasia, metaplasia, and dysplasia.

[0100] In some embodiments, the compounds of the present invention can be used to treat T-cell leukemia or T-cell lymphoma.

[0101] In some embodiments, the compounds of the present invention can be used to treat Hodgkin lymphoma or non-Hodgkin lymphoma.

[0102] In some embodiments, the compounds of the present invention can be used to treat myeloid leukemia.

[0103] In some embodiments, the compounds of the present invention can be used to treat non-small cell lung cancer (NSCLC).

[0104] In some embodiments, the compounds of the present invention can be used to treat melanoma.

[0105] In some embodiments, the compounds of the present invention can be used to treat triple-negative breast cancer (TNBC).

[0106] In some embodiments, the compounds of the present invention can be used to treat nasopharyngeal cancer (NPC).

[0107] In some embodiments, the compounds of the present invention can be used to treat microsatellite-stable colorectal cancer (mssCRC).

[0108] In some embodiments, the compounds of the present invention can be used to treat thymoma.

[0109] In some embodiments, the compounds of the present invention can be used to treat carcinoids.

[0110] In some embodiments, the compounds of the present invention can be used to treat gastrointestinal stromal tumors (GISTs).

[0111] The compounds of the present invention, as well as their pharmaceutically acceptable salts and stereoisomers, can be administered to patients, such as cancer patients, as monotherapy or in combination therapy. The treatment may be a “frontline / first-line therapy,” i.e., initial treatment in patients who have not previously received an anti-cancer treatment regimen, either alone or in combination with other therapies; a “second-line therapy,” either alone or in combination with other therapies, as treatment for patients who have received a prior anti-cancer treatment regimen; or a “third-line therapy,” “fourth-line therapy,” etc., either alone or in combination with other therapies. The treatment may also be administered to patients who have previously received treatment that has failed or was partially successful but resulted in unresponsiveness or intolerance to a particular treatment. The treatment may also be administered as adjuvant therapy, i.e., to prevent cancer recurrence in patients who do not currently have detectable disease or in patients after surgical removal of a tumor. Accordingly, in some embodiments, the compounds can be administered to patients who have previously received prior therapies such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0112] The methods of the present invention may involve administering the compound or pharmaceutical composition of the present invention to a patient in single or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 doses or more). For example, the frequency of administration may range from once a day to about once every 8 weeks. In some embodiments, the frequency of administration ranges from about once a day over 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments, it involves at least one 28-day cycle including daily administration for 3 weeks (21 days) followed by a 7-day rest period. In other embodiments, the compound may be administered twice a day (BID) (total 5 doses) over a 2.5-day cycle or once a day (QD) (total 2 doses) over a 2-day cycle. In other embodiments, the compound may be administered once a day (QD) over a 5-day cycle.

[0113] Combination therapy The compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers can be used in combination with or concurrently with at least one other active agent, such as an anticancer agent or regimen, when treating diseases and disorders. In this context, the terms “combined” and “concurrently” mean that the agents are administered simultaneously, including substantially simultaneous administration by identical or distinct dosage forms and by identical or different modes of administration, or sequential administration, for example, as part of the same treatment regimen or by a sequential treatment regimen. Thus, when administered sequentially, at the start of administration of the second agent, the first of the two agents may still be detectable at an effective concentration at the treatment site. The consecutive time intervals may be determined so that they act together (for example, providing a synergistically higher benefit than when administered separately). For example, the agents may be administered simultaneously or sequentially in any order at different time points, but if not administered simultaneously, they may be administered at sufficiently close intervals to provide the desired therapeutic effect, which may be in a synergistic manner. Thus, these terms are not limited to the administration of active agents precisely simultaneously.

[0114] In some embodiments, a therapeutic regimen may involve administering the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer of the present invention in combination with one or more additional therapeutic agents known to be used in the treatment of a disease or disorder (e.g., cancer). The dose of the additional anticancer agent may be the same as or less than known or recommended doses. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference, 60th ed., 2006. For example, anticancer agents that can be used in combination with the compound of the present invention are known in the art. See, for example, U.S. Patent No. 9,101,622 (Section 5.2) and U.S. Patent No. 9,345,705 (Columns 12-18). Representative examples of additional anticancer drugs and treatment regimens include radiotherapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, antihormone agents, autophagy inhibitors, alkylating agents, insertive antibiotics, growth factor inhibitors, antiandrogens, signaling pathway inhibitors, antimicrotubule agents, platinum-coordinated complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0115] In some embodiments, the compounds of the present invention and additional anticancer agents can be administered at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 to about 3 hours, about 3 to about 4 hours, about 4 to about 5 hours, about 5 to about 6 hours, about 6 to about 7 hours, about 7 to about 8 hours, about 8 to about 9 hours, about 9 to about 10 hours, about 10 to about 11 hours, about 11 to about 12 hours, about 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 ​​to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more types of anticancer drugs can be administered to the same patient during their hospital visit.

[0116] In some embodiments, the compounds of the present invention and additional therapeutic agents (e.g., anticancer drugs) are administered cyclically. As an example in relation to cancer treatment, cycling therapy involves administering one anticancer drug for a set period, followed by a second anticancer drug for a set period, and repeating this series of administrations, i.e., cycles, to reduce the development of resistance to one or both anticancer drugs, to avoid or reduce the side effects of one or both anticancer drugs, and / or to improve the efficacy of the drugs. As an example, cycling therapy involves administering a first anticancer drug for a set period, followed by a second anticancer drug for a set period, and optionally, then a third anticancer drug for a set period, and repeating this series of administrations, i.e., cycles, to reduce the development of resistance to one of the anticancer drugs, to avoid or reduce the side effects of one of the anticancer drugs, and / or to improve the efficacy of the drugs.

[0117] In some embodiments, depending on the specific cancer being treated, the compounds of the present invention may be used in combination with at least one other anticancer agent, e.g., paclitaxel (e.g., ovarian cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer), topotecan (e.g., ovarian cancer and lung cancer), irinotecan (e.g., colon cancer and small cell lung cancer), etoposide (e.g., testicular cancer, lung cancer, lymphoma, and non-lymphocytic leukemia), vincristine (e.g., leukemia), leucovorin (e.g., colon cancer), altoretamine (e.g., ovarian cancer), daunorubicin (e.g., For example, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), trastuzumab (e.g., breast cancer, gastric cancer, and esophageal cancer), rituximab (e.g., non-Hodgkin lymphoma), cetuximab (e.g., colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer), pertuzumab (e.g., metastatic HER2-positive breast cancer), alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), panitumumab (e.g., colorectal cancer), tamoxif Ethanol (e.g., breast cancer), fulvestrant (e.g., breast cancer), letrazole (e.g., breast cancer), exemestane (e.g., breast cancer), azacitidine (e.g., myelodysplastic syndrome), mitomycin C (e.g., gastrointestinal cancer, anal cancer, and breast cancer), dactinomycin (e.g., Wilms' tumor, rhabdomyosarcoma, Ewing's sarcoma, chorionic neoplasm, testicular cancer, and ovarian cancer), erlotinib (e.g., non-small cell lung cancer and pancreatic cancer), sorafenib (e.g., kidney cancer and liver cancer), temsirolimus (e.g., kidney cancer), bortezomib (e.g., , multiple myeloma and mantle cell lymphoma), pegaspar gauze (e.g., acute lymphoblastic leukemia), cabometyx (e.g., hepatocellular carcinoma, medullary thyroid carcinoma, and renal cell carcinoma), pembrolizumab (e.g., cervical cancer, gastric cancer, hepatocellular carcinoma, Hodgkin lymphoma, melanoma, Merkel cell tumor, non-small cell lung cancer, urothelial carcinoma, and squamous cell carcinoma of the head and neck), nivolumab (e.g., colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, small cell lung cancer, and urothelial carcinoma), regorafenib (e.g., colorectal cancer, gastrointestinal stromal tumor,It can be used in combination with cemiplimab (e.g., squamous cell carcinoma (CSCC)), avelumab (e.g., Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma), durvalumab (e.g., bladder cancer and lung cancer), atezolizumab (e.g., urothelial carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), small cell lung cancer, and hepatocellular carcinoma (HCC)), and lipilimumab (e.g., melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bladder cancer, and prostate cancer).

[0118] Medical kit The composition may also be assembled into a kit or pharmaceutical system. A kit or pharmaceutical system according to this aspect of the present invention includes a transport carrier or package, such as a box, carton, or tube, tightly packed inside one or more containers, such as vials, tubes, ampoules, or bottles, containing a pharmaceutical composition comprising the compound of the present invention, or a compound which may be placed in the same container or in a separate container, and a pharmaceutically acceptable carrier. The kit or pharmaceutical system of the present invention may also include printed instructions for using the compound and composition.

[0119] These and other aspects of the present invention will be further understood by considering the following embodiments, which are intended to illustrate specific embodiments of the invention but not to limit the scope as defined by the claims. [Examples]

[0120] These and other aspects of the present invention will be further understood by considering the following embodiments, which are intended to illustrate specific embodiments of the invention but not to limit the scope as defined by the claims.

[0121] Example 1: Synthesis of 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione [ka]

[0122] tert-butyl-4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0123] A mixture of 3-(6-bromo-3-oxo-1H-isoindole-2-yl)piperidine-2,6-dione (3.0 g, 9.3 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (11.5 g, 37.3 mmol), potassium phosphate (2.0 g, 9.3 mmol), and [1,1”-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.7 g, 1.9 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90°C for 4 hours. Next, the reaction mixture was concentrated to obtain a residue, which was dissolved in ethyl acetate (500 mL). Water (500 mL) was added, and the layers were separated. Solid NaCl was added to the aqueous layer with vigorous stirring until the NaCl reached saturation. Undissolved NaCl was removed by filtration, and the aqueous phase was further extracted with tetrahydrofuran (500 mL x 2). The combined organic layers were dried and concentrated to obtain the crude product, which was purified using silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 ~ 100% ethyl acetate) to obtain the marked compound as a yellow solid (1.1 g, 36%). MS[M+H] + = 426.3.

[0124] tert-butyl-4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperidine-1-carboxylate

[0125] A mixture of tert-butyl-4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.4 mmol) and 10% Pd / C (400 mg) was mixed with N,N-dimethylformamide (10 mL). The suspension was stirred under a hydrogen atmosphere at room temperature (rt) for 16 hours. The reaction mixture was then diluted with dichloromethane, filtered, and concentrated to obtain the marked compound as a yellow solid (1.0 g, 91%), which was used without further purification. MS[M+H] + = 428.3.

[0126] 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione

[0127] To tert-butyl 4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperidine-1-carboxylate (1.0 g, 2.3 mmol), 4.0 M HCl / dioxane (6 mL) was added, the reaction vessel was sealed, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum to obtain the marked compound as a yellow solid (1.0 g, 100%), which was used without further purification. MS[M+H] + = 328.3.

[0128] Example 2: Synthesis of 5-oxo-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbaldehyde [ka]

[0129] 7-Vinyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[0130] A mixture of 7-bromo-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (4.5 g, 18.7 mmol), trifluoro(vinyl)-borane potassium salt (5.0 g, 37.3 mmol), N-cyclohexyl-N-methylcyclohexamine (7.3 g, 37.3 mmol), and [1,1”-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.4 g, 1.9 mmol) in 1,4-dioxane (30 mL) was stirred at 90°C for 16 hours. The solution was concentrated and then diluted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL). The layers were separated, and NaCl was added to the aqueous layer until a saturated solution was formed. The aqueous layer was then extracted with tetrahydrofuran (500 mL x 2). The organic layers were combined, dried over MgSO4, and then filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluting at petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain the marked compound as a yellow solid (2.5 g, 71%). MS[M+H] + = 190.2.

[0131] 4-phenyl-7-vinyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one

[0132] A mixture of 7-vinyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (2.4 g, 12.7 mmol), iodobenzene (2.6 g, 12.7 mmol), potassium phosphate (0.7 g, 3.2 mmol), 1,10-phenanthroline (0.9 g, 5.1 mmol), and copper(I) iodide (1.0 g, 5.1 mmol) in toluene (20 mL) was stirred at 110 °C for 16 hours. The reaction mixture was concentrated and then diluted with ethyl acetate (500 mL). The organic phase was washed with water (500 mL). NaCl was added to the aqueous layer until a saturated solution was formed, and the mixture was extracted with tetrahydrofuran (500 mL x 2). The combined organic layers were dried and concentrated. The crude product was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate = 10:1 to 5:1) to obtain the marked compound as a yellow solid (1.9 g, 56%). MS[M+H] + = 266.2.

[0133] 5-Oxo-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbaldehyde

[0134] Potassium osmium(VI) dihydrate (40 mg, 0.1 mmol) was added to a room temperature solution of 4-phenyl-7-vinyl-3,4-dihydrobenzo[f][1,4]oxazepine-5(2H)-one (600 mg, 2.3 mmol), 4-methylmorpholine N-oxide (796 mg, 6.8 mmol), and sodium periodate (963 mg, 4.5 mmol) in acetone / water (15 mL, 3:2). The reaction mixture was stirred at room temperature for 16 hours. Then, ethyl acetate (500 mL) was added, and the organic layer was washed with water (500 mL). NaCl was added to the aqueous layer until a saturated solution was formed. The aqueous layer was extracted with THF (500 mL x 2). The combined organic layers were dried and concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate = 5:1~3:1) to obtain the marked compound as a yellow solid (300 mg, 50%). MS[M+H] + = 268.2.

[0135] Example 3: Synthesis of 3-(1-oxo-5-(1-((5-oxo-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (1) [ka]

[0136] A mixture of 5-oxo-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carbaldehyde (80 mg, 0.3 mmol), 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (98 mg, 0.3 mmol), and sodium triacetoxyborohydride (191 mg, 0.9 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The suspension was concentrated and purified by preparative HPLC to obtain the marked compound as a white solid (29.9 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),7.69-7.62(m,2H),7.55-7.39(m,8H),7.37-7.28(m,1H),7.09(d,J=8.4Hz, 1H),5.11(dd,J=13.3,5.2Hz,1H),4.49-4.39(m,3H),4.30(d,J=17.2Hz,1H),3.92(t,J=5 .2Hz,2H),3.56(s,2H),2.97(dd,J=8.4,5.5Hz,2H),2.94-2.87(m,1H),2.73-2.57(m,2H) ,2.48-2.34(m,1H),2.13(t,J=11.0Hz,2H),2.05-1.95(m,1H),1.84-1.67(m,4H).MS[M+H] + =579.8.

[0137] Example 4: Synthesis of 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde [ka]

[0138] Diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate

[0139] Diethyl 1H-pyrazole-3,5-dicarboxylate (2.0 g, 9.43 mmol) and tert-butyl (2-bromoethyl)carbamate (2.7 g, 12.2 mmol) were stirred in DMF (20 mL) and then K2CO3 (2.6 g, 18.8 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with water (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the marked compound as a white solid (2.6 g, 78%). MS[M+H] + = 356.17.

[0140] Ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

[0141] To a solution of diethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylate (2.6 g, 7.3 mmol) in CH3CN (20 mL), aqueous HCl (3 N, 5 mL) was added, and the reaction mixture was stirred at 80 °C for 1.5 hours. The reaction mixture was then neutralized to pH=7 with aqueous NaHCO3 and diluted with water (50 mL). The aqueous layer was extracted with dichloromethane (50 mL x 3). The organic layers were combined and concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the marked compound as a white solid (1.15 g, 62%). MS[M+H] + =210.08.

[0142] Ethyl 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

[0143] Under nitrogen, a solution of ethyl 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (1.15 g, 5.5 mmol), phenylboronic acid (1.05 g, 8.25 mmol), Cu(OAc)2 (995 mg, 5.5 mmol), and triethylamine (1.1 g, 11.0 mmol) in dichloromethane (DCM) (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with water (50 mL x 3). The organic layer was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain the marked compound as a white solid (700 mg, 44.6%). MS[M+H] + =286.10.

[0144] 2-(hydroxymethyl)-5-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one

[0145] A solution of ethyl 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (700 mg, 2.45 mmol) and CaCl2 (430 mg, 3.8 mmol) in EtOH (10 mL) was stirred at 0°C for 10 minutes. Solid NaBH4 (280 mg, 7.4 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dehydrated with Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the marked compound as a white solid (250 mg, 84%). MS[M+H] + = 244.10.

[0146] 4-Oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde

[0147] A suspension of 2-(hydroxymethyl)-5-phenyl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one (250 mg, 1.0 mmol), NaHCO3 (864 mg, 10 mmol), and des-martin periodinane (DMP, 875 mg, 2.0 mmol) in DCM (25 mL) was stirred at room temperature for 1 hour. Water (20 mL) was then added, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, dehydrated with Na2SO4, concentrated, and the residue was obtained. This residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain the marked compound as a white solid (150 mg, 62%). MS[M+H] + = 242.10.

[0148] Example 5: Synthesis of 3-(1-oxo-5-(1-((4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5a]pyrazine-2-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (8) [ka]

[0149] A solution of 4-oxo-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde (150 mg, 0.62 mmol), 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (203 mg, 0.62 mmol), and NaBH(OAc)3 (254 mg, 1.2 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and dehydrated with Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the marked compound as a white solid (12 mg, 3.5%). 1H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),8.17(s,1H),7.64(s,1H),7.51-7.37(m,5H),7.29(d,J=7.2Hz,1H),6.75(s,1H),5.09(s,1H),4.54-4.1 4(m,7H),3.09-2.85(m,3H),2.65(d,J=15.0Hz,1H),2.44-2.33(m,1H),2.23-1.94(m,3H),1.91-1.59(m,4H).MS[M+H] + = 553.20.

[0150] Example 6: Synthesis of 3-(5-(1-(3-((1-methyl-2-oxo-1,2-dihydropyridine-3-yl)amino)benzyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (12) [ka]

[0151] 3-((3-(hydroxymethyl)phenyl)amino)-1-methylpyridine-2(1H)-one

[0152] A solution of 3-bromo-1-methylpyridine-2(1H)-one (400 mg, 2.2 mmol) in 10 mL of anhydrous DMF was treated under a nitrogen atmosphere with (3-aminophenyl)methanol (320 mg, 2.6 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), xanthophos (64 mg, 0.11 mmol), and K3PO4 (552 mg, 2.6 mmol). The reaction mixture was stirred at 120°C for 16 hours. After completion, the reaction mixture was extracted with ethyl acetate (siRNA) (50 mL), and the layers were separated. The organic phase was concentrated to obtain the crude product, which was purified by preparative high-performance liquid chromatography (HPLC) to obtain the marked compound as a yellow solid (30 mg, 6%). MS[M+H] + = 231.0.

[0153] 3-((1-methyl-2-oxo-1,2-dihydropyridine-3-yl)aminobenzaldehyde

[0154] To a solution of 3-((3-(hydroxymethyl)phenyl)amino)-1-methylpyridine-2(1H)-one (20 mg, 0.09 mmol) in DCM (2 mL), des-martin periodinane (74 mg, 0.17 mmol) and NaHCO3 (34 mg, 0.40 mmol) were added. The mixture was stirred at room temperature for 2 hours. The suspension was then filtered, and the filtrate was concentrated to obtain the crude labeled compound as a yellow solid (10 mg, 49%), which was used without further purification. 1 H NMR(400MHz,CDCl3)δ 9.98(s,1H),7.71(dt,J=2.3,1.0Hz,1H),7.48-7.45(m,2H),7.39-7.36(m,1H),7.27(s,1H), 7.14(dd,J=7.4,1.8Hz,1H),6.83(dd,J=6.8,1.6Hz,1H),6.18(t,J=7.2Hz,1H),3.63(s,3H).

[0155] 3-(5-(1-(3-((1-methyl-2-oxo-1,2-dihydropyridine-3-yl)amino)benzyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione(12)

[0156] 3-((1-methyl-2-oxo-1,2-dihydropyridine-3-yl)amino)benzaldehyde (10 mg, 0.04 mmol) and 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (14 mg, 0.04 mmol) were dissolved in DMF (1 mL) and Na(OAc)3BH (17 mg, 0.08 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was concentrated to obtain the crude residue, which was purified by preparative HPLC to obtain compound 12 as a pale yellow solid (3.3 mg, 15%). 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.67-7.58(m,2H),7.49(s,1H),7.40(d,J=8.0Hz,1H),7.26-7.19(m,2H),7.13-7.06(m,3H),6 .88(d,J=7.6Hz,1H),6.17(t,J=7.2Hz,1H),5.09(dd,J=13.4,5.0Hz,1H),4.42(dd,J=17.2,2.6Hz,1H),4.29 (dd,J=17.4,2.8Hz,1H),3.80(d,J=13.0Hz,1H),3.52(s,3H),3.48(s,2H),3.21-3.11(m,1H),2.99-2.87(m, 3H),2.67-2.56(m,2H),2.44-2.33(m,1H),2.13-2.04(m,2H),2.01-1.96(m,1H),1.87-1.68(m,4H).MS[M+H] + =540.3.

[0157] Example 7: Synthesis of 3-[1-oxo-5-[1-[(2-oxo-1-phenylindoline-6-yl)methyl]-4-piperidyl]isoindoline-2-yl]piperidine-2,6-dione (18) [ka]

[0158] 6-Bromo-1-phenylindolin-2-one

[0159] Iodobenzene (5.53 g, 27.12 mmol) was added to a suspension of 6-bromoindolin-2-one (5 g, 23.58 mmol) in acetonitrile (ACN, 75 mL) under a nitrogen atmosphere. The suspension was heated to 40°C and a constant flow of nitrogen was bubbled over it while stirring for 30 minutes. K2CO3 (7.17 g, 51.88 mmol), CuI (449.08 mg, 2.36 mmol), and N,N'-dimethylethane-1,2-diamine (415.72 mg, 4.72 mmol) were added, and the reaction mixture was heated to 80°C under a nitrogen atmosphere for 5 hours. After the reaction was complete, it was cooled to room temperature, 100 mL of 1 M HCl was added, and the solution was extracted with siRNA (100 mL x 3). The combined organic extract was dehydrated with Na2SO4, and the solvent was removed under vacuum. The residue was purified by silica gel chromatography (eluent: 0-50% ethyl acetate / petroleum ether) to obtain the marked compound as an orange solid (3.3 g, yield 49%). MS[M+H] + =288.0.

[0160] Phenyl-6-vinyl-indolin-2-one

[0161] To a solution of 6-bromo-1-phenylindolin-2-one (2.8 g, 9.72 mmol) in dioxane (32 mL) and H2O (4 mL), potassium vinyl trifluoroborate (2.60 g, 19.44 mmol), Pd(dppf)Cl2 (711.04 mg, 0.972 mmol), and K2CO3 (4.03 g, 29.15 mmol) were added. The mixture was stirred at 110°C for 12 hours. After the reaction was complete, it was cooled to room temperature, poured into H2O (40 mL), and extracted with siRNA (40 mL x 3). The combined organic layer was washed with brine (40 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue. The residue was purified by MPLC (SiO2, petroleum ether: dimethyl=10 / 1 to 1 / 1) to obtain the marked compound as a red solid (1.5 g, yield 66%). 1H NMR(400MHz,CDCl3)δ 7.54-7.42(m,2H),7.40-7.28(m,3H),7.23-7.13(m,1H),7.08-6.97(m,1H),6.79-6. 69(m,1H),6.63-6.48(m,1H),5.63-5.49(m,1H),5.14(d,J=10.9Hz,1H),3.63(s,2H).

[0162] 2-Oxo-1-phenyl-indoline-6-carbaldehyde

[0163] Ozone was bubbling into a solution of 1-phenyl-6-vinyl-indolin-2-one (1.5 g, 6.38 mmol) in DCM (30 mL) for 30 minutes at -78°C. After purging excess O3 with N2, Me2S (7.92 g, 127.51 mmol) was added at -78°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under vacuum to obtain the crude product. The residue was purified by MPLC (SiO2, petroleum ether: siRNA = 10 / 1 to 1 / 1) to obtain the marked compound as a red solid (370 mg, yield 25%). MS[M+H] + = 238.1.

[0164] 3-[1-oxo-5-[1-[(2-oxo-1-phenylindoline-6-yl)methyl]-4-piperidyl]isoindoline-2-yl]piperidine-2,6-dione(18)

[0165] Compound 18 was prepared in the same manner as compound 12 in Example 6. 1H NMR:(400MHz,DMSO-d6)δ 11.07-10.93(m,1H),8.23(s,0.5H),7.64-7.53(m,3H),7.50-7.22(m,6H),7.05-6.99(m, 1H),6.71-6.65(m,1H),5.14-5.04(m,1H),4.47-4.20(m,2H),3.77-3.70(m,2H),3.44(br s,2H),2.89(br d,J=11.9Hz,2H),2.66-2.55(m,2H),2.46-2.34(m,2H),2.07-1.93(m,3H),1.78-1.69(m,2H),1.68-1.56(m,2H).MS[M+H] + =549.1.

[0166] Example 8: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (31) [ka]

[0167] 5-Bromo-2-nitro-N-(pyridine-2-yl)benzamide

[0168] 5-Bromo-2-nitrobenzoic acid (5 g, 20.32 mmol), pyridine-2-amine (1.91 g, 20.32 mmol), and N,N-diisopropylethylamine (7.88 g, 60.97 mmol) were dissolved in 50 mL of DMF, to which HATU (9.3 g, 24.38 mmol) was added. The mixture was stirred at room temperature for 16 hours. H2O (200 mL) was added, and the aqueous phase was extracted with DCM (2 × 200 mL). The organic phases were combined, concentrated, and purified by silica gel column chromatography (methanol (MeOH): DCM = 1 / 100 to 3 / 100) to obtain the labeled compound (3.6 g, 55%).

[0169] 2-amino-5-bromo-N-(pyridine-2-yl)benzamide

[0170] A solution of 5-bromo-2-nitro-N-(pyridine-2-yl)benzamide (2.60 g, 8.07 mmol) and NH4Cl (2.16 g, 40.36 mmol) in ethanol (EtOH) / H2O (30 mL, v:v=7 / 3) was stirred at 50°C for 30 minutes under an N2 atmosphere. Fe (2.25 g, 40.36 mmol) was added, and the reaction mixture was stirred for a further 2 hours. The suspension was filtered to obtain a clear organic phase, which was concentrated and purified by silica gel column chromatography (MeOH:DCM=1 / 100~5 / 100) to obtain the labeled compound (0.8 g, 33.9%).

[0171] 6-Bromo-3-(pyridine-2-yl)quinazoline-4(3H)-one

[0172] A solution of 2-amino-5-bromo-N-(pyridine-2-yl)benzamide (1.1 g, 3.77 mmol) in triethyl orthoformate (22 mL) was stirred at 140°C for 2 hours. The mixture was then concentrated to obtain the crude product, which was purified by silica gel column chromatography (MeOH:DCM = 1 / 100~3 / 100) to obtain the labeled compound (800 mg, 70%). 1 H NMR(400MHz,DMSO-d6)δ 8.69(ddd,J=4.9,1.9,0.8Hz,1H),8.64(s,1H),8.33(d,J=2.3Hz,1H),8.11(dd,J=8.0,1.9Hz,0H),8. 10-8.06(m,1H),7.86(dt,J=8.1,0.9Hz,1H),7.75(d,J=8.7Hz,1H),7.60(ddd,J=7.5,4.9,1.0Hz,1H).

[0173] 3-(pyridine-2-yl)-6-vinylquinazoline-4(3H)-one

[0174] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (97.1 mg, 0.13 mmol) was added to a solution of 6-bromo-3-(pyridine-2-yl)quinazoline-4(3H)-one (300 mg, 1.33 mmol), potassium vinyl trifluoroborate (357.13 mg, 2.67 mmol), and N-cyclohexyl-N-methylcyclohexaneamine (520.83 mg, 2.67 mmol) in 1,4-dioxane (6 mL). The mixture was stirred at 70°C for 16 hours under an N2 atmosphere. The mixture was then concentrated and purified by silica gel column chromatography (MeOH:DCM = 1 / 100~3 / 100) to obtain the labeled compound (180 mg, 73%).

[0175] 4-Oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-carbaldehyde

[0176] A solution of 3-(pyridine-2-yl)-6-vinylquinazoline-4(3H)-one (150 mg, 0.6 mmol) in 6 mL of MeOH was stirred at -78°C for 5 minutes, and then O3 was bubbling for 10 minutes. The mixture was then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain the marked compound (60 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),8.79(d,J=1.8Hz,1H),8.73(s,1H),8.70-8.66(m,2H),8.32(dd,J=8.4,1.9Hz,1H),8. 10(td,J=7.8,1.9Hz,1H),7.92(d,J=8.4Hz,1H),7.87(d,J=8.1Hz,1H),7.60(dd,J=7.0,5.3Hz,1H).

[0177] 3-(1-oxo-5-(1-((4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione(31)

[0178] Compound 31 was prepared in the same manner as compound 12 in Example 6, with a yield of 13%. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),8.67(dd,J=4.9,1.1Hz,1H),8.55(s,1H),8.18(d,J=1.7Hz,1H),8.08(td,J=7.8,1.9Hz,1H),7.88(dd,J=8.3,1.9H z,1H),7.84(d,J=8.1Hz,1H),7.75(d,J=8.3Hz,1H),7.64(d,J=7.8Hz,1H),7.57(ddd,J=7.5,4.9,1.0Hz,1H),7.51(s,1H),7.41( d,J=7.9Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.42(d,J=17.3Hz,1H),4.28(d,J=17.4Hz,1H),3.70(s,2H),2.97(d,J=11.3Hz,3H ),2.94-2.82(m,1H),2.70-2.54(m,1H),2.46-2.29(m,1H),2.16(t,J=10.0Hz,2H),2.05-1.93(m,1H),1.82-1.69(m,3H).MS[M+H] + =563.0.

[0179] Example 9: Synthesis of 3-[1-oxo-5-[1-[(2-phenylpyrazolo[1,5-a]pyridine-6-yl)methyl]-4-piperidyl]isoindorin-2-yl]piperidine-2,6-dione (38) [ka]

[0180] 1-aminopyridinium salt

[0181] A mixture of amino-2,4,6-trimethylbenzenesulfonate (17.06 g, 79.27 mmol) in 200 mL of DCM at 0°C was to be droppedly mixed with a solution of 3-bromopyridine (12 g, 75.95 mmol) in 150 mL of DCM. The mixture was stirred at 20°C for 12 hours. The white solid was collected by filtration and washed with SiO2 (100 mL). The filtration cake was dried under vacuum to obtain the marked compound as a white solid (23.3 g, 78.7%), which was used without further purification.

[0182] Methyl 6-bromo-2-phenyl-pyrazolo[1,5-a]pyridine-3-carboxylate

[0183] To a solution of 1-aminopyridinium salt (23.30 g, 62.43 mmol) in dimethylformamide (DMF) (100 mL), K2CO3 (21.57 g, 156.09 mmol) and methyl 3-phenylpropane-2-inoate (6.25 g, 39.02 mmol) were added at 0°C. The mixture was then stirred at 20°C for 16 hours. Water (300 mL) was added to the reaction product, and the aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phase was dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 4 / 1) to obtain the marked compound as a pale yellow solid (5.2 g, 32%).

[0184] 6-Bromo-2-phenyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0185] To a solution of methyl 6-bromo-2-phenyl-pyrazolo[1,5-a]pyridine-3-carboxylate (5.2 g, 15.70 mmol) in H2O (26 mL) and MeOH (50 mL), KOH (4.41 g, 78.51 mmol) was added in one step. The mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under vacuum. The aqueous phase was acidified to pH=3 with 1N HCl, and the resulting white solid was filtered and washed with water (20 mL). The filtered cake was dried under vacuum to obtain the marked compound as a white solid (4.6 g), which was used without further purification.

[0186] 6-Bromo-2-phenyl-pyrazolo[1,5-a]pyridine

[0187] A suspension of 6-bromo-2-phenyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (4.6 g, 14.50 mmol) in 1,2-dichlorobenzene (30 mL) was degassed, purged three times with N2, and the mixture was stirred under N2 at 170°C for 3 hours. The reaction product was then cooled to room temperature and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain the marked compound as a white solid (2.1 g, 53%). 1 H NMR:(400MHz,CDCl3)δ 8.63(d,J=0.4Hz,1H),7.95(d,J=7.2Hz,2H),7.37-7.49(m,4H),7.15-7.18(m,1H),6.82(s,1H).

[0188] 2-phenyl-6-vinyl-pyrazolo[1,5-a]pyridine

[0189] To a solution of 6-bromo-2-phenyl-pyrazolo[1,5-a]pyridine (200 mg, 0.73 mmol) in dimethoxyethane (1.6 mL) and H2O (0.8 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (169.17 mg, 1.10 mmol), Na2CO3 (256.12 mg, 2.42 mmol), and Pd(PPh3)2Cl2 (51.40 mg, 73 μmol) were added. The mixture was stirred at 70°C for 12 hours under N2. The mixture was then diluted with water (15 mL), and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dehydrated with Na2SO4, filtered, and concentrated under vacuum. The crude material was purified by silica gel column chromatography (hexane:SiO=4:1) to obtain the labeled compound as a brown solid (130 mg, 81%). 1 H NMR:(400MHz,CDCl3)δ 8.42(s,1H),7.97(d,J=7.2Hz,2H),7.44-7.51(m,3H),7.36-7.40(m,1H),7.33-7.34( m,1H),6.79(s,1H),6.64-6.72(m,1H),5.76(d,J=17.6Hz,1H),5.33(d,J=11.2Hz,1H).

[0190] 2-Phenylpyrazolo[1,5-a]pyridine-6-carbaldehyde

[0191] A solution of 2-phenyl-6-vinyl-pyrazolo[1,5-a]pyridine (730 mg, 3.31 mmol) in dioxane (20 mL) and H2O (10 mL) was treated with NaIO4 (1.77 g, 8.29 mmol) and OsO4 (42.13 mg, 166 μmol) at 20°C for 12 hours. The mixture was quenched with saturated Na2SO3 (20 mL), and the aqueous phase was extracted with SiO4 (2 × 10 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the marked compound as a yellow solid (200 mg, 27%).

[0192] 3-[1-oxo-5-[1-[(2-phenylpyrazolo[1,5-a]pyridine-6-yl)methyl]-4-piperidyl]isoindoline-2-yl]piperidine-2,6-dione(38)

[0193] Compound 38 was prepared in the same manner as compound 12 in Example 6 and obtained as a white solid in 18% yield. 1 H NMR(400MHz,DMSO-d6)δ 11.00(s,1H),10.71(s,1H),8.67(s,1H),9.00(s,1H),8.01(d,J=7.2Hz,2H),7.79 (d,J=8.8Hz,1H),7.70(d,J=8.0Hz,1H),7.45-7.52(m,4H),7.37-7.43(m,2H),7.1 6(s,1H),5.08-5.13(m,1H),4.47(s,1H),4.40-4.43(m,2H),4.28-4.33(m,1H),3. 06-3.15(m,3H),2.86-3.01(m,3H),2.35-2.40(m,1H),1.69-2.12(m,6H).MS[M+H] + =534.3.

[0194] Example 10: Synthesis of 3-[1-oxo-5-[1-[[4-oxo-3-(2-pyridyl)phthalazine-6-yl]methyl]-4-piperidyl]isoindorin-2-yl]piperidine-2,6-dione (43) [ka]

[0195] 3,6-Dibromo-3H-Isobenzofuran-1-one

[0196] To a solution of 6-bromo-3H-isobenzofuran-1-one (5.7 g, 26.76 mmol) in CHCl3 (60 mL), NBS (5.24 g, 29.46 mmol) and AIBN (439.37 mg, 2.68 mmol) were added. The mixture was stirred at 80°C for 2 hours. The reaction product was then filtered, and the filtrate was concentrated under vacuum to obtain the marked compound as a white solid (10 g), which was used without further purification.1 H NMR(400MHz,DMSO-d6)δ 7.92-7.90(m,1H),7.56(d,J=7.9Hz,1H),6.58(s,1H).

[0197] 6-Bromo-3-hydroxy-3H-isobenzofuran-1-one

[0198] A suspension of 3,6-dibromo-3H-isobenzofuran-1-one (5.7 g, 19.53 mmol) in H2O (30 mL) was degassed, purged three times with N2, and then the mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The reaction mixture was poured into H2O (20 mL), and the aqueous phase was extracted with siRNA (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the marked compound as a white solid (6.87 g), which was used without further purification. 1 H NMR(400MHz,DMSO-d6)δ 8.32(br s,1H),8.11-7.98(m,3H),7.70(d,J=8.0Hz,1H),6.71(br s,1H).

[0199] 7-Bromo-2-(2-pyridyl)phthalazine-1-one

[0200] 6-bromo-3-hydroxy-3H-isobenzofuran-1-one (1 g, 4.37 mmol) was dissolved in AcOH (30 mL) and 2-pyridylhydrazine (476.49 mg, 4.37 mmol) was added. The reaction mixture was stirred at 100 °C for 12 hours, then concentrated under vacuum to obtain a crude residue, which was suspended in H₂O (50 mL) and siRNA (50 mL). The aqueous phase was extracted with siRNA (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dehydrated with Na₂SO₄, filtered, and concentrated under vacuum to obtain the marked compound as a yellow solid (0.94 g), which was used without further purification. 1H NMR(400MHz,DMSO-d6)δ 8.62-8.58(m,1H),8.57(s,1H),8.38(d,J=2.0Hz,1H),8.19(dd,J=2.0,8.3Hz,1H),8.05-7.95(m,2H),7.67-7.60(m,1H),7.55-7.48(m,1H).

[0201] 2-(2-pyridyl)-7-vinylphthalazine-1-one

[0202] A mixture of 7-bromo-2-(2-pyridyl)phthalazine-1-one (0.84 g, 2.78 mmol), potassium vinyltrifluoroborate (558.63 mg, 4.17 mmol), di-tert-butyl(cyclopentyl)phosphine dichloropalladium iron (181.20 mg, 278 μmol), and K3PO4 (1.18 g, 5.56 mmol) in THF (16 mL) and H2O (4 mL) was degassed and purged three times with N2. The reaction mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with SiO2 (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the crude residue. The crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain the labeled compound as a yellow solid (0.5 g, 72%). 1 H NMR(400MHz,DMSO-d6)δ 8.63(dd,J=1.1,4.8Hz,1H),8.54(s,1H),8.31(s,1H),8.19(dd,J=1.6,8.2Hz,1H),8.07-7.98(m,2H),7.65(d,J=8.0Hz, 1H),7.53(dd,J=4.9,7.3Hz,1H),7.02(dd,J=11.0,17.6Hz,1H),6.15(d,J=17.6Hz,1H),5.53(d,J=11.0Hz,1H).MS[M+H] + =250.2.

[0203] 7-(1,2-dihydroxyethyl)-2-(2-pyridyl)phthalazine-1-one

[0204] 2-(2-pyridyl)-7-vinylphthalazine-1-one (0.3g, 1.20 mmol) in THF (3mL) and H2O (0.3mL) is mixed with K2OsO4. . 2H₂O (44.35 mg, 120 μmol) and NMO (422.98 mg, 3.61 mmol) were added. The mixture was stirred at 20°C for 12 hours. The reaction product was quenched with saturated Na₂SO₃ aqueous solution (20 mL), and the aqueous phase was extracted with SiO₂ (2 x 10 mL). The combined organic phase was dehydrated with Na₂SO₄, filtered, and concentrated to obtain the labeled compound (0.27 g) as a yellow liquid, which was used without further purification.

[0205] 4-Oxo-3-(2-pyridyl)phthalazine-6-carbaldehyde

[0206] 7-(1,2-dihydroxyethyl)-2-(2-pyridyl)phthalazine-1-one (0.27 g, 0.95 mmol) was dissolved in dioxane (4 mL) and H2O (0.4 mL), to which NaIO4 (407.72 mg, 1.91 mmol) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into H2O (10 mL) and extracted with SiO4 (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the crude residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain the marked compound as a yellow solid (0.05 g, 21%). 1 H NMR(400MHz,DMSO-d6)δ 10.25(s,1H),8.83(s,1H),8.68(s,1H),8.64(dd,J=1.1,4.7Hz,1H),8.66-8.60(m,1H),8.41(dd,J=1.4,8.1Hz,1 H),8.21(d,J=8.1Hz,1H),8.06(dt,J=1.9,7.8Hz,1H),7.69(d,J=7.9Hz,1H),7.55(dd,J=5.0,6.8Hz,1H).MS[M+H] + =252.1.

[0207] 3-[1-oxo-5-[1-[[4-oxo-3-(2-pyridyl)phthalazine-6-yl]methyl]-4-piperidyl]isoindoline-2-yl]piperidine-2,6-dione(43)

[0208] Compound 43 was prepared in the same manner as compound 12 in Example 6, with a yield of 27%. 1 H NMR(400MHz,DMSO-d6)δ 11.18(br s,1H),10.98(s,1H),8.66-8.59(m,2H),8.57(s,1H),8.36(dd,J=1.5,8.1Hz,1H),8.15(d,J=8.1Hz,1H),8.06(dt,J=1.9,7.8Hz ,1H),7.68(dd,J=7.9,13.1Hz,2H),7.58-7.52(m,1H),7.45(s,1H),7.39(d,J=7.9Hz,1H),5.10(dd,J=5.0,13.3Hz,1H),4.61(br d,J=4.8Hz,2H),4.49-4.27(m,2H),3.48(br d,J=11.4Hz,2H),3.21-3.06(m,2H),3.00-2.85(m,2H),2.59(br d,J=16.9Hz,1H),2.44-2.34(m,1H),2.15(br d,J=12.9Hz,2H),2.00(br d,J=11.1Hz,3H).MS[M+H] + =563.1.

[0209] Example 11: Synthesis of 3-(4-fluoro-1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride [ka]

[0210] 5-Bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one

[0211] To a solution of 2,2,6,6-tetramethylpiperidine (48.4 g, 342 mmol) in THF (150 mL), n-BuLi (2 M in cyclohexane, 137 mL, 274 mmol) was added dropwise at -75°C, and the mixture was warmed to 0°C and stirred for 20 minutes. The reaction mixture was then cooled to -75°C, and a solution of 4-bromo-3-fluorobenzoic acid (15.0 g, 68.5 mmol) in THF (30 mL) was added dropwise. The reaction mixture was stirred for 40 minutes, and then DMF (10.0 g, 137 mmol) in THF (15 mL) was added dropwise at -75°C, and the resulting mixture was stirred for a further 2 hours. The reaction mixture was quenched with 5 M HCl (10 mL) and diluted with brine solution (50 mL). The resulting mixture was extracted with DCM (2 × 100 mL), and the combined organic extract was dehydrated with anhydrous Na₂SO₄ and filtered. The solvent was removed under reduced pressure, and the crude material was purified by silica gel column chromatography using toluene in toluene (60-80%) as the eluent to obtain the marked compound as an off-white solid (14.0 g, 71%). MS[MH] + = 244.8.

[0212] 3-(5-bromo-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione

[0213] 5-Bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (2.00 g, 8.10 mmol) was dissolved in 1,2-dichloroethane (DCE, 20 mL), to which 3-aminopiperidine-2,6-dione hydrochloride (2.00 g, 12.1 mmol) was added under an N2 atmosphere at 25°C. The reaction mixture was stirred for 30 minutes, then sodium triacetoxyborohydride (5.15 g, 24.3 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine (15 mL), and the aqueous layer was extracted with ELISA (2 × 100 mL). The combined organic extracts were dehydrated with anhydrous Na₂SO₄ and filtered. The solvent was removed under reduced pressure to obtain a crude residue, which was dissolved in ACN (5 mL) / methyl tert-butyl ether (MTBE, 5 mL). The mixture was stirred for 10 minutes to obtain the labeled compound as a pale blue solid. This solid was isolated by filtration, washed with excess MTBE, and dried under vacuum (1.32 g, 48%). 1 H NMR(400MHz,DMSO-d6)δ 11.20-10.76(m,1H),7.88(dd,J=6.1,7.9Hz,1H),7.55(d,J=8.0Hz,1H),5.13(dd,J=5.1,13.4Hz,1H),4.67-4.59(m,1H),4.50 -4.43(m,1H),2.98-2.86(m,1H),2.66-2.56(m,1H),2.44(dd,J=4.4,12.9Hz,1H),2.01(dtd,J=2.3,5.2,12.7Hz,1H).MS[M+H] + =340.9.

[0214] tert-butyl-4-(2-(2,6-dioxopiperidine-3-yl)-4-fluoro-1-oxoisoindorin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0215] To a solution of 3-(5-bromo-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione (1.32 g, 3.87 mmol) stirred at room temperature in dioxane (20 mL) / water (2.2 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.39 g, 7.74 mmol), N,N-diisopropylethylamine (DIPEA, 1.00 g, 7.74 mmol), and Pd(tBu3P)2 (0.198 g, 0.387 mmol) were added for 20 minutes under continuous N2 bubbling. The reaction mixture was stirred at 100 °C for 15 hours. The excess solvent was removed under reduced pressure to obtain a crude residue, which was dissolved in ACN (5 mL) / MTBE (5 mL) and stirred for 10 minutes to obtain the labeled compound as a white solid. This was isolated by filtration, washed with excess MTBE, and dried under vacuum (1.30 g, 72%). 1 H NMR(400MHz,DMSO-d6)δ 11.01(s,1H),7.80-7.35(m,2H),6.11(brs,1H),5.12(dd,J=5.1,13.3Hz,1H),4.62-4.49(m,1H),4.46-4.25(m,1H),4.03(brs,2H), 3.56(t,J=5.5Hz,2H),2.98-2.81(m,1H),2.73-2.56(m,1H),2.49-2.41(m,2H),2.4(m,1H),2.08-1.89(m,1H),1.44(s,9H).MS[M+H] + =444.2.

[0216] tert-butyl-4-(2-(2,6-dioxopiperidine-3-yl)-4-fluoro-1-oxoisoindorin-5-yl)-piperidine-1-carboxylate

[0217] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidine-3-yl)-4-fluoro-1-oxoisoindorin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.500 g, 1.13 mmol) in DMF (10 mL), Pd / C (10-50% wet, 0.120 g, 0.113 mmol) was added at room temperature under an N2 atmosphere, and the mixture was stirred under a hydrogen atmosphere for 60 hours. The reaction mixture was filtered through Celite® and washed with THF (50 mL x 2). The solvent was removed under reduced pressure to obtain the crude residue, which was dissolved in ACN (5 mL) / MTBE (5 mL) and stirred for 10 minutes to obtain the marked compound as a white solid. This was isolated by filtration, washed with excess MTBE, and dried under vacuum (0.380 g, 73%). 1 H NMR(400MHz,DMSO-d6)δ 11.00(s,1H),7.55-7.50(m,2H),5.14-5.08(m,1H),4.55(d,J=17.4Hz ,1H),4.42-4.34(m,1H),4.10(d,J=11.0Hz,2H),3.16-3.06(m,1H),2.9 8-2.78(m,3H),2.66-2.55(m,1H),2.44(dd,J=4.6,13.1Hz,1H),2.05-1.95(m,1H),1.81-1.69(m,2H),1.67-1.54(m,2H),1.43(s,9H).MS[MH] + =444.

[0218] 3-(4-fluoro-1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride

[0219] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidine-3-yl)-4-fluoro-1-oxoisoindorin-5-yl)piperidine-1-carboxylate (0.45 g, 1.0 mmol) in 1,4-dioxane (2 mL), HCl (4 M in 1,4-dioxane, 5.0 mL, 20 mmol) was added at 0°C, the mixture was stirred for 10 minutes, and then heated to room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was dissolved in ACN (5 mL) / MTBE (5 mL) and stirred for 10 minutes to obtain the marked compound as an off-white solid. This was isolated by filtration, washed with excess MTBE, and dried under vacuum (0.32 g, 91%). 1 H NMR(400MHz,DMSO-d6)δ 11.35-10.61(m,1H),8.37(s,1H),7.59(d,J=7.9Hz,1H),7.52-7.45(m,1H),5.16-5.07(m,1H),4.61-4.51(m,1H),4.43-4.3 3(m,1H),3.19(brs,3H),2.83(brs,3H),2.64-2.58(m,1H),2.47-2.37(m,2H),2.05-1.94(m,1H),1.84-1.74(m,3H).MS[M+H] + =346.

[0220] Example 12: Synthesis of 6-methyl-3-(6-(trifluoromethyl)pyridine-2-yl)quinazoline-4(3H)-one [ka]

[0221] To a stirred solution of 6-methylquinazoline-4(3H)-one (0.500 g, 3.12 mmol) in 1,4-dioxane (10 mL), 2-bromo-6-(trifluoromethyl)pyridine (1.13 g, 4.99 mmol), cesium carbonate (3.05 g, 9.36 mmol), and 1,2-dimethylethylenediamine (DMEDA, 0.549 g, 6.24 mmol) were added at 25 °C. After degassing the reaction mixture with N2 for 10 minutes, copper(I) iodide (0.297 g, 1.56 mmol) was added at room temperature, and the reaction mixture was heated at 120 °C for 24 hours. The reaction mixture was cooled to room temperature, and volatile substances were evaporated under reduced pressure. The crude substance was purified by reverse-phase chromatography using 10 mM aqueous ammonium acetate and ACN, followed by lyophilization to obtain the marked compound as an off-white solid (130 mg, 33%). 1 H NMR(400MHz,DMSO-d6)δ 8.53(s,1H),8.38(t,J=7.9Hz,1H),8.23-7.99(m,3H),7.77-7.58(m,2H),2.51(br s,3H).MS[M+H] + =306.

[0222] Example 13: Synthesis of 3-(6-methyl-4-oxoquinazoline-3(4H)-yl)benzonitrile [ka]

[0223] To a solution of 6-methylquinazoline-4(3H)-one (1.00 g, 6.24 mmol) in DCM (20 mL), 3 Å molecular sieves (2.00 g, 6.24 mmol), (3-cyanophenyl)boronic acid (1.84 g, 12.5 mmol), pyridine (1.01 mL, 12.5 mmol), and copper(II) acetate (1.13 g, 6.24 mmol) were added at 25 °C. The reaction mixture was stirred at room temperature for 14 hours under an air-filled balloon. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure to obtain a solid (1.5 g), which was purified by silica gel column chromatography using ethyl acetate-hexane to obtain the marked compound as an off-white solid (0.300 g, 17%). 1 H NMR(400MHz,DMSO-d6)δ 8.44-8.30(m,1H),8.15(t,J=1.7Hz,1H),8.05-7.99(m,2H),7.95(ddd,J=1.1,2.1 ,8.1Hz,1H),7.85-7.71(m,2H),7.70-7.62(m,1H),2.53(d,J=2.0Hz,3H).MS[M+H] + =262.1.

[0224] Example 14: Synthesis of 5-fluoro-6-methyl-3-(pyridine-2-yl)quinazoline-4(3H)-one [ka]

[0225] 6-amino-2-fluoro-3-methylbenzoic acid (0.500 g, 2.96 mmol) was dissolved in triethyl orthoformate (5 mL), to which pyridine-2-amine (0.278 g, 2.96 mmol) was added at room temperature. The resulting reaction mixture was stirred at 140 °C for 24 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography using hexane with toluene (30%) as the eluent to obtain the labeled compound as an off-white solid (0.150 g, 19%). MS[M+H] + = 256.4.

[0226] Example 15: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(6-(trifluoromethyl)pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (64) [ka]

[0227] 6-(bromomethyl)-3-(6-(trifluoromethyl)pyridine-2-yl)quinazoline-4(3H)-one

[0228] To a stirred solution of 6-methyl-3-(6-(trifluoromethyl)pyridine-2-yl)quinazoline-4(3H)-one (0.250 g, 0.819 mmol) in ACN (10 mL), N-bromosuccinimide (NBS, 0.292 g, 1.64 mmol) and azobisisobutyronitrile (AIBN, 0.067 g, 0.41 mmol) were added at 25°C. The reaction mixture was heated under reflux for 24 hours. The reaction mixture was evaporated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography using 15% ethyl acetate in hexane to obtain the marked compound as a pale yellow solid (100 mg, 25%). MS[M+H] + = 384.2.

[0229] 3-(1-oxo-5-(1-((4-oxo-3-(6-(trifluoromethyl)pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione

[0230] To a solution of 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride (90.0 mg, 0.246 mmol) in DMF (2 mL), DIPEA (0.209 mL, 1.23 mmol) was added at 0°C, and the mixture was stirred for 10 minutes. 6-(bromomethyl)-3-(6-(trifluoromethyl)pyridine-2-yl)quinazolin-4(3H)-one (95.0 mg, 0.246 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure to obtain a crude solid, which was purified by preparative HPLC [Method information: Column: X select (150 mm * 19) 5 μm, 0.1% HCOOH H2O:ACN, Flow rate: 15 mL / min]. The pure fraction was freeze-dried to obtain the labeled compound as an off-white solid (5.8 mg, 4%). 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),8.59(brs,1H),8.46-8.34(m,1H),8.19(d,J=8.1Hz,1H),8.15-8.09(m,1H),8.01-7 .74(m,2H),7.66(d,J=7.8Hz,1H),7.56-7.36(m,2H),6.53(s,1H),5.11(dd,J=5.1,13.3Hz,1H),4 .49-4.38(m,1H),4.33-4.24(m,1H),3.92-3.64(m,1H),3.17-2.84(m,3H),2.71(m,1H),2.66-2.5 6(m,3H),2.39(dd,J=4.3,12.9Hz,2H),2.14(m,1H),2.06-1.95(m,1H),1.91-1.74(m,3H).MS[M+H] + =631.1.

[0231] Example 16: Synthesis of 6-bromo-3-(pyridine-3-yl)quinazoline-4(3H)-one [ka]

[0232] A solution of 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol) and pyridine-3-amine (4.36 g, 46.3 mmol) in triethyl orthoformate (100 mL, 600 mmol) was heated at 140°C for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude solid. The crude solid was washed with 2-propanol, and the solid was filtered to obtain the labeled compound as a light brown solid (9.00 g, 52%). 1 H NMR(400MHz,DMSO-d6)δ 8.78(d,J=2.0Hz,1H),8.72(dd,J=1.6,3.6Hz,1H),8.48(s,1H),8.30(d,J=2.4Hz ,1H),8.08-8.04(m,2H),7.74(d,J=8.8Hz,1H),8.66-8.63(m,1H).MS[M+H,M+2H] + =302.0,304.0.

[0233] Example 17: Synthesis of 6-bromo-2-methyl-3-(pyridine-2-yl)quinazoline-4(3H)-one [ka]

[0234] A mixture of 6-bromo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (3.00 g, 12.4 mmol), 2-aminopyridine (1.28 g, 13.6 mmol), and triethyl orthoacetate (3.02 g, 18.6 mmol) was stirred at 140°C for 24 hours under N2. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure to obtain the crude residue. The crude residue was purified by silica gel column chromatography using 50-90% phenylethylamine in hexane as the eluent to obtain the marked compound as a pale yellow solid (1.80 g, 46%). 1 H NMR(400MHz,DMSO-d6)δ 8.76-8.64(m,1H),8.20(d,J=2.3Hz,1H),8.12(dt,J=1.9,7.7Hz,1H),8.03(dd,J=2.4,8.6Hz,1H),7.71-7.60(m,3H),2.11(s,3H).MS[M+H,M+2H] +=316.2,318.2.

[0235] Example 18: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (67) [ka]

[0236] 3-(pyridine-3-yl)-6-vinylquinazoline-4(3H)-one

[0237] To a solution of 6-bromo-3-(pyridine-3-yl)quinazolin-4(3H)-one (700 mg, 2.32 mmol) in 1,4-dioxane (8 mL), potassium vinyltrifluoroborate (310 mg, 2.32 mmol) was added, followed by the addition of solutions of cesium carbonate (2 M in water, 1.16 mL, 2.32 mmol) and PdCl2(dppf)2-CH2Cl2 adduct (1.89 g, 2.32 mmol) at room temperature under continuous N2 bubbling. The reaction mixture was stirred at 85 °C for 18 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography using ethyl acetate and hexane to obtain the marked compound as a pale yellow solid (475 mg, 71%). 1 H NMR(400MHz,DMSO-d6)δ 8.79(d,J=2.0Hz,1H),8.71(dd,J=1.2,4.8Hz,1H),8.41(s,1H),8.16(d,J=2.0Hz,1H),8.11-8.05(m,2H),7.75(d,J= 8.4Hz,1H),8.66-8.63(m,1H),6.96(dd,J=11.0,17.6Hz,1H),6.02(d,J=17.6Hz,1H),5.42(d,J=11.0Hz,1H).MS[M+H] + =250.3.

[0238] 4-Oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-carbaldehyde

[0239] To a solution of 3-(pyridine-3-yl)-6-vinylquinazoline-4(3H)-one (475 mg, 1.91 mmol) in 1,4-dioxane (7 mL) and water (0.2 mL) at 0°C, sodium periodate (815 mg, 3.81 mmol) and 4-methylmorpholine (0.105 mL, 0.953 mmol) were added, followed by the dropwise addition of osmium(VIII) oxide (4% by weight in water, 1.50 mL, 0.191 mmol) at 0°C. The reaction mixture was heated to 25°C and stirred for 3 hours. Large amounts of solid formation were observed during the reaction. The reaction mixture was filtered, and the solid residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude residue, which was purified by silica gel column chromatography using ethyl acetate in hexane (45-95%) as the eluent to obtain the marked compound as a pale yellow solid (225 mg, 45%). 1 H NMR(400MHz,DMSO-d6)δ 10.19(s,1H),8.82(d,J=2.0Hz,1H),8.78(d,J=2.0Hz,1H),8.73(dd,J=1.6,4.8Hz,1H),8.59(s, 1H),8.32(dd,J=2.0,4.4Hz,1H),8.11-8.07(m,1H),7.92(d,J=8.4Hz,1H),6.68-6.65(m,1H).MS [M+H] + =252.1.

[0240] 3-(1-oxo-5-(1-((4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione

[0241] A solution of 4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-carbaldehyde (121 mg, 0.481 mmol) and 3-(1-oxo-5-(piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione, HCl (175 mg, 0.481 mmol) in DMF (3 mL) was stirred at room temperature for 15 minutes. Sodium triacetoxyhydroborate (255 mg, 1.20 mmol) was added to this reaction mixture under N2 at room temperature, and the reaction mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude solid, which was dissolved in ACN:water (1:1) and purified by reverse-phase column chromatography using a C-18 column and eluted with 10-50% acetonitrile in water containing 0.1% formic acid. The fraction was lyophilized to obtain the marked compound as an off-white solid (40 mg, 14%). A portion of the solid (6.3 mg, 11 μmol) was dissolved in acetonitrile (0.50 mL) and water (0.50 mL). Formic acid (5.0 μL, 0.13 mmol) was added to the suspension at room temperature. The resulting solution was stirred at room temperature for 10 minutes and then lyophilized to obtain 3-(1-oxo-5-(1-((4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione formate as an off-white solid (6.0 mg, 9.9 μmol). 1H NMR(500MHz,DMSO-d6)δ 10.97(s,1H)8.78(br s,1H)8.70(br d,J=4.4Hz,1H)8.39(s,1H)8.16(br s,1H)8.05(br d,J=7.7Hz,1H)7.87(br d,J=8.2Hz,1H)7.75(br d,J=8.2Hz,1H)7.63(br d,J=7.1Hz,2H)7.51(br s,1H)7.41(br d,J=7.7Hz,1H)5.09(br s,1H)4.24-4.51(m,2H)3.70(br s,1H)3.32(br s,3H)2.84-3.04(m,3H)2.56-2.72(m,2H)2.33-2.45(m,1H)2.15(br t,J=10.4Hz,2H)1.93-2.06(m,1H)1.67-1.85(m,3H).MS[M+H] + =563.2.

[0242] Example 19: Synthesis of 3-(1-oxo-5-(1-((2-phenylimidazo[1,2-a]pyridine-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (54) [ka]

[0243] 6-iodo-2-phenylimidazo[1,2-a]pyridine

[0244] A mixture of 2-bromo-1-phenylethane-1-one (5.00 g, 25.1 mmol) and 5-iodopyridine-2-amine (5.53 g, 25.1 mmol) in ethanol (100 mL) was refluxed with stirring for 2 hours. Sodium bicarbonate (4.64 g, 55.3 mmol) was added to the reaction mixture at room temperature, and the mixture was heated under reflux for 5 hours. The reaction mixture was diluted with toluene (300 mL), and the mixture was washed with water (2 × 150 mL). The organic layer was dehydrated with sodium sulfate and concentrated under reduced pressure to obtain the crude compound. The crude compound was polished with hexane, filtered, and dried under vacuum to obtain the marked compound as a light brown solid (5.70 g, 67%). 1H NMR(400MHz,CDCl3)δ 8.42(dd,J=0.9,1.7Hz,1H),7.96(dd,J=1.3,8.3Hz,2H),7.84(d,J=0.6Hz,1H),7.52-7.42(m,3H),7.41-7.33(m,2H).MS[M+H] + =321.

[0245] 2-phenyl-6-vinylimidazo[1,2-a]pyridine

[0246] To a stirred solution of 6-iodo-2-phenylimidazo[1,2-a]pyridine (5.70 g, 17.8 mmol) in 1,4-dioxane (57 mL), water (26.7 mL) containing potassium vinyltrifluoroborate (2.39 g, 17.8 mmol) and Cs2CO3 (17.4 g, 53.4 mmol) was added, followed by the addition of PdCl2(dppf)-CH2Cl2 adduct (1.45 g, 1.78 mmol) at room temperature under continuous N2 bubbling. The reaction mixture was stirred at 85 °C for 14 hours. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate. The combined organic layer was washed with water, dehydrated with anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure to obtain the marked compound as a light brown solid (3.50 g, 79%). 1 H NMR(400MHz,CDCl3)δ 8.09(s,1H),8.02-7.95(m,1H),7.86(s,1H),7.68(s,1H),7.53-7.41(m,5H),6.68 (dd,J=11.0,17.4Hz,1H),5.79(d,J=17.4Hz,1H),5.38(d,J=11.0Hz,1H).MS[M+H] + =221.

[0247] 2-Phenylimidazo[1,2-a]pyridine-6-carbaldehyde

[0248] A solution of 2-phenyl-6-vinylimidazo[1,2-a]pyridine (1.00 g, 4.54 mmol) in 1,4-dioxane (12.5 mL) / water (1.3 mL) was cooled to 0°C. Sodium periodate (1.94 g, 9.08 mmol) and N-methylmorpholine (0.230 g, 2.27 mmol) were added, followed by the dropwise addition of osmium tetroxide (4% by weight in water, 2.89 g, 0.454 mmol) at the same temperature. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with ice-cold brine (100 mL) and extracted with SiO2 (3 × 200 mL). The combined organic extract was dehydrated with anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using 40-60% ethyl acetate in hexane as the eluent to obtain the labeled compound as a yellow solid (250 mg, 25%). 1 H NMR(400MHz,CDCl3)δ 9.98(s,1H),8.70(s,1H),8.04-7.94(m,3H),7.77-7.64(m,2H),7.54-7.46(m,2H),7.45-7.35(m,1H).MS[M+H] + =223.

[0249] 3-(1-oxo-5-(1-((2-phenylimidazo[1,2-a]pyridine-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione

[0250] 2-phenylimidazo[1,2-a]pyridine-6-carbaldehyde (100 mg, 0.450 mmol) was stirred in DMF (2 mL), to which 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride (180 mg, 0.495 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then sodium triacetoxyhydroborate (238 mg, 1.13 mmol) was added at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was diluted with cold water (2 × 30 mL) and extracted with 10% MeOH / DCM (2 × 100 mL). The combined organic layers were washed with brine, dehydrated with sodium sulfate, and concentrated to obtain a crude residue, which was purified by preparative HPLC [(column: X select (150 mm*19) 5 μM, mobile phase A: 0.1% HCOOH in H2O, mobile phase B: acetonitrile, flow rate: 15 mL / min)]. The ACN / water was removed by freeze-drying to obtain the marked compound as a white solid (51 mg, 21%). 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),8.46(s,1H),8.37(s,1H),8.00-7.92(m,2H),7.65(d,J=7.9Hz,1H),7.59-7.48 (m,2H),7.47-7.39(m,3H),7.35-7.29(m,1H),7.26(dd,J=1.6,9.3Hz,1H),5.10(dd,J=5.1,1 3.3Hz,1H),4.47-4.38(m,1H),4.33-4.25(m,1H),3.54(s,2H),3.06-2.84(m,3H),2.66-2.55 (m,2H),2.48-2.36(m,1H),2.20-2.08(m,2H),2.04-1.95(m,1H),1.86-1.68(m,4H).MS[M+H] + =534.2.

[0251] Example 20: Synthesis of 3-(1-oxo-5-(1-((2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (55) [ka]

[0252] N-(5-bromopyridine-2-yl)benzimamide

[0253] Sodium hydride (0.555 g, 13.9 mmol) was added at 0°C to a stirred solution of 5-bromopyridine-2-amine (2.00 g, 11.6 mmol) in DMF (6 mL). The resulting reaction mixture was stirred at 0°C for 30 minutes, and then benzonitrile (1.43 g, 13.9 mmol) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. A 5% aqueous sodium bicarbonate solution (20.0 mL) was added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic layer was dehydrated with Na₂SO₄ and evaporated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using ethyl acetate in hexane (8-10%) as the eluent to obtain the marked compound as a white solid (1.00 g, 23%). 1 H NMR(400MHz,DMSO-d6)δ 8.44(dd,J=0.4,2.8Hz,1H),8.04(dd,J=1.6,8.4Hz,2H),7.88(dd,J=2.4,8.8Hz,1H),7.53-7.47(m,3H),7.06(d,J=8.8Hz,1H).MS[M+H,M+2H] + =276.0,278.0.

[0254] 6-Bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine

[0255] A mixture of potassium iodide (0.812 g, 4.89 mmol) and iodine (0.993 g, 3.91 mmol) in DMSO (15 mL) was stirred at room temperature for 10 minutes. N-(5-bromopyridine-2-yl)benzimidoamide (0.900 g, 3.26 mmol) and K2CO3 (1.35 g, 9.78 mmol) were added to the mixture at room temperature. The mixture was heated at 100 °C for 2 hours under a nitrogen atmosphere. 5 mL of 5% aqueous Na2S2O3 solution and 50 mL of brine were added to the reaction mixture. The mixture was extracted with ethyl acetate (2 × 40 mL). The combined organic layers were dehydrated with anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using ethyl acetate in hexane (4-6%) as the eluent to obtain the marked compound as a white solid (0.580 g, 61%). 1 H NMR(400MHz,DMSO-d6)δ 8.77(dd,J=0.8,1.6Hz,1H),8.29-8.27(m,2H),7.68(d,J=9.2Hz,1H),7.61(dd,J=2.0,9.2Hz,1H),7.54-7.50(m,3H).MS[M+H,M+2H] + =273.8, 275.8.

[0256] 2-phenyl-6-vinyl-[1,2,4]triazolo[1,5-a]pyridine

[0257] To a stirred solution of 6-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (0.580 g, 2.12 mmol) in 1,4-dioxane (8 mL), potassium vinyltrifluoroborate (0.850 g, 6.35 mmol), cesium carbonate (2 M, 1.06 mL, 2.12 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.173 g, 0.212 mmol) were added at room temperature under continuous N2 bubbling. The resulting mixture was stirred at 85 °C for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using ethyl acetate in hexane (9-10%) as the eluent to obtain the marked compound as a white solid (0.340 g, 72%). 1H NMR(400MHz,DMSO-d6)δ 8.56(s,1H),8.31-8.28(m,2H),7.74-7.71(m,2H),7.55-7.48(m,3H),6.75(dd ,J=11.2,17.6Hz,1H),5.85(d,J=17.6Hz,1H),5.46(d,J=11.2Hz,1H).MS[M+H] + =222.3.

[0258] 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde

[0259] To a stirred solution of 2-phenyl-6-vinyl-[1,2,4]triazolo[1,5-a]pyridine (0.340 g, 1.54 mmol) in 1,4-dioxane (6 mL):water (0.2 mL), sodium periodate (0.657 g, 3.07 mmol) and N-methylmorpholine (0.084 mL, 0.768 mmol) were added, followed by the dropwise addition of osmium tetroxide (4 wt% water, 1.21 mL, 0.154 mmol) at 0°C. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with ice-cold brine (20 mL) and extracted with pharmaceutically acceptable phosphate (3 × 30 mL). The combined organic extract was dehydrated with anhydrous sodium 2SO4 and filtered. The solvent was removed under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using ethyl acetate in hexane (25-28%) as the eluent to obtain the labeled compound as a white solid (0.120 g, 32%). 1 H NMR(400MHz,DMSO-d6)δ 10.07(s,1H),9.77(dd,J=0.8,1.6Hz,1H),8.27-8.25(m,2H),8.04-7.96(m,2H),7.61-7.56(m,3H).MS[M+H] + =224.2.

[0260] 3-(1-oxo-5-(1-((2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione

[0261] To a stirred solution of 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride (0.160 g, 0.440 mmol) in DMF (4 mL), 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboaldehyde (0.118 g, 0.528 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0°C, and sodium triacetoxyborohydride (0.242 g, 1.143 mmol) was added gradually. The resulting reaction mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude residue, which was purified using reverse-phase column chromatography eluting with 0.1% HCOOH in water:acetonitrile. The acetonitrile / water was removed by freeze-drying to obtain the labeled compound as a white solid (0.074 g, 30%). 1 H NMR(400MHz,DMSO-d6)δ 10.98(br s,1H),8.92(s,1H),8.20(dd,J=1.6,4.0Hz,2H),7.84(d,J=9.2Hz,1H),7.71-7.63(m, 2H),7.57-7.51(m,4H),7.43-7.41(m,1H),5.10(dd,J=5.2,13.2Hz,2H),4.43(d,J=17 .2Hz,2H),4.29(d,J=17.2Hz,2H),3.65(s,2H),3.02-2.87(m,3H),2.68-2.62(m,1H), 2.428-2.37(m,1H),2.20-2.15(m,2H),2.00-1.98(m,1H),1.79-1.74(m,2H).MS[M+H] + = 535.2.

[0262] Example 21: Synthesis of 3-(5-(1-((6-bromoimidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0263] 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride (0.628 g, 1.73 mmol) was stirred in DMF (5 mL), to which 6-bromoindridin-2-carbaldehyde (0.300 g, 1.15 mmol) and DIPEA (0.603 mL, 3.45 mmol) were added at 25°C. The mixture was stirred for 10 minutes. Sodium triacetoxyborohydride (1.22 g, 5.76 mmol) was added gradually at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 18 hours. The reaction mixture was then concentrated under reduced pressure to obtain a crude residue, which was purified by normal-phase column chromatography using a gradient of 12% IPA in DCM as the eluent to obtain the marked compound as a pale yellow solid (0.240 g). A portion of the isolated compound (70 mg, 0.124 mmol) was further purified by preparative HPLC [Method information: Column: X select (150 mm × 19) 5 μm, 0.1% HCl in H2O and ACN, flow rate: 15 mL / min]. The collected fraction was lyophilized to obtain the labeled compound as an off-white solid (17 mg, 11%). 1 1H NMR (400MHz, DMSO-d6)δ 11.0(s,1H),10.65(brs,1H),9.10(s,1H),8.20(s,1H),7.80-7.60(m,2H),7.5 5-7.50(m,1H),7.5-7.4(m,1H),7.40-7.30(m,1H),5.15-5.05(m,1H),4.55-4. 35(m,3H),4.32(d,J=17.6Hz,1H),3.60-3.50(m,2H),3.25-3.10(m,2H),3.00- 2.85(m,2H),2.65-2.50(m,1H),2.34-2.20(m,1H),2.15-1.90(m,5H).MS[M+2H] + =538.1.

[0264] Example 22: Synthesis of 3-(1-oxo-5-(1-((6-phenylimidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (96) [ka]

[0265] To a stirred solution of 3-(5-(1-((6-bromoimidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (100 mg, 0.186 mmol) in 1,4-dioxane (3 mL) / water (0.15 mL), phenylboronic acid (34.1 mg, 0.280 mmol) and tribasic K3PO4 (4 M, 0.140 mL, 0.559 mmol) in H2O were added, followed by the addition of PdCl2(dppf)-CH2Cl2 adduct (15 mg, 0.019 mmol) for 10 minutes under continuous bubbling of N2. The reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by normal-phase column chromatography using a gradient of 16% IPA in DCM as the eluent to obtain the marked compound as a light brown solid (80 mg). This substance was further purified by preparative HPLC [Method information: Column: X select (150 mm × 19) 5 μm, 0.1% HCl in H2O and ACN, flow rate: 15 mL / min]. The collected fraction was lyophilized to obtain 3-(1-oxo-5-(1-((6-phenylimidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride as an off-white solid (6.5 mg, 6.4%). 1 H NMR(400MHz,DMSO-d6)δ 10.99(s,1H),10.55(brs,1H),9.12(s,1H),8.26(s,1H),7.90-7.65(m,5H),7.6 0-7.50(m,2H),7.50-7.32(m,3H),5.20-5.05(m,1H),4.60-4.51(m,2H),4.45(d, J=17.2Hz,1H),4.32(d,J=17.6Hz,1H),3.64-3.61(m,2H),3.31-3.11(m,2H),3.0 5-2.85(m,2H),2.65-2.55(m,1H),2.44-2.35(m,1H),2.10-1.90(m,5H).MS[M+H] + =534.2.

[0266] Example 23: Synthesis of 3-(1-oxo-5-(1-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (97) [ka]

[0267] To a stirred solution of 3-(5-(1-((6-bromoimidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (0.100 g, 0.186 mmol) in 1,4-dioxane (3 mL) / water (0.15 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.057 g, 0.28 mmol) and DIPEA (0.072 g, 0.56 mmol), followed by bis(tri-t-butylphosphine)palladium (0) (9.50 mg, 0.019 mmol), were added for 10 minutes under continuous bubbling of N2. The reaction mixture was irradiated with microwaves at 140°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by reverse-phase column chromatography using 4% ACN in water as the eluent to obtain the labeled compound (30 mg). The isolated compound was further purified by preparative HPLC [Method information: Column: X select (150 mm × 19) 5 μm, 0.1% HCl in H2O and ACN, flow rate: 15 mL / min]. The collected fraction was lyophilized to obtain 3-(1-oxo-5-(1-((6-(pyridine-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione hydrochloride as a pale yellow solid (6.1 mg, 6%). 1H NMR(400MHz,DMSO-d6)δ 11.28(brs,1H),11.0(s,1H),9.42(s,1H),9.21(s,1H),8.84(s,1H),8.69-8.58(m,1H),8.12-8. 01(m,1H),7.95-7.87(m,2H),7.79-7.67(m,1H),7.48(s,1H),7.41-7.33(m,1H),5.19-5.06(m,1 H),4.65-4.50(m,2H),4.46(d,J=17.6Hz,1H),4.32(d,J=17.6Hz,1H),3.68-3.55(m,2H),3.30-3 .11(m,2H),3.05-2.85(m,2H),2.65-2.55(m,1H),2.45-2.35(m,1H),2.23-1.90(m,5H).MS[M+H] + = 535.3.

[0268] Example 24: Synthesis of 3-(1-oxo-5-(1-((2-(pyridine-3-yl)-2H-indazole-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (95) [ka]

[0269] Methyl 2-(pyridine-3-yl)-2H-indazole-6-carboxylate

[0270] To a vial containing 4-(methoxycarbonyl)-2-nitrobenzaldehyde (500 mg, 2.39 mmol), isopropanol (6.0 mL), followed by 3-aminopyridine (247 mg, 2.63 mmol). Nitrogen was passed through the vial, and then the mixture was heated at 80°C. After 4 hours, the mixture was cooled to room temperature, and then tri-n-butylphosphine (1.77 mL, 7.17 mmol) was added. The resulting mixture was heated overnight at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (4 mL), and washed with saturated ammonium chloride aqueous solution and brine. The organic layer was dehydrated with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography using a C18 reversed-phase column, eluting with 20-100% acetonitrile in water containing 0.1% formic acid. The fractions containing the product were combined and freeze-dried to obtain methyl 2-(pyridine-3-yl)-2H-indazole-6-carboxylate formate as a yellowish-brown solid (255 mg, 42%). 1 H NMR(500MHz,CDCl3)δ 9.14-9.30(m,1H)8.70(dd,J=1.0,4.8Hz,1 H)8.58(s,1H)8.52(s,1H)8.31-8.43(m,1H)8.11(s,1H)7.77(s,2H)7.57(dd,J=4.8,8.4Hz,1H)3.98(s,3H).MS[M+H] + =254.1.

[0271] (2-(pyridine-3-yl)-2H-indazole-6-yl)methanol

[0272] A solution of methyl 2-(pyridine-3-yl)-2H-indazole-6-carboxylate (255 mg, 1.01 mmol) in THF (10 mL) was cooled to 0°C. LiAlH4 (1 M in THF, 3.00 mL, 3.00 mmol) was added to this solution, and the mixture was slowly warmed to room temperature. The mixture was quenched with MeOH (dropwise addition), and the solution was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate x 2. The combined organic layers were washed with water and brine, dehydrated with sodium sulfate, filtered, and concentrated to obtain the crude residue, which was purified by silica gel column chromatography eluted with 40-100% ethyl acetate in hexane, followed by up to 10% methanol in ethyl acetate, to obtain the marked compound as a yellow solid (78 mg, 34%). 1 H NMR(500MHz,methanol-d4)δ 9.18-9.29(m,1H)8.86(s,1H)8.61(d,J=4.9Hz,1H)8.45(dd,J=1.4,8.5Hz,1H)7.75(d,J=8 .8Hz,1H)7.68(s,1H)7.65(dd,J=4.9,8.2Hz,1H)7.14(d,J=8.8Hz,1H)4.72(s,2H).MS[M+H] + =226.1.

[0273] 2-(pyridine-3-yl)-2H-indazole-6-carbaldehyde

[0274] (2-(pyridine-3-yl)-2H-indazole-6-yl)methanol (75 mg, 0.33 mmol) was dissolved in DCM (1.7 mL) and DMP (0.17 g, 0.40 mmol) was added at room temperature. The mixture became a homogeneous orange solution upon addition of DMP. After stirring for 30 minutes, the solution was passed through a syringe filter and purified by silica gel column chromatography eluted with 30-100% ethyl acetate in hexane. The fractions containing the product were combined and concentrated to obtain the labeled compound (43 mg, 58%). 1H NMR(500MHz,CDCl3)δ 10.07-10.17(m,1H)9.22(d,J=2.2Hz,1H)8.72(d,J=3.8Hz,1H)8.54(s,1H)8.27-8.36(m, 2H)7.83(d,J=8.8Hz,1H)7.68(dd,J=1.1,8.8Hz,1H)7.54(dd,J=4.7,8.2Hz,1H).MS[M+H] + =224.1.

[0275] 3-(1-oxo-5-(1-((2-(pyridine-3-yl)-2H-indazole-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione

[0276] To a solution of 3-(1-oxo-5-(piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (40 mg, 0.12 mmol) and 2-(pyridine-3-yl)-2H-indazole-6-carbaldehyde (40 mg, 0.18 mmol) in dimethylacetamide (DMA, 4 mL), sodium triacetoxyborohydride (78 mg, 0.37 mmol), followed by DIPEA (64 μL, 0.37 mmol), was added at room temperature. After stirring for 18 hours, the mixture was diluted with water (20 mL) and then extracted with ethyl acetate (3 × 10 mL). The combined organic matter was washed with brine (2 × 30 mL), dehydrated with sodium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography using a C18 column, eluting with 10-100% acetonitrile in water containing 0.1% formic acid, to obtain the marked compound as a white solid. MS[M+H] + = 535.3.

[0277] Example 25: Synthesis of 3-(5-(1-((3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (28) [ka]

[0278] Compound 28 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 580.2.

[0279] Example 26: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (60) [ka]

[0280] Compound 60 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 630.1.

[0281] Example 27: Synthesis of 3-(6-((4-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)piperidine-1-yl)methyl)-4-oxoquinazoline-3(4H)-yl)benzonitrile (61) [ka]

[0282] Compound 61 was prepared according to the same procedure as described in Examples 13 and 15. MS[M+H] + = 587.2.

[0283] Example 28: Synthesis of 3-(5-(1-((3-(6-methylpyridine-2-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (62) [ka]

[0284] Compound 62 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 577.1.

[0285] Example 29: Synthesis of 3-(5-(1-((3-(6-isopropylpyridine-2-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (63) [ka]

[0286] Compound 63 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 605.1.

[0287] Example 30: Synthesis of 3-(5-(1-((3-(6-methoxypyridine-2-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (65) [ka]

[0288] Compound 65 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 593.1.

[0289] Example 31: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(thiazole-5-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (66) [ka]

[0290] Compound 66 is prepared according to the same procedure as described in Examples 16 and 18.

[0291] Example 32: Synthesis of 3-(5-(1-((3-(2-methylpyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (68) [ka]

[0292] Compound 68 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 577.4.

[0293] Example 33: Synthesis of 3-(5-(1-((3-(6-methylpyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (69) [ka]

[0294] Compound 69 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 577.3.

[0295] Example 34: Synthesis of 3-(5-(1-((3-(2,6-dimethylpyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (70) [ka]

[0296] Compound 70 is prepared according to the same procedure as described in Examples 16 and 18.

[0297] Example 35: Synthesis of 3-(5-(1-((3-(6-isopropylpyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (71) [ka]

[0298] Compound 71 is prepared according to the same procedure as described in Examples 16 and 18.

[0299] Example 36: Synthesis of 3-(5-(1-((3-(2-isopropylpyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (72) [ka]

[0300] Compound 72 is prepared according to the same procedure as described in Examples 16 and 18.

[0301] Example 37: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(6-(trifluoromethyl)pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (73) [ka]

[0302] Compound 73 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 631.1.

[0303] Example 38: Synthesis of 3-(5-(1-((3-(6-methoxypyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (74) [ka]

[0304] Compound 74 is prepared according to the same procedure as described in Examples 16 and 18.

[0305] Example 39: Synthesis of 3-(5-(1-((3-(5-fluoropyridine-3-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (75) [ka]

[0306] Compound 75 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 581.3.

[0307] Example 40: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridazin-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (76) [ka]

[0308] Compound 76 is prepared according to the same procedure as described in Examples 16 and 18.

[0309] Example 41: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyrazine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (77) [ka]

[0310] Compound 77 is prepared according to the same procedure as described in Examples 16 and 18.

[0311] Example 42: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(pyridine-4-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (78) [ka]

[0312] Compound 78 is prepared according to the same procedure as described in Examples 16 and 18.

[0313] Example 43: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(2-oxo-1,2-dihydropyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (79) [ka]

[0314] Compound 79 is prepared according to the same procedure as described in Examples 16 and 18.

[0315] Example 44: Synthesis of 3-(1-oxo-5-(1-((4-oxo-3-(6-oxo-1,6-dihydropyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (80) [ka]

[0316] Compound 80 is prepared according to the same procedure as described in Examples 16 and 18.

[0317] Example 45: Synthesis of 3-(5-(1-((3-(1-methyl-1H-imidazole-5-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (81) [ka]

[0318] Compound 81 is prepared according to the same procedure as described in Example 8.

[0319] Example 46: Synthesis of 3-(5-(1-((3-(1-methyl-1H-pyrazole-4-yl)-4-oxo-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (82) [ka]

[0320] Compound 82 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 566.2.

[0321] Example 47: Synthesis of 3-(5-(1-((2-methyl-4-oxo-3-phenyl-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (83) [ka]

[0322] Compound 83 was prepared according to the same procedure as described in Examples 17 and 18. MS[M+H] + = 576.8.

[0323] Example 48: Synthesis of 3-(5-(1-((2-methyl-4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (84) [ka]

[0324] Compound 84 was prepared according to the same procedure as described in Examples 17 and 18. MS[M+H] + = 577.3.

[0325] Example 49: Synthesis of 3-(4-fluoro-1-oxo-5-(1-((4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (85) [ka]

[0326] Compound 85 was prepared according to the same procedure as described in Examples 11, 16, and 18. MS[M+H] + = 581.7.

[0327] Example 50: Synthesis of 3-(5-(1-((8-fluoro-4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (86) [ka]

[0328] Compound 86 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 581.0.

[0329] Example 51: Synthesis of 3-(5-(1-((7-fluoro-4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (87) [ka]

[0330] Compound 87 was prepared according to the same procedure as described in Examples 16 and 18. MS[M+H] + = 581.4.

[0331] Example 52: Synthesis of 3-(5-(1-((5-fluoro-4-oxo-3-(pyridine-2-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (88) [ka]

[0332] Compound 88 was prepared according to the same procedure as described in Examples 14 and 15. MS[M+H] + = 581.2.

[0333] Example 53: Synthesis of 3-(4-fluoro-1-oxo-5-(1-((4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)isoindoline-2-yl)piperidine-2,6-dione (89) [ka]

[0334] Compound 89 was prepared according to the same procedure as described in Examples 11, 16, and 18. MS[M+H] + = 581.2.

[0335] Example 54: Synthesis of 3-(5-(1-((7-fluoro-4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (90) [ka]

[0336] Compound 90 is prepared according to the same procedure as described in Examples 16 and 18.

[0337] Example 55: Synthesis of 3-(5-(1-((5-fluoro-4-oxo-3-(pyridine-3-yl)-3,4-dihydroquinazoline-6-yl)methyl)piperidine-4-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (91) [ka]

[0338] Compound 91 is prepared according to the same procedure as described in Examples 16 and 18.

[0339] Example 56: Synthesis of 3-(1-oxo-5-(1-((2-(pyridine-2-yl)pyrazolo[1,5-a]pyridine-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (92) [ka]

[0340] Compound 92 was prepared according to the same procedure as described in Example 9. MS[M+H] + = 535.4.

[0341] Example 57: Synthesis of 3-(1-oxo-5-(1-((2-(pyridine-3-yl)pyrazolo[1,5-a]pyridine-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (93) [ka]

[0342] Compound 93 is prepared according to the same procedure as described in Example 9.

[0343] Example 58: Synthesis of 3-(1-oxo-5-(1-((2-(pyridine-2-yl)-2H-indazole-6-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (94) [ka]

[0344] Compound 94 is prepared according to the same procedure as described in Example 24.

[0345] Example 59: Synthesis of 3-(1-oxo-5-(1-((7-phenylimidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (98) [ka]

[0346] Compound 98 was prepared according to the same procedure as described in Examples 21 and 22. MS[M+H] + = 534.2.

[0347] Example 60: Synthesis of 3-(1-oxo-5-(1-((7-(pyridine-3-yl)imidazo[1,2-a]pyridine-2-yl)methyl)piperidine-4-yl)isoindorin-2-yl)piperidine-2,6-dione (99) [ka]

[0348] Compound 99 was prepared according to the same procedure as described in Examples 21 and 23. MS[M+H] + = 535.3.

[0349] Example 61: Liquid chromatography-mass spectrometry (LCMS) data

[0350] Reaction monitoring and characterization of the final compound were performed using a Shimadzu LC-20 AD series (binary pump and diode array detector) equipped with a Luna®-C18 column (3 μm, 2.0 × 30 mm). Mobile phase: A: 0.04% trifluoroacetic acid (v / v) in water, B: 0.02% trifluoroacetic acid (v / v) in MeCN. Flow rate: 1 mL / min (0.00~1.80 min) and 1.2 mL / min (1.81~2.00 min) at 25°C. MS: 2020, quadrupole LC / MS, ion source: API-ESI, TIC: 100~1000 m / z; dry gas flow rate: 15 L / min; nebulizer pressure: 1.5 L / min; dry gas temperature: 250°C, Vcap: 1400 V. [Table 1]

[0351] Example 62: Additional LCMS data

[0352] Reaction monitoring and characterization of the final compound were collected using a Shimadzu N-Series UPLC-MS system (LCMS-2020). All reported masses are in m / z for the protonated parent ion unless otherwise recorded. Samples were dissolved in a suitable solvent such as methanol, acetonitrile, or DMSO and injected directly into the column using an automated sample handler. Analysis was performed using a Waters® Acquity UPLC CSH C 18 1.7 μm, 2.1 × 30 mm column: flow rate: 1.0 mL / min; 40°C (column temperature); solvent A: 0.1% formic acid in water; solvent B: 0.1% formic acid in acetonitrile; gradient: solvent A: 0.01 min - 3.0%, 1.5~1.9 min - 97.0%, 2.0 min - 3.0%. Agilent Zorbax eclipse plus C 18 2.1×50mm 1.8μm: Flow rate: 0.8mL / min: 40℃ (column temperature) Solvent A: 0.1% formic acid in water, Solvent B: 0.1% formic acid in acetonitrile, Gradient: Solvent A: 0.01~0.25 min - 5.0%, 2.5~3.0 min - 100.0%, 3.1~4.0 min - 5.0%. Waters X-Bridge C8 (50×4.6) mm, 3.5μm: Flow rate 0.8mL / min; 40℃ (column temperature): Solvent A: 10mM ammonium bicarbonate in water, Solvent B: acetonitrile, Gradient: Solvent A: 0.01 min - 5.0%, 1.5~3.0 min - 95.0%, 3.5~4.0 min - 5.0%. Waters X-Bridge C8 (50 × 4.6) mm, 3.5 μm: Flow rate 0.8 mL / min; 40°C (column temperature): Solvent A: 10 mm ammonium acetate in water, Solvent B: Acetonitrile, Gradient: Solvent A: 0.01 min - 5.0%, 1.5~3.0 min - 95.0%, 3.5~4.0 min - 5.0%. [Table 2]

[0353] Example 63: HiBiT Protocol

[0354] The HiBiT protein tagging system was applied to MOLT4 cells by inserting a HiBiT peptide tag (Promega®) into the N-terminus of the IKZF2 gene locus via CRISPR / Cas (Neon® Transfection System). The resulting HiBiT-Helios stable cell line was triple-treated with the following compounds of the present invention according to a 13-point concentration scheme ranging from 10 μM to 0.00026 μM. At the indicated time points, the Nano-Glo® HiBiT Lytic Detection system (Promega®) was used to detect the bioluminescence of the HiBiT tag in the treated cells: the abundance of the tag was proportional to the level of luminescence. After normalization to DMSO, dose-response curves were plotted (GraphPad Prism) to determine the concentration point at which 50% of HiBiT-Helios degradation was achieved by each compound. Dmax was determined by calculating the degree of degradation (luminescence range) from the highest to the lowest concentration point. The results are shown in Table 3. [Table 3]

[0355] Example 64: MOLT4 IKZF2 HiBit Assay Protocol

[0356] This protocol uses MOLT4 cells manipulated with HiBit CRISPR / Cas9-mediated genomic insertion tagged at the N-terminus of the IKZF2 coding sequence. Day 1. Ten dose-response points were created using a Tecan D300e, starting at 30 μM and progressing to 1 nM. Next, 8,000 cells / well of MOLT4 IKZF2 HiBit cells were added to compound plates. Incubated for 24 hours. Day 2. Nano-Glo® HiBit Lytic Buffer / Nano-Glo® HiBit Lytic Substrate / LgBit Protein mix was added to each well and incubated for 15 minutes. Finally, the luminescence signal was read using a BMG Labtech PHERAstar® FSX. The data were normalized to DMSO and graphed using GraphPad Prism to determine the concentration point at which 50% HiBiT-Helios degradation was achieved by each compound. The degree of decomposition (luminescence range) from the highest to the lowest concentration point was calculated to determine Dmax. The data for the selected compounds are provided in Table 4. [Table 4]

[0357] All patent publications and non-patent publications demonstrate the level of skill of those skilled in the art to which the present invention relates. All of these publications are incorporated herein by reference to the same extent as each individual publication is specifically and individually incorporated by reference.

[0358] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. Therefore, it should be understood that many modifications can be made to the exemplary embodiments, and other configurations can be devised without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. Equation (I): 【Chemistry 1】 Compounds having the structure represented by, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers or tautomers thereof. (In the formula, Each R １ａ , R １ｂ , R １ａ 'and R １ｂ ' is independently of hydrogen or (C １ -C ６ ) is alkyl; Each R ２ is independently selected from the group consisting of hydrogen, hydroxy, amino, cyano, halo, (C １ -C ６ )alkyl, and (C １ -C ６ )haloalkyl; R ３ (C) １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyl; Each R ４ and R ４ ' is independently hydrogen, hydroxyl, amino, amide, carbonyl, cyano, halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyls, R ４ and R ４ ', together with the same carbon atom to which they are bonded, form C=(O); R ５ and R ５ ' is independently of hydrogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinnil, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Hydroxyalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; R ６ R ７ - Substituting aryl, or R ６ teeth, 【Chemistry 2】 【Transformation 3】 And, R ７ teeth, 【Chemistry 4】 Selected from the group consisting of; R ８ is, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each R ９ Independently, hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each R １１ and R １１ ' is independently of hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ２ -C ６ ) Alkenyl and (C ２ -C ６ ) Selected from the group consisting of alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base, or R １１ and R １１ ', together with the same carbon atom to which they are bonded, spiro(C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R １１ and R １１ ' together with the same carbon atom to which they are bonded, they form C=(O), or R １１ and R １１ ’, when on different carbon atoms, together with the atoms to which they are attached, form a (C ３ -C ７ ) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl or heterocycloalkyl may be further independently substituted by one or more identical or different R １５ groups; R １２ and R １３ together with the carbon atom to which they are attached form a (C ６ -C １０ )aryl, or a monocyclic or bicyclic 5- to 10-membered heteroaryl, and said aryl or heteroaryl may be further independently substituted by one or more identical or different R １５ groups; Each R １４ and R １４ ' is independently of hydrogen, (C １－ C ６ ) alkyl, (C １－ C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １－ C ６ ) Alkoxy, (C １－ C ６ ) Haloalkoxy, (C ２－ C ６ ) Alkenyl and (C ２－ C ６ ) Selected from the group consisting of alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base, or R １４ and R １４ ', together with the same carbon atom to which they are bonded, spiro(C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R １４ and R １４ ' together with the same carbon atom to which they are bonded, they form C=(O), or R １４ and R １４ 'When they are on different carbon atoms, they become together with the atom they are bonded to, (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group comprises one or more identical or different R １５ It may be further independently substituted by the base, However, at least one R １４ and at least one R １４ ', together with the same carbon atom to which they are bonded, form C=(O); Each R １５ These are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl , containing formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, at least one nitrogen atom,Selected from the group consisting of 4- to 7-membered heterocycloalkyl, aryl, and heteroaryl groups linked via a nitrogen atom, and also two adjacent R groups, １５ These, together with the individual atoms to which they are bonded, form aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl groups; R １６ Independently, hydrogen, (C １－ C ６ ) alkyl, (C １－ C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １－ C ６ ) Alkoxy, (C １－ C ６ ) Haloalkoxy, (C ２－ C ６ ) Alkenil, (C ２－ C ６ ) Selected from the group consisting of alkynyls and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each G is independent of C(R) １１ ) (Caution １１ '), NR １１ and selected from O, provided that at least one G is NR １１ or O; W １ -O-, -S-, and -NR ９ Selected from the group consisting of: W ２ is -O-, -S-, -SO ２ -, -C=(O)- and -NR ９ Selected from the group consisting of: Each W ３ is nitrogen or CR １６ And; Y is -SO ２ - or -C = (O)-; Each Q is independent of C, C(R) １６ ), C=(O), O, S, N and NR １６ Selected from; n １ is 0, 1, or 2; n ３ They are independently 1, 2, or 3; n ４ They are independently 1 or 2; and n ５ (These are independently either 0 or 1).

2. During the ceremony: Each R １ａ , R １ｂ , R １ａ 'and R １ｂ ' is hydrogen; Each R ２ These independently produce hydrogen, halo, and (C １ -C ６ ) Selected from the group consisting of alkyl groups; R ３ However, hydrogen, amino, hydroxyl, cyano, halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyl; Each R ４ and R ４ ' independently of hydrogen, hydroxyl, halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyl; R ５ and R ５ ' independently of hydrogen or (C １ -C ６ ) an alkyl group, wherein the alkyl group is one or more identical or different R １５ It may be further independently substituted by the base; R ６ However, R ７ - Substituting aryl, or R ６ but, 【Transformation 6】 And, R ７ but, 【Transformation 7】 Selected from the group consisting of; R ８ However, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each R ９ Hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each R １１ and R １１ ' independently, hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Haloalkoxy, (C ２ -C ６ ) Alkenyl and (C ２ -C ６ ) Selected from the group consisting of alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base, or R １１ and R １１ 'But together with the same carbon atom that is bonded to them, spiro(C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R １１ and R １１ ', together with the same carbon atom to which they are bonded, form C=(O), or R １１ and R １１ 'If they are on different carbon atoms, they will be together with the atoms they are bonded to, (C ３ -C ７ ) Forms a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group has one or more identical or different R １５ It may be further independently substituted by the base; R １２ and R １３ However, together with the carbon atoms to which they are bonded, (C ６ -C １０ ) Forms an aryl, or a monocyclic or bicyclic 5-10 member heteroaryl, wherein the aryl or heteroaryl has one or more identical or different R １５ It may be further independently substituted by the base; Each R １４ and R １４ ' independently, hydrogen, (C １－ C ６ ) alkyl, (C １－ C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １－ C ６ ) Alkoxy, (C １－ C ６ ) Haloalkoxy, (C ２－ C ６ ) Alkenyl and (C ２－ C ６ ) Selected from the group consisting of alkynyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base, or R １４ and R １４ 'But together with the same carbon atom that is bonded to them, spiro(C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R １４ and R １４ ', together with the same carbon atom to which they are bonded, form C=(O), or R １４ and R １４ 'If they are on different carbon atoms, they will be together with the atoms they are bonded to, (C ３ -C ７ ) Forms a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group or heterocycloalkyl group has one or more identical or different R １５ It may be further independently substituted by the base, However, at least one R １４ and at least one R １４ 'But together with the same carbon atom to which they are bonded, they form C=(O); Each R １５ These independently include alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl , containing formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, at least one nitrogen atom,Selected from the group consisting of 4- to 7-membered heterocycloalkyl, aryl, and heteroaryl groups linked via a nitrogen atom, and also two adjacent R groups, １５ However, together with the individual atoms to which they are bonded, they form aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl groups; R １６ Hydrogen, (C １－ C ６ ) alkyl, (C １－ C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １－ C ６ ) Alkoxy, (C １－ C ６ ) Haloalkoxy, (C ２－ C ６ ) Alkenil, (C ２－ C ６ ) Selected from the group consisting of alkynyls and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each G is independent of C(R) １１ ) (Caution １１ '), NR １１ and selected from O, provided that at least one G is NR １１ or O; W １ However, -O-, -S- and -NR ９ Selected from the group consisting of: W ２ However, -O-, -S-, -SO ２ -, -C=(O)- and -NR ９ Selected from the group consisting of: Each W ３ However, nitrogen or CR １６ And; Y is -SO ２ - or -C = (O)-; Each Q is independent of C, C(R) １６ ), C=(O), O, S, N and NR １６ Selected from; n １ However, it is 0, 1, or 2; n ３ They are independently 1, 2, or 3; n ４ They are independently 1 or 2; and n ５ These are independently either 0 or 1. The compound according to claim 1.

3. During the ceremony, Each R ２ is hydrogen; R ３ However, it is hydrogen or hydroxyl; Each R ４ and R ４ ' independently of hydrogen or (C １ -C ６ ) is alkyl; R ５ and R ５ ' independently of hydrogen or (C １ -C ６ ) Selected from alkyl; R ６ but, 【Transformation 8】 And; Each R １１ and R １１ ' independently of hydrogen or (C １ -C ６ ) an alkyl group, wherein the alkyl group is one or more identical or different R １５ It may be further independently substituted by the base, or R １１ and R １１ 'But together with the same carbon atom that is bonded to them, spiro(C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R １１ and R １１ ', together with the same carbon atom to which they are bonded, form C=(O), or R １１ and R １１ 'If they are on different carbon atoms, they will be together with the atoms they are bonded to, (C ３ -C ７ ) Forms a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein the cycloalkyl group or heterocycloalkyl group has one or more identical or different R １５ It may be further independently substituted by the base; R １６ Hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Selected from the group consisting of haloalkoxys and radicals involved in the formation of single bonds, wherein the alkyl is one or more identical or different R １５ It may be further independently substituted by the base; and n １ It is 1. The compound according to claim 2.

4. In the formula, R ６ but, 【Chemistry 9】 And R ６ However, (C １－ C ６ ) may be further independently substituted with one or more groups selected from alkyl, halo, and cyano; and Each R １１ and R １１ ' independently of hydrogen or (C １－ C ６ ) is alkyl, The compound according to claim 3.

5. In the formula, R ８ but, 【Chemistry 10】 Selected from, R ８ However, 1 or more R １５ And they may be substituted independently, Optional, R ８ but, 【Chemistry 11】 Selected from, R ８ However, 1 or more R １５ The compound according to claim 3 or 4, which may be further independently substituted.

6. Formula (II): 【Chemistry 12】 Compounds having the structure represented by, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers or tautomers thereof. (In the formula: Each R １ａ , R １ｂ , R １ａ 'and R １ｂ ' is independently of hydrogen or (C １ -C ６ ) is alkyl; Each R ２ These are independently hydrogen, hydroxyl, amino, cyano, halo, (C １ -C ６ ) alkyl and (C １ -C ６ ) Selected from the group consisting of haloalkyl; Each R ４ and R ４ ' is independently hydrogen, hydroxyl, amino, amide, carbonyl, cyano, halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) Selected from the group consisting of haloalkyls, R ４ and R ４ ', together with the same carbon atom to which they are bonded, form C=(O); R ５ and R ５ ' is independently of hydrogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinnil, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Hydroxyalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Each R １５ These are independently alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl , containing formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, at least one nitrogen atom,Selected from the group consisting of 4- to 7-membered heterocycloalkyl, aryl, and heteroaryl groups linked via a nitrogen atom, and also two adjacent R groups, １５ These, together with the individual atoms to which they are bonded, form aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl groups; R ２１ is substitution C ６ - It is an aryl, wherein the aryl is at least two R １５ It is substituted with and two R15s on adjacent carbon atoms are at least one (C ６ -C １０ ) Forms a 5 or 6-membered heteroaryl substituted with an aryl, or a monocyclic or bicyclic 5 to 10-membered heteroaryl, and the (C6-C10)aryl and the 5 or 6-membered heteroaryl are one or more R １５ It may be further independently substituted by the base, or R ２１ is a substituted 5- or 6-membered heteroaryl, wherein the heteroaryl has at least two R １５ It is substituted with, and the two R15 atoms on adjacent atoms are C ６ - Aryl or at least one (C ６ -C １０ ) Forms a 5 or 6-membered heteroaryl substituted with an aryl, or a monocyclic or bicyclic 5 to 10-membered heteroaryl, and the (C6-C10)aryl and the 5 or 6-membered heteroaryl are one or more R １５ It may be further independently substituted by the base, or R ２１ teeth 【Chemistry 13】 And; R ８ is, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 member heteroaryls, wherein the aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; W １ -O-, -S-, and -NR ９ Selected from the group consisting of: Each R ９ Independently, hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Selected from the group consisting of aryls and monocyclic and bicyclic 5-10 membered heteroaryls, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; Y is -SO ２ - or -C = (O)-; Each Q is independent of C, C(R) １６ ), C=(O), O, S, N and NR １６ Selected from; R １６ Independently, hydrogen, (C １－ C ６ ) alkyl, (C １－ C ６ ) Haloalkyl, (C ３ -C ７ ) Cycloalkyl, 4-7 member heterocycloalkyl, (C ６ -C １０ ) Aryl, monocyclic and bicyclic 5- to 10-membered heteroaryls, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １－ C ６ ) Alkoxy, (C １－ C ６ ) Haloalkoxy, (C ２－ C ６ ) Alkenil, (C ２－ C ６ ) Selected from the group consisting of alkynyls and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; n １ is 0, 1 or 2; and n ５ (These are independently either 0 or 1).

7. During the ceremony, Each R １ａ , R １ｂ , R １ａ 'and R １ｂ ' is hydrogen; Each R ２ is hydrogen; Each R ４ and R ４ ' independently of hydrogen or (C １ -C ６ ) is alkyl; R ５ and R ５ ' is either hydrogen or (C １ -C ６ ) is alkyl; R ２１ but, 【Chemistry 14】 And; Each Q １ They are independent of C, C(R １６ ), C=(O), O, S, N, and NR １６ Selected from, but with at least one Q １ is N; R １６ Hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, halo, cyano, -N(R ９ ) ２ , -OR ９ , (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Selected from the group consisting of haloalkoxys and radicals involved in the formation of single bonds, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or more identical or different R １５ It may be further independently substituted by the base; and n １ is 1, The compound according to claim 6.

8. In the formula, R ２１ but, 【Chemistry 15】 Selected from, R ２１ However, one Territory (C １－ C ６ The compound according to claim 7, which may be independently substituted with alkyl, halo, and cyano.

9. In the formula, R ８ but, 【Chemistry 16】 Selected from, R ８ However, 1 or more R １５ And they may be substituted independently, Optional, R ８ but, 【Chemistry 17】 Selected from, R ８ However, 1 or more R １５ The compound according to claim 7 or 8, which may be further independently substituted.

10. The compound according to claim 6, represented by formula IIa, IIb, IIc, IId, or IIe: 【Transformation 30】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof. (In the formula, Each R ２ independently selected from the group consisting of hydrogen and halos; and Each R １６ Independently, hydrogen, (C １－ C ６ ) alkyl, (C １－ C ６ (Selected from the group consisting of haloalkyl and halo).

11. In the formula, R ８ but, 【Chemistry 31】 Selected from, R ８ However, 1 or more R １５ And they may be substituted independently, Optional, R ８ but, 【Chemistry 32】 Selected from, R ８ However, one Territory (C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) Alkyl, cyano, halo, and R １５ They may be further independently substituted by one or more groups selected from; and R １６ 'but hydrogen and (C １ -C ６ ) Selected from the group consisting of alkyl groups, The compound according to claim 10.

12. Each R １５ (C １ -C ６ ) alkyl, (C ２ -C ６ ) Alkenil, (C ２ -C ６ ) Alkinil, Halo, CF ３ , (C ５ -C １０ ) Cycloalkyl, 3-12 member heterocycloalkyl, hydroxy, (C １ -C ６ ) Alkoxy, 3-12 membered cycloalkoxy, 3-12 membered heterocycloalkoxy, haloalkoxy, (C ６ -C １２ ) Aryloxy, 5-6 member heteroaryloxy, aralkyloxy, (C ２ -C ６ ) Alkyenyloxy, (C ２ -C ６ ) Alkinyloxy, amino, (C １ -C ６ ) alkylamino, (C ５ -C １０ ) Cycloalkylamino, 3-12 member heterocycloalkylamino, (C ６ -C １２ ) Arylamino, 5-6 member heteroarylamino, aralkylamino, N-(C １ -C ６ ) Alkyl-N-(C ６ -C １２ ) Arylamino, N-(C １ -C ６ ) Alkyl-N-5 to 6-membered heteroarylamino, N-(C １ -C ６ ) Alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, (C １ -C ６ ) Alkylthio, Haloalkylthio, (C １ -C ６ ) Alkyl sulfonyl, haloalkyl sulfonyl, (C ５ -C １０ ) Cycloalkylsulfonyl, 3-12 member heterocycloalkylsulfonyl, (C ６ -C １２ ) Aryl sulfonyl, 5-6 member heteroaryl sulfonyl, aminosulfonyl, (C １ -C ６ ) Alkylaminosulfonyl, (C ５ -C １０ ) Cycloalkylaminosulfonyl, 3-12 member heterocycloalkylaminosulfonyl, (C ６ -C １２ ) Arylaminosulfonyl, 5-6 member heteroarylaminosulfonyl, N-(C １ -C ６ ) Alkyl-N-(C ６ -C １２ ) Arylaminosulfonyl, N-(C １ -C ６ ) Alkyl-N-5 to 6-membered heteroarylaminosulfonyl, formyl, (C １ -C ６ ) Alkylcarbonyl, Haloalkylcarbonyl, (C ２ -C ６ ) Alkenylcarbonyl, (C ２ -C ６ ) Alkynylcarbonyl, Carboxylate, (C １ -C ６ ) Alkoxycarbonyl, (C １ -C ６ ) Alkylcarbonyloxy, amino, (C １ -C ６ ) Alkyl sulfonyl amino acids, haloalkyl sulfonyl amino acids, (C ５ -C １０ ) Cycloalkylsulfonylamino, 3-12 member heterocycloalkylsulfonylamino, (C ６ -C １２ ) Aryl sulfonylamino, 5-6 member heteroaryl sulfonylamino, aralkyl sulfonylamino, (C １ -C ６ ) Alkylcarbonylamino, Haloalkylcarbonylamino, (C ５ -C １０ ) Cycloalkylcarbonylamino, 3-12 member heterocycloalkylcarbonylamino, (C ６ -C １２ ) Arylcarbonylamino, 5-6 member heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, (C １ -C ６ ) Alkylaminocarbonyl, (C ５ -C １０ ) Cycloalkylaminocarbonyl, 3-12 member heterocycloalkylaminocarbonyl, (C ６ -C １２ ) Arylaminocarbonyl, 5-6 member heteroarylaminocarbonyl, N-(C １ -C ６ ) Alkyl-N-(C ６ -C １２ ) Arylaminocarbonyl, N-(C １ -C ６ ) alkyl-N-5 to 6-membered heteroarylaminocarbonyl, cyano, nitro, azide, phosphinyl, phosphine oxide and phosphonate phosphoryl, cyclic acetal, 4 to 7-membered heterocycloalkyl, containing at least one nitrogen atom and linked via a nitrogen atom, (C ６ -C １２ ) Selected from the group consisting of aryls and 5-6 member heteroaryls, and also two adjacent R １５ The compound according to any one of claims 1 to 11, wherein each of the compounds combines with the individual atoms to which it is bonded to form an aryl, heteroaryl, 5-8 membered cycloalkyl, or 5-8 membered heterocycloalkyl.

13. The following compounds: [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, A compound that is a pharmaceutically acceptable salt form of which is of optional choice.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, A pharmaceutical composition wherein the compound is optionally in the form of a cocrystal.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer, for treating a disease or disorder in a subject that benefits from the degradation of IKZF2, relating to IKZF2 (Helios), or the pharmaceutical composition according to claim 14, A pharmaceutical composition in which, optionally, the disease or disorder is cancer.

16. The pharmaceutical composition according to claim 15, wherein the cancer is T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).

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