Helios small molecule degraders and methods of use

Abstract

Disclosed are compounds and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof 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] Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 928,139, filed October 30, 2019, U.S. Provisional Patent Application No. 63 / 035,272, filed June 5, 2020, and U.S. Provisional Patent Application No. 63 / 047,411, filed July 2, 2020, each of which is incorporated herein by reference in its entirety.

[0002] Government Licensing Rights This invention was made with government support under Grant No. R01 CA21460803 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. [Background technology]

[0003] Imide molecules, such as thalidomide and its analogs, bind to cereblon (CRBN), a substrate adaptor for the ubiquitously expressed Cullin ring ligase 4 (CUL4)-RBX1-DDB1-CRBN (CUL4CRBN) E3 ligase (Kronke et al., Science 343:301-305 (2014); Ito et al., Science 327:1345-1350 (2010)). This leads to the recruitment, ubiquitination, and subsequent proteasomal degradation of neosubstrates, namely Ikaros (IKZF1) and Aiolos (IKZF3), but not 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 also induces degradation of GSPT1, a key translation termination factor (Matyskiela et al., Nature 535:252-257 (2016)).

[0004] Helios (IKZF2), a member of the IKZF family, is a key regulator of T cell activity and function. Genetic 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 (Elkord et al., Expert Opin. Biol. Ther. 12:1423-1425 (2012)), a subpopulation of T cells that limit the activity of effector T cells. Selective deletion of Helios in regulatory T cells resulted in both loss of suppressive activity and acquisition of effector T cell function (Najagawa et al., Proc. Natl. Acad. Sci. USA 113:6248-6253 (2016); Yates et al., Proc. Natl. Acad. Sci. USA 115:2162-2167 (2018)). Thus, Helios is an important factor in limiting T cell effector function in Tregs.

[0005] Helios expression has also been shown to be a key factor in "exhausted" T cells during 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 Helios has been reported to be upregulated in both inflammatory and immunological settings (Schietinger 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 aberrant expression of Helios and various splice isoforms has been reported in several hematological malignancies, including T-cell leukemia and lymphoma (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 lineage 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]

[0006] [Non-licensed 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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[0007] A first aspect of the present invention is a compound of formula (I):

[0008] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R 2、 R 3、 R 4、R4', R 5、 R5', R6, and n1 are as defined herein.

[0009] A second aspect of the present invention is a compound of formula (II):

[0010] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L and R2 are as defined herein.

[0011] 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 the compound.

[0012] A further aspect of the invention relates to methods for treating diseases or disorders that would benefit from IKZF2 (Helios) degradation.

[0013] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is T-cell leukemia, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, or carcinoid.

[0014] As demonstrated in the Examples, the compounds of the present invention exhibit potent degradation of IKZF2 (Helios).

[0015] Without intending to be bound by any particular theory of operation, it is believed that the compounds of the present invention may enhance anti-tumor immune responses by enabling regulatory T cells to assume effector T cell function and by rescuing effector T cell function in exhausted T cells or CAR-T cells. [Brief explanation of the drawings]

[0016] [Figure 1] [Figures 1A-1C] Plots of green fluorescent protein (GFP) assay of cellular IKZF2 degradation for compounds 36, 72, and 79 of the present invention, where IC50 values indicate the combined effect of cell permeability and the ability of the compounds to degrade IKZF2 in cells. DETAILED DESCRIPTION OF THE INVENTION

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings set forth to facilitate understanding of the invention.

[0018] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "composition" includes mixtures of two or more such compositions, reference to an "inhibitor" includes mixtures of two or more such inhibitors, and so forth.

[0019] Unless otherwise specified, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value modified by the term "about."

[0020] The transitional term "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. When used in reference to the number of heteroatoms in a heterocyclic ring structure, it refers to the heterocyclic ring group of that minimum number of heteroatoms. In contrast, the transitional phrase "consisting of" excludes elements, steps, or ingredients not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to certain materials or steps, "and which do not materially affect the basic and novel characteristics" of the claimed invention.

[0021] To the extent that the following terms are used herein with respect to and to further describe the compounds of the present invention, the following definitions apply.

[0022] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon radical. In one embodiment, an alkyl radical is C-C 18 In other embodiments, the alkyl radical is a C0-C6, C0-C5, C-0-C3, C1-C 12, C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3 group (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.

[0023] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing no unsaturation, having 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc., that connects the rest of the molecule to a radical group. The alkylene chain can be attached to the rest of the molecule through a single bond or to the radical group through a single bond. In some embodiments, an alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, an alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, an alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, an alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, an alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, an alkylene group contains one carbon atom (C1 alkylene).

[0024] As used herein, the term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, an alkenyl radical is C2-C 18 In other embodiments, the alkenyl radical is a C-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

[0025] As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, an alkynyl radical is C2-C 18 In another example, the alkynyl radical is a C-C 12 , C2-C 10 , C2-C8, C2-C6 or C2-C3. Examples include ethynylprop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0026] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto, which is the point of attachment. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbyl groups covalently linked by an oxygen. Thus, the alkyl substituent that makes the alkyl an ether is an alkoxyl or similar to an alkoxyl, and can be represented, for example, by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0027] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0028] As used herein, the term "cyclic group," used alone or as part of a larger moiety, broadly refers to any group containing saturated, partially saturated, or aromatic ring systems, such as carbocyclic groups (cycloalkyl, cycloalkenyl), heterocyclic groups (heterocycloalkyl, heterocycloalkenyl), aryl groups, and heteroaryl groups. A cyclic group can have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0029] As used herein, the term "carbocycle" (also "carbocyclyl"), used alone or as part of a larger moiety, refers to a group, alone or as part of a larger moiety (e.g., an alkyl carbocyclic group), containing saturated, partially unsaturated, or aromatic ring systems having from 3 to 20 carbon atoms. The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spirocyclic ring systems, and combinations thereof. In one embodiment, a carbocyclyl contains from 3 to 15 carbon atoms (C3-C 15 In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C3-C 12 In another embodiment, the carbocyclyl is C3-C 8、 C3-C 10 or C5-C 10 In another embodiment, the carbocyclyl, as a monocycle, includes C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl, as a bicycle, includes C7-C 12 In another embodiment, the carbocyclyl, as a spiro system, includes C5-C 12Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, 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 monocyclic, bicyclic, or spirocarbocycles). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., aryl or heterocyclic rings), where the radical or point of attachment is on the carbocyclic ring.

[0030] Thus, the term carbocycle as used herein means R c is an alkylene chain of formula --R c The term carbocyclyl, as used herein, also encompasses carbocyclylalkyl groups, which refer to the group R c is an alkylene chain of the formula --O--R c Also included are carbocyclylalkoxy groups, which refer to groups attached through the oxygen atom of a -carbocyclyl.

[0031] As used herein, the term "aryl," used alone or as part of a larger moiety (e.g., "aralkyl" where the terminal carbon atom on an alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an aryl group), refers to a group containing a monocyclic, bicyclic, or tricyclic carbocyclic ring system, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, an 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 another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthyridinyl, and the like, which may be substituted or independently substituted with one or more substituents described herein. A particular aryl is phenyl. In some embodiments, an aryl group comprises an aryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the radical or point of attachment is on the aryl ring.

[0032] Thus, the term aryl refers to R c is an alkylene chain such as methylene or ethylene; c -aryl groups, including aralkyl groups (e.g., benzyl). In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, refers to an R c is an alkylene such as methylene or ethylene; c Also included is an aralkoxy group, which refers to a group bonded through the oxygen atom of an --aryl.

[0033] As used herein, the term "heterocyclyl," used alone or as part of a larger moiety, refers to "carbocyclyl," including saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., O, N, N(O), S, S(O), or S(O)). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spirocyclic ring systems, and combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 15-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5- to 14-membered heteroaryl ring system. The term heterocyclyl also includes C3-C8 heterocycloalkyl, which are saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring systems containing 3 to 8 carbons and one or more (1, 2, 3, or 4) heteroatoms.

[0034] In some embodiments, heterocyclyl groups contain 3 to 12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic systems, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3 to 7-membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 4 to 6-membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3-membered monocyclic rings. In some embodiments, heterocyclyls contain 4-membered monocyclic rings. In some embodiments, heterocyclyls contain 5 to 6-membered monocyclic rings. In some embodiments, heterocyclyl groups contain 0 to 3 double bonds. In any of the foregoing embodiments, heterocyclyls contain 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR]). + Cl - , [NR4] + OH -Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, Thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl , oxazolidinonyl, imidazolidinonyl, 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, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolyl nyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, 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-azaspiro[4.5]decane-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing a sulfur atom or an oxygen atom and 1 to 3 nitrogen atoms include thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, such as oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyls such as imidazol-2-yl; triazolyls such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyls such as 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzthiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyls contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, for example, pyridyls such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyls such as pyrimid-2-yl and pyrimid-4-yl; triazinyls such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyls, especially pyridazin-3-yl, and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide and pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl groups are further examples of heterocyclyl groups. In some embodiments, heterocyclic groups include heterocyclic rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the radical or point of attachment is on the heterocyclic ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0035] Thus, the term heterocycle, as used herein, includes N-heterocyclyl groups, which refer to heterocyclyl groups containing at least one nitrogen atom, where the heterocyclyl group is attached to the rest of the molecule through 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. The term heterocycle, as used herein, also includes C-heterocyclyl groups, which refer to heterocyclyl groups containing at least one heteroatom, where the heterocyclyl group is attached to the rest of the molecule through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocycle refers to a heterocyclic ring, as disclosed above, c is an alkylene chain of formula --R c -heterocyclyl groups, which refer to the group heterocyclyl, are also included. The term heterocycle as used herein refers to R c is an alkylene chain of the formula --O--R c Also included are heterocyclylalkoxy groups, which refer to radicals attached through the oxygen atom of a -heterocyclyl.

[0036] As used herein, the term "heteroaryl," used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also "heteroaralkyl") or "heteroarylalkoxy" (also "heteroaralkoxy"), refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms is 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, pyridyl, pyrimidyl, pyrid ... Examples include lysyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, and the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, heteroaryl groups comprise a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0037] Thus, the term heteroaryl, as used herein, encompasses N-heteroaryl groups, which refer to heteroaryl groups, as defined above, containing at least one nitrogen, where the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl, as used herein, also encompasses C-heteroaryl groups, which refer to heteroaryl groups, as defined above, where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also encompasses R, as disclosed above. c is an alkylene chain as defined above; c The term heteroaryl, as used herein, also refers to the group R c is an alkylene chain as defined above, c -includes heteroaralkoxy (or heteroarylalkoxy) groups, which refers to groups attached through an oxygen atom of a heteroaryl.

[0038] Unless otherwise specified, and unless further defined for any particular group, any of the groups described herein can be substituted or unsubstituted. As used herein, the term "substituted" refers broadly to all permissible substituents, with the implicit proviso that such substitution is consistent with the permissible valences 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, and the like. Representative substituents include halogens, hydroxyl groups, and any other organic group containing any number of carbon atoms, e.g., 1 to 14 carbon atoms, and may include one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as oxygen, sulfur, and nitrogen, grouped in the form of a straight-chain, branched-chain, or cyclic structure.

[0039] Unless otherwise disclosed for any particular group, representative 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-C 2、 C1), substituted alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C 2、 C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C 3、 C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C 3、 C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C 3、 C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C 3、 C2), cyclic (e.g., C3-C 12、 C5-C6), substituted cyclic (e.g., C3-C 12、 C5-C6), carbocyclic (e.g., C3-C 12 , C5-C6), substituted carbocyclic (e.g., C3-C 12、 C5-C6), heterocyclic (e.g., C3-C 12 , C5-C6), substituted heterocyclic (e.g., C3-C12、 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-C 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), substituted arylthio (e.g., C6-C 12 , C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups.

[0040] In one aspect, the compound of the present invention has formula (I):

[0041] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof; During the ceremony, each R2 is independently selected from the group consisting of hydrogen, 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; or R2 and R3, together with the atoms to which they are attached, form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl, heterocycloalkyl may be one or more of the same or different R 15 and optionally further substituted independently by groups, Each R4 and R4' is independently selected from hydrogen, hydroxyl, amino, amido, carbonyl, cyano, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl and (C2-C6) alkynyl, wherein said alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, or R3 and R4' together with the atoms to which they are attached form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R4 and R4' 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 R4 and R4', when on different carbon atoms, together with the atom to which they are attached, form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; or When R4 and R4' are on adjacent atoms, they together with the atoms to which they are attached form (C6-C 10 ) aryl or 5- or 6-membered heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be one or more of the same or different R 15 and optionally further substituted independently by groups, R5 and R5' are each independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R6 is an optionally substituted aryl or heteroaryl, or an R7-substituted aryl or R7-substituted heteroaryl, wherein said R7-substituted aryl or R7-substituted heteroaryl may be joined by one or more of the same or different R 15 and optionally further substituted independently by groups, Or R6:

[0042] [ka] with the proviso that when R6 is an optionally substituted aryl or heteroaryl, at least one of R4 and R4' is alkynyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5- to 10-membered heteroaryl, wherein said alkynyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R7 is -C(O)NR8R9, -SO2NR8R9, -S(O)(=NH)R9, -OR8, -N(R8R9), -N(R9)C(O)R8, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, -N(R9)S(O)2N(R9)2,

[0043] [ka] is selected from the group consisting of R8 is (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R9 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 10 and R 10 ' is hydrogen, (C 1- C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, halo, cyano, -N(R9)2, -OR 9、 independently selected from the group consisting of (C-C)alkoxy, (C-C)haloalkoxy, (C-C)alkenyl, and (C-C)alkynyl, provided that at least one R 10 and at least one R 10 ', when attached to the same carbon atom, form a spiro 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, or, when attached to different carbon atoms, form a heterocycle or carbocycle, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be optionally joined by one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 11 and R 11' is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, halo, cyano, —N(R)2, —OR9, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, 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 ' are on different carbon atoms, together with the atom to which they are attached form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl or heterocycloalkyl may be selected from one or more of the same or different R 15 and optionally further substituted independently by groups, R 12 and R 13 together with the carbon atoms to which they are attached (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 14 and R 14 ' together with the same carbon atom to which they are attached form a spiro 4- to 7-membered heterocycloalkyl, or (C3-C7)cycloalkyl, wherein said cycloalkyl or heterocycloalkyl may be joined by one or more of the same or different R 15and optionally further substituted independently by groups, R 15is alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-hetero arylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkynylcarbonyloxy, 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, azido, phosphinyl, phosphoryl including phosphine oxide and phosphonate, cyclic acetal,independently selected from the group consisting of 4-7 membered heterocycloalkyl, aryl, and heteroaryl, each of which contains at least one nitrogen atom and is linked via a nitrogen atom, wherein two adjacent R, 15 are taken together with the atoms to which they are attached to form an aryl, heteroaryl, 5- to 8-membered cycloalkyl, or 5- to 8-membered heterocycloalkyl; 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 is nitrogen, CR 11 and a carbon atom that is the point of attachment; Y is selected from the group consisting of —SO— and —C(O)—; n1 is 0, 1 or 2; n2 is 0, 1, 2 or 3; n3 is independently 1, 2 or 3.

[0044] In some embodiments, the compound is represented by Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is hydrogen, halo, or (C1-C6) alkyl; R3 is selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; Each R4 and R4' is hydrogen, amide, halogen, (C1-C6) alkyl, (C6-C 10 )aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl and (C2-C6)alkynyl, wherein said alkyl, alkynyl, aryl or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, or R4 and R4' 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 and R′, when on different carbon atoms, together with the atom to which they are attached, form a (C-C) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl or heterocycloalkyl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R5 and R5' are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, and (C1-C6) hydroxyalkyl, wherein said alkyl is selected from one or more of the same or different R 15 and optionally further substituted independently by groups, R6 is an optionally substituted aryl or heteroaryl, or R6 is an R7-substituted aryl or R7-substituted heteroaryl, wherein said R7-substituted aryl or R7-substituted heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Or each R6,

[0045] [ka] and provided that when R6 may be optionally substituted aryl or heteroaryl, at least one of R4 or R4' may be alkynyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkynyl, alkyl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R7 is -C(O)NR8R9, -SO2NR8R9, -S(O)(=NH)R9, -OR8, -N(R8R9), -N(R9)C(O)R8, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, -N(R9)S(O)2N(R9)2,

[0046] [ka] is selected from the group consisting of R8 is (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R9 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 10 and R 10 ' is hydrogen, (C 1- C6) alkyl, (C1-C6) haloalkyl, (C6-C 10 ) independently selected from the group consisting of aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, and halo, provided that at least one R 10 and at least one R 10 ', when attached to the same carbon atom, form a spiro 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, or when attached to different carbon atoms, form a 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, wherein said alkyl, heterocycle, or carbocycle may be optionally joined by one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 11 and R 11 ' is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C6-C 10) independently selected from the group consisting of aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, and halo, wherein said alkyl, aryl, or heteroaryl is / are selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, 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 ' are on different carbon atoms, together with the atom to which they are attached form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl or heterocycloalkyl may be selected from one or more of the same or different R 15 and optionally further substituted independently by groups, R 12 and R 13 together with the carbon atoms to which they are attached (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 14 and R 14 ' together with the same carbon atom to which they are attached form a spiro 4- to 7-membered heterocycloalkyl, or (C3-C7)cycloalkyl, wherein said cycloalkyl or heterocycloalkyl may be joined by one or more of the same or different R 15 and optionally further substituted independently by groups, W1 is selected from the group consisting of -O-, -S- and -NR9-; W2 is selected from the group consisting of -O-, -S-, and -NR9-; Each W3 is nitrogen, CR 11 and a carbon atom that is the point of attachment; Y is selected from the group consisting of —SO— and —C(O)—; n1 is 0, 1 or 2; n2 is 0, 1, 2 or 3; n3 is independently 1, 2 or 3.

[0047] In some embodiments, R2 is hydrogen.

[0048] In some embodiments, R3 is independently selected from the group consisting of amino, hydroxyl, cyano, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl.

[0049] In some embodiments, R5 and R5' are independently hydrogen or methyl.

[0050] In some embodiments, R6 is

[0051] [ka] is.

[0052] In some embodiments, R6 is

[0053] [ka] is.

[0054] In some embodiments, R6 is an R7-substituted aryl or an R7-substituted heteroaryl, wherein said R7-substituted aryl or R7-substituted heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups,

[0055] In some embodiments, R7 is -C(O)NR8R9, -SO2NR8R9, -OR8, -N(R8R9), -N(R9)C(O)R8, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2,

[0056] [ka] is.

[0057] In some embodiments, R7 is -C(O)NR8R9, -SO2NR8R9, -OR8, -N(R8R9), -N(R9)C(O)R8, -N(R9)SO2R9, -N(R9)C(O)N(R9)2,

[0058] [ka] is.

[0059] In some embodiments, W1 is -O-.

[0060] In some embodiments, W1 is -NR9-.

[0061] In some embodiments, W3 is nitrogen.

[0062] In some embodiments, W3 is CR 11 is.

[0063] In some embodiments, W3 is the carbon atom that is the point of attachment.

[0064] In some embodiments, Y is —SO 2 —.

[0065] In some embodiments, Y is —C(O)—.

[0066] In some embodiments, n1 is 0.

[0067] In some embodiments, n1 is 1.

[0068] In some embodiments, n1 is 2.

[0069] In some embodiments, n2 is 0.

[0070] In some embodiments, n2 is 1.

[0071] In some embodiments, n2 is 2.

[0072] In some embodiments, n2 is 3.

[0073] In some embodiments, each R2 is hydrogen, R3 is hydrogen or hydroxyl, R4 and R4' are each hydrogen, halo, or (C1-C6) alkyl, R5 and R5' are each hydrogen, and n1 is 1.

[0074] In a second aspect, the compound of the present invention has the formula (II):

[0075] [ka] or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof; During the ceremony, L is

[0076] [ka] Selected from the group consisting of: each R2 is independently selected from the group consisting of hydrogen, 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; or R3 and R4 together with the atoms to which they are attached 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 attached, form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein the cycloalkyl, heterocycloalkyl group may be one or more of the same or different R 15 and optionally further substituted independently by groups, Each R4 and R4' is independently selected from hydrogen, hydroxyl, amino, amido, carbonyl, cyano, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, (C2-C6) alkenyl and (C2-C6) alkynyl, wherein said alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, or R4 and R4' 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 R4 and R4', when on different carbon atoms, together with the atom to which they are attached, form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; or When R4 and R4' are on adjacent atoms, they together with the atoms to which they are attached form (C6-C 10 ) aryl or 5- or 6-membered heteroaryl, wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be one or more of the same or different R 15 and optionally further substituted independently by groups, R5 and R5' are each independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R6 is an optionally substituted aryl or heteroaryl, or R6 is an R7-substituted aryl or R7-substituted heteroaryl, wherein said R7-substituted aryl or R7-substituted heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Or each R6,

[0077] [ka] and When R6 is an optionally substituted aryl or heteroaryl, at least one of R4 or R4' is an alkynyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkynyl, aryl, or heteroaryl may be independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R7 is -C(O)NR8R9, -SO2NR8R9, -S(O)(=NH)R9, -OR8, -N(R8R9), -N(R9)C(O)R8, -N(R9)SO2R9, -N(R9)C(O)N(R9)2, -P(O)(R9)2, -N(R9)S(O)2N(R9)2,

[0078] [ka]

[0079] [ka] is selected from the group consisting of R8 is (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R9 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 10 and R 10 ' is hydrogen, (C 1- C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, halo, cyano, -N(R9)2, -OR 9、 independently selected from the group consisting of (C-C)alkoxy, (C-C)haloalkoxy, (C-C)alkenyl, and (C-C)alkynyl, provided that at least one R 10 and one R 10 ', when attached to the same carbon atom, form a spiro 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, or, when attached to different carbon atoms, form a heterocycle or carbocycle, wherein said alkyl, cycloalkyl, heterocycle, or carbocycle may be joined by one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 11 and R 11' is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl, halo, cyano, —N(R)2, —OR9, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, 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 ' are on different carbon atoms, together with the atom to which they are attached form a (C3-C7)cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl or heterocycloalkyl may be selected from one or more of the same or different R 15 and optionally further substituted independently by groups, R 12 and R 13 together with the carbon atoms to which they are attached (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 14 and R 14 ' together with the same carbon atom to which they are attached form a spiro 4- to 7-membered heterocycloalkyl, or (C3-C7)cycloalkyl, wherein said cycloalkyl or heterocycloalkyl may be joined by one or more of the same or different R 15and optionally further substituted independently by groups, R 15is alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-hetero arylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkynylcarbonyloxy, 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, azido, phosphinyl, phosphoryl including phosphine oxide and phosphonate, cyclic acetal,independently selected from the group consisting of 4-7 membered heterocycloalkyl, aryl, and heteroaryl, each of which contains at least one nitrogen atom and is linked via a nitrogen atom, wherein two adjacent R, 15 are taken together with the atoms to which they are attached to form an aryl, or heteroaryl, or a 5- to 8-membered cycloalkyl or a 5- to 8-membered heterocycloalkyl; R 21 is R6, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 25 and optionally independently substituted by groups, R 22 is alkyl, haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 23 is selected from the group consisting of amino, hydroxyl, cyano, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; or R 23 and R4 together with the atoms to which they are attached form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R 23 and R2, together with the atoms to which they are attached, form a (C3-C7) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl, heterocycloalkyl may be one or more of the same or different R 15 and optionally further substituted independently by groups, R 24is selected from the group consisting of -N(R9)2 and 4- to 7-membered heterocyclylalkyl, wherein said heterocyclylalkyl contains at least one nitrogen atom and is bonded through a nitrogen atom; R 25 is (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)R 26 , -(CH2) 0-3 C(O)OR 26 , --C(O)NR 26 R 27 , -NR 26 C(O)R 27 , -NR 26 C(O)OR 27 , -S(O)pNR 26 R 27 , -S(O)pR 28 , (C1-C6) hydroxyalkyl, halogen, -OH, -O(CH2) 1-3 CN, -(CH2) 1-3 CN, -(CR 29 R 29 ')CN, -NH2, CN, -O(CH2) 0-3 (C6-C 10 ) aryl, adamantyl, -O(CH2) containing 1 to 3 heteroatoms selected from O, N and S 0-3 - 5- or 6-membered heteroaryl, (C6-C 10 )aryl, monocyclic and / or bicyclic 5- to 10-membered heteroaryl, (C-C)cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, or The Two R's 25 Groups, when located on adjacent atoms, together with the atoms to which they are attached, can form one or more R 15 or forming an optionally substituted aryl or 5- or 6-membered heteroaryl with a group The Two R's25 Groups, together with the atoms to which they are attached, consist of one or more R 15 forming an optionally substituted (C5-C7)cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring; R 26 and R 27 are independently selected from the group consisting of hydrogen and alkyl; R 28 is (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 29 and R 29 ' is R 29 and R 29 are independently selected from the group consisting of R4, with the proviso that at least one of ' together with the same carbon atom to which they are attached form a spiro(C3-C7)cycloalkyl; or R 29 and R 29 ', when on adjacent carbon atoms, together with the same carbon atom to which they are attached form a (C3-C7)cycloalkyl, wherein said cycloalkyl is optionally joined to one or more of the same or different R 15 and optionally further substituted independently by groups, 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 is nitrogen, CR 11 and a carbon atom that is the point of attachment; Y is selected from the group consisting of —SO— and —C(O)—; n1 is independently 0, 1 or 2; n2 is 、 is 0, 1, 2 or 3, n3 is independently 1, 2 or 3; n6 and n6' are independently 0, 1, 2, 3, 4, or 5, provided that n6 and n6' cannot both be 0; n7 is 1 or 2, p is 0, 1 or 2.

[0080] In some embodiments, the compound of the present invention is represented by Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R2 is hydrogen, halo, or (C1-C6)alkyl; R3 is selected from the group consisting of hydrogen, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; Each R4 and R4' is hydrogen, amide, halogen, (C1-C6) alkyl, (C6-C 10 )aryl, monocyclic and / or bicyclic 5-10 membered heteroaryl and (C2-C6)alkynyl, wherein said alkyl, alkynyl, aryl or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, or R4 and R4' 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 When R and R′ are on different carbon atoms, they together with the atom to which they are attached form a (C-C) cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein said cycloalkyl, heterocycloalkyl may be one or more of the same or different R 15 and optionally further substituted independently by groups, R5 and R5' are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) hydroxyalkyl, wherein said alkyl is selected from one or more of the same or different R15 and optionally further substituted independently by groups, Each R9 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5- to 10-membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 21 is R6, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 22 is alkyl, (C6-C 10 ) aryl, and monocyclic and / or bicyclic 5-10 membered heteroaryl, wherein said alkyl, aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, R 23 is selected from the group consisting of halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; R 24 is selected from the group consisting of -N(R9)2 and 4- to 12-membered heterocyclylalkyl, wherein said heterocyclylalkyl contains at least one nitrogen atom and is bonded through a nitrogen atom; R 25 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -C(O)NR 26 R 27 , -NR 26 C(O)R 27 , -S(O)pNR 26 R27 , -S(O)pR 28 , halogen, -O(CH2) 1-3 CN, -NH2, CN, -(CR 29 R 29 ') -O(CH2) containing 1 to 3 heteroatoms selected from CN, O, N and S 0-3 - 5- or 6-membered heteroaryl, (C6-C 10 )aryl, monocyclic and / or bicyclic 5- to 10-membered heteroaryl, (C-C)cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further independently substituted by groups, or The Two R's 25 are on adjacent atoms, together with the atoms to which they are attached, form one or more R 15 or forming an optionally substituted aryl or 5- or 6-membered heteroaryl with a group The Two R's 25 Groups, together with the atoms to which they are attached, consist of one or more R 15 forming a (C5-C7)cycloalkyl or 5- to 7-membered heterocycloalkyl optionally substituted with a group; R 26 and R 27 are independently selected from the group consisting of hydrogen and alkyl; R 28 is hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl and (C6-C 10 ) aryl, wherein said alkyl, cycloalkyl or aryl is selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, Each R 29 and R 29 ' is a string containing at least one R 29 and one R 29are independently selected from the group consisting of R4, with the proviso that R', ... R 29 and R 29 ', when on adjacent carbon atoms, together with the atoms to which they are attached, may form one or more identical or different R 15 forming a (C-C)cycloalkyl optionally further substituted independently by a group; n1 is independently 0, 1 or 2; n6 and n6' are independently 0, 1, 2, 3, 4, or 5, provided that n6 and n6' cannot both be 0; n7 is 1 or 2, p is 0, 1 or 2; W1 is selected from the group consisting of -O- and -NR9-.

[0081] In some embodiments, R3 is independently selected from the group consisting of amino, hydroxyl, cyano, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl.

[0082] In some embodiments, R 23 is selected from the group consisting of amino, hydroxyl, cyano, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl.

[0083] In certain embodiments, n1 is 1.

[0084] In certain embodiments, n2 is 0, 1, or 2.

[0085] In certain embodiments, n3 is 1 or 2.

[0086] In certain embodiments, p is 2.

[0087] In some embodiments, each R2 is hydrogen.

[0088] In some embodiments, R 21 is a substituted C6 aryl, provided that the aryl is substituted with at least two R 25 is replaced by R 25 If two of these are on adjacent atoms, then at least one (C6-C 10 ) 5- or 6-membered heterocyclyl substituted with aryl, or one or more R 15 forming a monocyclic or bicyclic 5-10 membered heteroaryl which may be optionally and independently substituted by R 21 is a substituted 5- or 6-membered heteroaryl, provided that said heteroaryl is substituted with at least two R 25 is replaced by R 25 are on adjacent atoms, it is a C6 aryl, or at least one (C6-C 10 ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R 15 and forming an optionally independently substituted monocyclic or bicyclic 5-10 membered heteroaryl.

[0089] In some embodiments, R2 is hydrogen, R3 is hydrogen or hydroxyl, R4 and R4' are each hydrogen, halo, or C(1-6)alkyl, R5 and R5' are each hydrogen, and n1 is 1.

[0090] In some embodiments, L is

[0091] [ka] wherein R2 is hydrogen, R4 and R4' are each hydrogen, halo, or (C1-C6) alkyl, and R5 and R5' are each hydrogen.

[0092] In some embodiments, R 23 is hydroxyl and n1 is 1 or 2.

[0093] In some embodiments, R21 is a substituted C6 aryl, provided that the aryl is substituted with at least two R 25 is replaced by R 25 If two of these are on adjacent atoms, then at least one (C6-C 10 ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R 15 forming a monocyclic or bicyclic 5-10 membered heteroaryl which may be optionally and independently substituted by R 21 is a substituted 5- or 6-membered heteroaryl, provided that said heteroaryl is substituted with at least two R 25 is replaced by R 25 are on adjacent atoms, it is a C6 aryl, or at least one (C6-C 10 ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R 15 forming an optionally independently substituted monocyclic or bicyclic 5-10 membered heteroaryl; n1 is 1.

[0094] In some embodiments, R 21 is (C6-C 10 ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl, wherein the aryl or heteroaryl is selected from the group consisting of one or more of the same or different R 25 and optionally independently substituted by groups, R 25 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, -O(CH2)(C6-C 10 )aryl, —O(CH2)-5- or 6-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N and S, (C6-C 10)aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C-C)cycloalkyl, and 4-7 membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R 15 and optionally further substituted independently by groups, n1 is 1.

[0095] In some embodiments, the compound of Formula II has Formula IIa, IIb, or IIc:

[0096] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0097] In some embodiments, R 21 is a substituted C6 aryl, provided that the aryl is substituted with at least two R 25 is replaced by R 25 If two of these are on adjacent atoms, then at least one (C6-C 10 ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R 15 forming a monocyclic or bicyclic 5-10 membered heteroaryl which may be optionally and independently substituted by R 21 is a substituted 5- or 6-membered heteroaryl, provided that said heteroaryl is substituted with at least two R 25 is replaced by R 25 are on adjacent atoms, it is a C6 aryl, or at least one (C6-C 10 ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R 15 and forming an optionally independently substituted monocyclic or bicyclic 5-10 membered heteroaryl.

[0098] Representative compounds of the present invention have the following structure:

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[0147] [ka]

[0148] [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0149] Compounds 9-12, 18, 26-27, 42-64, 67-69, 78-202, 209, 213-218, 221-224, and 226-233 are encompassed by Formula I. Compounds 1-8, 13-17, 19-25, 28-41, 65-66, 70-77, 203-208, 210-212, 219-220, 225, 234-258, and 260-287 are encompassed by Formula II.

[0150] The compounds of the present invention may be in the form of free acid or free base, or in the form of a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" in the context of a salt refers to a relatively non-toxic salt of a compound that does not abolish the biological activity or properties of the compound. That is, a compound in salt form can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or interacting in a harmful manner with any of the other components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to the product obtained by reacting a 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 hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, or p-toluenesulfonate. 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 aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts.

[0151] The compounds of the present invention may have at least one chiral center and therefore, as used herein, may be in the form of stereoisomers, which 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 compounds with multiple chiral centers that are not mirror images of one another (diastereoisomers). The chiral centers of a compound may undergo epimerization in vivo. Therefore, for these compounds, administration of the (R-) form of a compound is considered equivalent to administration of the (S-) form of the compound. Thus, the compounds of the present invention may be prepared and used in the form of a single isomer, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0152] In some embodiments, the compounds are isotopic derivatives because they have at least one desired isotopic substitution of an atom at a level above the natural abundance of the isotope, i.e., enriched. In one embodiment, the compounds contain deuterium or multiple deuterium atoms. Deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances.

[0153] The compounds of formula (I) and (II) may also be in the form of N-oxides, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, prodrugs of the compounds, tautomers, and unsolvated and solvated (e.g., hydrated) forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0154] The compounds of the present invention may be prepared by crystallization under different conditions and may exist as one or a combination of polymorphic forms of the compound. For example, different polymorphs can be identified and / or prepared by performing crystallization at different temperatures, or by using various cooling modes ranging from very fast to very slow cooling during crystallization, or by using different solvents or different solvent mixtures for recrystallization. Polymorphs can also be obtained by heating or melting the compound followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and / or other known techniques.

[0155] In some embodiments, the pharmaceutical composition comprises a co-crystal of a compound of the present invention. As used herein, the term "co-crystal" refers to a stoichiometric multi-component system comprising a compound of the present invention and a co-crystal former, wherein the compound of the present invention and the co-crystal former are linked by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that can form an intermolecular interaction with a compound of the present invention and co-crystallize therewith. Representative examples of co-crystal formers 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-aminosalicyclic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0156] Synthesis method In another aspect, the present invention relates to methods for preparing the compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers. Generally, the compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers may be prepared by any process known to be applicable to the preparation of chemically-related compounds. The compounds of the present invention will be better understood in connection with the synthetic schemes described in the various examples, which illustrate non-limiting methods by which the compounds of the present invention may be prepared.

[0157] Pharmaceutical Composition Another aspect of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a 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," as known in the art, refers to a pharmaceutically acceptable material, composition, or vehicle suitable for administering a compound of the present invention to a mammal. Suitable carriers can 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, which function to carry or transport a compound from one organ or part of the body to another. A carrier is "acceptable" in the sense of being physiologically inert, compatible with the other ingredients of the formulation, and not harmful to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0158] 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 conventional mixing, dissolving, granulating, dragee-making, wet-milling, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. A.R. Gennaro, Lippincott Williams & Wilkins, 2000, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 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, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). Generally, the most appropriate administration route will depend on various factors, including, for example, the nature of the agent (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.

[0159] In some embodiments, the compounds are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0160] Thus, 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 in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles, or nanoparticles, syrups, and elixirs); 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, intermediate, or sustained release.

[0161] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate, and additional carriers or excipients, such as a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked calcium carbonate, and the like). The formulation may be mixed with disintegrating agents such as 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 accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite; 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 contain buffering agents. Similar types of solid compositions can also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings. They may further contain opacifying agents.

[0162] In some embodiments, the compound of the present invention can be formulated into hard or soft gelatin capsules.Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose and croscarmellose sodium.The gelatin shell can contain gelatin, titanium dioxide, iron oxide and coloring agent.

[0163] The liquid dosage form for oral administration includes solution, suspension, emulsion, microemulsion, syrup and elixir.In addition to compound, liquid dosage form can contain aqueous or non-aqueous carriers (depending on the solubility of 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, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and their mixtures.Oral composition can also contain excipients, such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and fragrances.

[0164] Injectable preparations for parenteral administration may include sterile aqueous or oily suspensions. These can be formulated according to standard techniques using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations 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 solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. The effect of a compound can be prolonged by delaying its absorption, which can be achieved by using a liquid suspension with poor water solubility or a crystalline or amorphous material. Prolonged absorption of a compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oil vehicle.

[0165] In certain embodiments, the compounds of the present invention can be administered locally rather than systemically, for example, by injecting the conjugate directly into an organ, often in a depot or sustained-release formulation. In certain embodiments, long-acting formulations are administered by infusion (e.g., subcutaneously or intramuscularly) or intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). The release rate of the compound can be controlled by varying the ratio of compound to polymer and the properties of the particular polymer used. Depot injectable formulations can also be prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ.

[0166] The compositions may be formulated for buccal or sublingual administration and examples include tablets, lozenges and gels.

[0167] The compounds of the present invention can be formulated for administration by inhalation.Various forms suitable for administration by inhalation include aerosol, mist or powder.The pharmaceutical composition can be delivered in the form of 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 to deliver a metered amount.In some embodiments, capsules and cartridges containing, for example, gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0168] The compounds of the present invention can be formulated for topical administration, which as used herein refers to intradermal administration of the formulations of the invention to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0169] The representative examples of carriers useful for formulating compounds for topical application include solvents (e.g., alcohol, polyalcohol, water), creams, lotions, ointments, oils, plasters, 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.Cream can also contain nonionic surfactants, such as polyoxy-40-stearate.

[0170] In some embodiments, topical formulations can also contain excipients, such as penetration enhancers.These agents can transport pharmacologically active compounds through the stratum corneum, preferably to the epidermis or dermis with little or no systemic absorption.A wide variety of compounds have been evaluated for their effectiveness in improving the penetration rate of drugs through the skin.For example, see Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which summarizes 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). Representative 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-decylmethyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate and propylene glycol monooleate), and N-methylpyrrolidone.

[0171] Representative examples of other excipients that may be included in topical and other types of formulations (to the extent they are compatible) include preservatives, antioxidants, moisturizers, 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 citric acid. Suitable moisturizers include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citrate buffer, hydrochloric acid buffer, and lactic acid buffer. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0172] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches, where the compound is formulated in a lipophilic emulsion or buffered aqueous solution and dissolved and / or dispersed in a polymer or adhesive. Patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoretic patches. Transdermal patches can provide controlled delivery of compounds, and the absorption rate can be slowed by using a rate-controlling membrane or by trapping the compound within a polymer matrix or gel. Absorption enhancers can be used to increase absorption, and examples include pharmaceutically acceptable absorbable solvents that aid passage through the skin.

[0173] Ophthalmic preparations include eye drops.

[0174] Preparations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. 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, a mixture of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof.All of these are solid at ambient temperature but liquid at body temperature, so they melt in the rectum or vaginal cavity and release the compound.

[0175] Dosage As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof that is effective in producing a desired therapeutic response in a patient suffering from a disease or disorder involving IKZF2 (Helios) and that would benefit from IKZF2 degradation. Thus, the term "therapeutically effective amount" includes an amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, when administered, that is sufficient to induce positive changes in the disease or disorder being treated, or to prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject, or simply kill or inhibit the growth of diseased cells, or reduce the amount of IKZF2 in diseased cells.

[0176] The total daily dosage of compound and its method of use can be determined according to standard medical practice, for example, by attending physician with sound medical judgment.The specific therapeutically effective dose for any specific subject will depend on various factors, including the disease or disorder being treated and its severity (for example, its current state); the activity of the compound being used; the specific composition being used; the age, weight, general health, sex and diet of subject; the administration time, route of administration and excretion rate of the compound being used; treatment period; the drug that is used in combination with or simultaneously with the specific compound being used; and similar factors known in the medical field (for example, see Hardman et al., eds., Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Edition, McGraw-Hill Press, 155-173, 2001).

[0177] The compounds of the present invention may be effective over a wide dosage range. In some embodiments, the total daily dose (e.g., for an adult) 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 about 400 mg / day, about 1 to about 50 mg / day, about 5 to about 40 mg / day, and in other embodiments, about 10 to about 30 mg / day. Individual doses may be formulated to contain the desired dosage depending on the number of times the compound is administered per day. For example, capsules may be formulated containing about 1 to about 200 mg of compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the compounds may be administered at doses ranging from about 0.01 mg to about 200 mg / kg body weight per day. In some embodiments, one or more doses per day may be effective, with doses ranging from 0.1 to 100, e.g., 1 to 30 mg / kg per day. By way of 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.

[0178] How to use In some aspects, the present invention relates to a method for treating a disease or disorder involving IKZF2, the method involving administering to a subject in need thereof 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.

[0179] Generally, diseases or disorders that may be suitable for treatment with the compounds of the present invention involve IKZF2 or other functionally abnormal IKZF2 activity compared to non-pathological conditions. A "disease" is generally considered to be a subject's health condition in which the subject is unable to maintain homeostasis and, unless the disease is improved, the subject's health will continue 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 favorable than in the absence of the disorder. If left untreated, the disorder does not necessarily cause further deterioration of the subject's health condition. In some embodiments, the compounds of formula (I) and (II) may be useful for treating cell proliferative diseases and disorders (e.g., cancer or benign neoplasms). As used herein, the term "cell proliferative disease or disorder" refers to a condition characterized by unregulated or abnormal cell proliferation, or both, including non-cancerous conditions such as neoplasms, pre-cancerous conditions, benign tumors, and cancers.

[0180] The term "subject" (or "patient") as used herein includes all members of the animal kingdom susceptible to or suffering from the indicated disease or disorder. In some embodiments, the subject is a mammal, such as a human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as livestock such as cows, horses, sheep, goats, pigs, and other farm animals, and wild animals. A subject "in need" of treatment according to the present invention may be "suffering from or suspected of having" a particular disease or disorder, may have been positively diagnosed, or may otherwise exhibit a sufficient number of risk factors, or a sufficient number or combination of signs or symptoms, such that a medical professional can diagnose or suspect the subject has the disease or disorder. Thus, subjects suffering from a particular disease or disorder and subjects suspected of having the disease are not necessarily two distinct populations.

[0181] Exemplary types of non-cancerous (e.g., cell proliferative) diseases or disorders that may be suitable for treatment with the compounds of the invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, cardiac diseases, viral diseases, chronic and acute kidney disease or injury, metabolic diseases, and allergic and genetic diseases.

[0182] Representative examples of specific non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative conditions, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, true erythrocytic anemia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic fever syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, and adult respiratory distress syndrome. , chronic obstructive pulmonary disease, chronic pulmonary inflammation, chronic transplant rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behçet's disease, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile-onset diabetes, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigus, 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, sarcoidosis rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, dermatitis herpetiformis, ulcerative colitis, pancreatic fibrosis, hepatitis, liver fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel disease, pyresis, restenosis, cervicitis, stroke and ischemic injury, neurotrauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leprosy rhinitis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendinitis, synovitis, tenosynovitis neonatorum, herniated, ruptured or prolapsed disc syndrome, osteopetrosis, rhinosinusitis, thrombosis, silicosis, pulmonary sarcosis, bone resorption diseases such as osteoporosis, fibromyalgia, AIDS and other viral diseases such as shingles, herpes simplex type 1 or 2, influenza virus and cytomegalovirus, type 1 and type 2 diabetes, 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-the-cat syndrome, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, interstitial pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, atherosclerosis, arteriosclerosis, amyotrophic lateral sclerosis, asociality, varicose veins, vaginitis, depression, and sudden infant death syndrome.

[0183] In other embodiments, the method relates to treating a subject with cancer. Generally, the compounds of the present invention can be effective in treating carcinomas (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers that affect the blood, including lymphocytes, bone marrow, and / or lymph nodes), such as leukemia, lymphoma, and multiple myeloma. Adult tumors / cancers and pediatric tumors / cancers are included. The cancer can be a tumor that is vascularized, or not yet substantially vascularized, or not vascularized.

[0184] Representative examples of cancer include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's and AIDS-related lymphoma), appendix 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, and urinary bladder cancer.cancer), brain cancer (e.g., glioma and glioblastoma, e.g., brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway 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), true myeloma Polycythemia, lymphoid neoplasms, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), germ cell tumors, ovarian germ cell tumors, head and neck cancer, Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hepatocellular carcinoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, pancreatic islet cell tumors (endocrine pancreas), kidney cancer (e.g., Will tumor, clear cell renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and large cell lung cancer), Waldenstrom's macroglobulinemia, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma, metastatic cervical squamous cell carcinoma of unknown primary, multiple endocrine neoplasia (MEN), myelodysplastic syndrome, essential thrombocythemia, myelodysplastic / myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer (e.g., mouth cancer, lip cancer, oral cavity cancer, tongue cancer, oropharynx cancer, throat cancer, larynx cancer), ovarian cancer (e.g., ovarian epithelial carcinoma) , ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, pituitary tumor, plasma cell neoplasm, pleuroblastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial cancer, uterine sarcoma, endometrial carcinoma), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, urethral cancer, gestational trophoblastic tumor, vaginal cancer, and vulvar cancer.

[0185] Sarcomas that may be treatable with the compounds of the invention include both soft tissue and bone cancers alike, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelioma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (fatty tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), and mesenchymal or mixed mesodermal tumor (mixed connective tissue type).

[0186] In some embodiments, the methods of the present invention involve treating a subject with a cell proliferative disease or disorder of the blood system, liver, brain, lung, colon, pancreas, prostate, ovary, breast, skin, and endometrium.

[0187] As used herein, "cell proliferative diseases or disorders of the blood system" includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, primary myelofibrosis, and essential thrombocythemia. Thus, representative examples of hematological cancers include multiple myeloma, lymphomas (T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., B-cell non-Hodgkin's lymphoma selected from 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's lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, and ALK+ anaplastic large cell lymphoma (ACL). leukemias, myeloid neoplasms and mast cell neoplasms, including lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B-cell non-Hodgkin's lymphoma and relapsed B-cell non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin, e.g., small lymphocytic lymphoma, childhood leukemia, hairy cell leukemia, acute lymphocytic 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.

[0188] As used herein, "liver cell proliferative disease or disorder" includes all forms of cell proliferative disorders that affect the liver.Liver cell proliferative disorders can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), precancerous or precancerous conditions of the liver, benign growths or lesions of the liver, and malignant growths or lesions of the liver, as well as metastatic lesions in tissues and organs other than the liver.Brain cell proliferative disorders can include hyperplasia, metaplasia, hepatic dysplasia, hepatocellular carcinoma, intrahepatic cholangiocarcinoma (cholangiocarcinoma), angiosarcoma, hemangioendothelioma, hepatoblastoma, and secondary liver cancer (metastatic liver cancer).

[0189] As used herein, "brain cell proliferative disease or disorder" includes all forms of cell proliferative disorders that affect the brain.Brain cell proliferative disorders can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and primitive neuroectodermal tumor (medulloblastoma)), precancerous or precancerous conditions of the brain, benign brain growth or lesion, and malignant brain growth or lesion, as well as metastatic lesions in tissues and organs other than the brain.Brain cell proliferative disorders can include brain hyperplasia, metaplasia, and dysplasia.

[0190] As used herein, "pulmonary cell proliferative diseases or disorders" include all forms of cell proliferative disorders affecting lung cells. Pulmonary cell proliferative disorders include lung cancer, precancerous and precancerous conditions of the lung, benign lung growths or lesions, pulmonary hyperplasia, metaplasia, and dysplasia, as well as metastatic lesions in tissues and organs other than the lung. 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. Lung cancer may include "scar carcinoma," bronchioloalveolar 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 types). 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 ROS1 fusion gene, lung adenocarcinoma, and squamous cell lung carcinoma).

[0191] As used herein, "colon cell proliferative diseases or disorders" includes all forms of cell proliferative disorders affecting colon 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 colon neoplasms, carcinoma in situ, typical carcinoid tumors, atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer may be associated with genetic syndromes, such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis. Colon cell proliferative disorders may also be characterized by colonic hyperplasia, metaplasia, or dysplasia.

[0192] As used herein, "pancreatic cell proliferative diseases or disorders" include all forms of cell proliferative disorders affecting pancreatic cells. Pancreatic cell proliferative disorders may include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign pancreatic growths or lesions, and malignant pancreatic growths or lesions, as well as metastatic lesions in tissues and organs other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, 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).

[0193] As used herein, "prostate cell proliferative disease or disorder" includes all forms of prostate cell proliferative disorders that affect the prostate.Prostate cell proliferative disorders can include prostate cancer, prostate precancerous or precancerous conditions, benign prostate growths or lesions, and malignant prostate growths or lesions, as well as metastatic lesions in tissues and organs other than the prostate.Prostate cell proliferative disorders can include prostate hyperplasia, metaplasia, and dysplasia.

[0194] As used herein, "ovarian cell proliferative diseases or disorders" include all forms of cell proliferative disorders affecting cells of the ovary. Cell proliferative disorders of the ovary can include precancerous or precancerous conditions of the ovary, benign ovarian growths or lesions, ovarian cancer, and metastatic lesions in tissues and organs of the body other than the ovaries. Cell proliferative disorders of the ovary can include ovarian hyperplasia, metaplasia, and dysplasia.

[0195] As used herein, "cell proliferative diseases or disorders of the breast" include all forms of cell proliferative disorders affecting breast cells. Cell proliferative disorders of the breast can include breast cancer, precancerous or precancerous conditions of the breast, benign growths or lesions of the breast, and metastatic lesions in tissues and organs of the body other than the breast. Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0196] As used herein, "cell proliferative diseases or disorders of the skin" includes all forms of cell proliferative disorders affecting skin cells. Cell proliferative disorders of the skin can include precancerous or precancerous conditions of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions in tissues and organs of the body other than the skin. Cell proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.

[0197] As used herein, "endometrial cell proliferative diseases or disorders" include all forms of cell proliferative disorders affecting endometrial cells. Endometrial cell proliferative disorders may include precancerous or precancerous conditions of the endometrium, benign endometrial proliferations or lesions, endometrial cancer, and metastatic lesions in tissues and organs of the body other than the endometrium. Endometrial cell proliferative disorders may include endometrial hyperplasia, metaplasia, and dysplasia.

[0198] In some embodiments, the compounds of the present invention can be used to treat T-cell leukemia or T-cell lymphoma.

[0199] In some embodiments, the compounds of the present invention can be used to treat Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0200] In some embodiments, the compounds of the present invention can be used to treat myeloid leukemia.

[0201] In some embodiments, the compounds of the present invention can be used to treat non-small cell lung cancer (NSCLC).

[0202] In some embodiments, the compounds of the present invention can be used to treat melanoma.

[0203] In some embodiments, the compounds of the present invention can be used to treat triple-negative breast cancer (TNBC).

[0204] In some embodiments, the compounds of the present invention can be used to treat nasopharyngeal carcinoma (NPC).

[0205] In some embodiments, the compounds of the present invention can be used to treat microsatellite-stable colorectal cancer (mssCRC).

[0206] In some embodiments, the compounds of the present invention can be used to treat thymoma.

[0207] In some embodiments, the compounds of the present invention can be used to treat carcinoids.

[0208] In some embodiments, the compounds of the present invention can be used to treat gastrointestinal stromal tumors (GIST).

[0209] The compounds of the present invention and their pharmaceutically acceptable salts and stereoisomers can be administered to patients, e.g., cancer patients, as monotherapy or in combination therapy. Therapy can be "front / first-line," as the initial treatment for patients who have not previously received an anticancer treatment regimen, alone or in combination with other treatments; or "second-line," as the treatment for patients who have previously received an anticancer treatment regimen, either alone or in combination with other treatments; or "third-line," "fourth-line," etc., treatment, alone or in combination with other treatments. Therapy can also be administered to patients who have previously received unsuccessful or partially successful treatments, except for patients who have become non-responsive or intolerant to a particular treatment. Therapy can also be administered as adjuvant treatment, i.e., to prevent cancer recurrence in patients who currently have no detectable disease or after surgical resection of a tumor. Thus, in some embodiments, the compounds can be administered to patients who have received prior therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0210] The methods of the present invention can involve administering a compound of the present invention or a pharmaceutical composition thereof to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the dosing frequency can range from once daily to approximately once every 8 weeks. In some embodiments, the dosing frequency varies from about once daily for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments, involves at least one 28-day cycle comprising daily dosing for 3 weeks (21 days) followed by a 7-day rest period. In other embodiments, the compound can be administered twice daily (BID) over a period of 2.5 days (5 doses total), or once daily (QD) over a period of 2 days (2 doses total). In other embodiments, the compound can be administered once daily (QD) for 5 days.

[0211] 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 simultaneously with at least one other active agent, such as an anticancer agent or regimen, in the treatment of diseases and disorders. In this context, the terms "in combination" and "simultaneously" mean that the agents are administered simultaneously, including substantially simultaneously, in the same or separate dosage form, by the same or separate administration method, or sequentially, for example, as part of the same treatment regimen or by a continuous treatment regimen. Thus, when administered sequentially, the first of the two agents may still be detectable at effective concentrations at the treatment site at the time the second agent begins to be administered. The order and time intervals can be determined so that they can act together (e.g., to synergistically provide a greater benefit than if they were administered in another way). For example, the agents can be administered simultaneously or sequentially in any order at different times. However, if not administered simultaneously, they can be administered sufficiently close in time to provide the desired therapeutic effect, which may be in the form of a synergistic effect. Thus, the terms are not limited to administration of active agents at exactly the same time.

[0212] In some embodiments, a treatment regimen may include administering a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in combination with one or more additional therapeutic agents known for use in treating a disease or disorder (e.g., cancer). The dosage of the additional anticancer therapeutic agent may be the same as or lower than the known or recommended dose. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis of 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 compounds of the present invention are known in the art. See, for example, U.S. Pat. No. 9,101,622 (section 5.2 thereof) and U.S. Pat. No. 9,345,705 B2 (columns 12-18 thereof). Representative examples of additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., antimitotic agents, antiangiogenic agents, antihormonal agents, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogens, signal transduction pathway inhibitors, microtubule inhibitors, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0213] In some embodiments, the compounds of the invention and the additional anticancer therapeutic agent are administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, The anticancer therapeutic agents may be administered at intervals of 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 anticancer therapeutic agents may be administered during a single patient visit.

[0214] In some embodiments, the compounds of the present invention and additional therapeutic agents (e.g., anticancer therapeutic agents) are administered cyclically. For example, in the context of cancer treatment, cyclic therapy involves administering one anticancer therapeutic agent for a certain period of time, followed by administering a second anticancer therapeutic agent for a certain period of time, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one or both of the anticancer therapeutic agents, to avoid or reduce the side effects of one or both of the anticancer therapeutic agents, and / or improve the effectiveness of the therapy. In one example, cyclic therapy involves administering a first anticancer therapeutic agent for a certain period of time, followed by administering a second anticancer therapeutic agent for a certain period of time, optionally followed by administering a third anticancer therapeutic agent for a certain period of time, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one anticancer therapeutic agent, to avoid or reduce the side effects of one anticancer therapeutic agent, and / or improve the effectiveness of the anticancer therapeutic agent.

[0215] In some embodiments, depending on the particular cancer being treated, the compounds of the present invention may be administered with or without other therapeutic agents, such as 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), altretamine (e.g., ovarian cancer), daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphocytic 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's 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), alemtumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphoma), panitumumab (e.g., colorectal cancer), tamoxifen (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, trophoblastic tumor, 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., liver cancer), bortezomib (e.g., multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., , acute lymphoblastic leukemia), Cabometyx (e.g., hepatocellular carcinoma, medullary thyroid carcinoma, and renal cell carcinoma), Keytruda (e.g., cervical cancer, gastric cancer, hepatocellular carcinoma, Hodgkin's lymphoma, melanoma, Merkel cell carcinoma, 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), and regorafenib (e.g., colorectal, gastrointestinal stromal tumor, and hepatocellular carcinoma).

[0216] Medicine Kit The composition of the present invention can be assembled into a kit or pharmaceutical system.The kit or pharmaceutical system according to this aspect of the present invention comprises a carrier or package such as a box, a carton, a tube, etc., in which one or more containers such as a vial, a tube, an ampoule or a bottle containing the compound of the present invention or a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier are tightly enclosed, and the compound and the carrier can be placed in the same or separate containers.The kit or pharmaceutical system of the present invention can also comprise printed instructions for using the compound and the composition.

[0217] These and other aspects of the present invention will be further understood in light of the following examples, which are intended to illustrate particular embodiments of the invention but are not intended to limit its scope, which is defined by the claims. [Example]

[0218] These and other aspects of the present invention will be further understood in light of the following examples, which are intended to illustrate particular embodiments of the invention but are not intended to limit its scope, which is defined by the claims.

[0219] Example 1: Synthesis of 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)-N-phenylbenzenesulfonamide (79) - General Method A

[0220] [ka]

[0221] tert-Butyl-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate A mixture of 3-(6-bromo-3-oxo-1H-isoindol-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 (DMF) (20 mL) was stirred at 90° C. for 4 hours. The reaction mixture was then concentrated to give a residue, which was then dissolved in ethyl acetate (EtOAc) (500 mL). Water (500 mL) was added, and the layers were separated. Solid sodium chloride was added to the aqueous phase with vigorous stirring until saturation with NaCl was reached (solid NaCl was visible but not dissolved). Undissolved NaCl was removed, and the aqueous phase was further extracted with tetrahydrofuran (THF) (500 mL × 2). The combined organic layers were dried and concentrated to give the crude product, which was purified using silica gel column chromatography (petroleum ether / EtOAc = 1:1 to 100% EtOAc) to give the title compound as a yellow solid (1.1 g, 36%). ESI-MS (EI + , m / z):426.3.

[0222] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate To a mixture of tert-butyl-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g, 2.4 mmol) and 10% Pd / C (400 mg) was added DMF (10 mL). The suspension was stirred under a hydrogen atmosphere at room temperature (rt) for 16 h. The reaction mixture was then diluted with dichloromethane (DCM), filtered, and concentrated to give the title compound as a yellow solid (1.0 g, 91%), which was used without further purification. ESI-MS (EI + , m / z):428.3.

[0223] 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione To tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (1.0 g, 2.3 mmol) was added 4.0 M HCl / dioxane (6 mL), the reaction vessel was closed, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (1.0 g, 100%), which was used without further purification. ESI-MS (EI + , m / z):328.3.

[0224] 3-(chloromethyl)-N-phenylbenzenesulfonamide To a room temperature solution of aniline (46 mg, 0.491 mmol) in DCM (4 mL) was added pyridine (35.3 mg) and the reaction mixture was cooled to 0 °C. A solution of 3-(chloromethyl)benzenesulfonyl chloride (100 mg, 0.447 mmol) in DCM (2 mL) was then added and the reaction was stirred at 0 °C for 4 h. The reaction mixture was then partitioned between EtOAc and water, and the pH was adjusted to 4-5 by adding citric acid. The combined organic phase was washed with water and brine, dried over Na SO , and concentrated. The crude product was purified by column chromatography (petroleum ether / EtOAc = 3 / 1) to give the title compound (110 mg) as a yellow oil. LC-MS (EI - , m / z):280.

[0225] 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)-N-phenylbenzenesulfonamide (79) To a solution of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (117 mg, 0.36 mmol), triethylamine (TEA) (360 mg, 3.6 mmol) in DMF (2 mL) was added 3-(chloromethyl)-N-phenylbenzenesulfonamide (100 mg, 0.36 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 16 hours. The reaction was then concentrated, and the residue was purified by preparative HPLC to give the title compound (56.1 mg, 32%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 10.9(s,1H),10.24(br,1H),8.16(d,J=8.0 Hz,1H),7.66(d,J=8.0 Hz,1H),7.54-7.48(m,3H),7.41(t,J=8.0 Hz,1H),7.20(t,J=8.0 Hz,1H),7.08(d,J=8.0 Hz,2H),7.00(t,J=4.0 Hz,1H),5.0(dd,J=12.0,4.0 Hz,1H),4.46-4.28(m,2H),3.55(d,J=8.0 Hz,2H),2.91-2.87(m,1H),2.78(d,J=12.0 Hz,2H),2.64-2.58(m,2H),2.45-2.34(m,1H),2.05-1.98(m,3H),1.77-1.63(m,4H).ESI-MS(EI + , m / z):573.3.

[0226] Example 2: Synthesis of N-(3-chloro-4-methylphenyl)-4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxamide (36)

[0227] [ka]

[0228] To a solution of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.25 mmol), TEA (252 mg, 10.0 mmol) in DCM (5 mL) was added a solution of 2-chloro-4-isocyanato-1-methylbenzene (41 mg, 0.25 mmol) in DCM (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then concentrated, and the crude product was purified by preparative HPLC to give the title compound (17.1 mg, 13%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6):δ 11.97(s,1H),8.58(s,1H),7.66(s,1H),7.55(s,1H),7.51(d,J=4.0 Hz,1H),7.45(d,J=8.0 Hz,1H),7.38(dd,J=12.0,8.0 Hz,1H),7.28(d,J=8.0 Hz,1H),5.12-5.07(m,1H),4.43(d,J=2.0 Hz,1H),4.30(t,J=4.0 Hz,3H),2.96-2.90(m,4H),2.63(d,J=12.0 Hz,1H),2.48-2.37(m,1H),2.31(s,3H),2.04-2.00(m,1H),1.85(d,J=12.0 Hz,2H),1.69-1.60(m,2H).ESI-MS(EI + , m / z):495.2.

[0229] Example 3: Synthesis of 3-(1-oxo-5-(2-phenylpiperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (72) - General Method B

[0230] [ka]

[0231] Benzyl 4-hydroxy-6-phenylpyridine-1(2H)-carboxylate To anhydrous THF (400 mL) in a round-bottom flask under nitrogen, PhMgBr (91.63 mL, 91.63 mmol) was added, and the resulting solution was cooled to −25° C. 4-Methoxypyridine (10.00 g, 91.63 mmol) was added, followed by CbzCl (15.58 g, 91.32 mmol). The mixture was stirred under N at −25° C. for 1.5 h. The mixture was slowly quenched with aqueous HCl (2 M, 60 mL) at −25° C. After stirring for 15 min, the mixture was diluted with H2O (80 mL) and extracted with EtOAc (240 mL). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography (petroleum ether: EtOAc = 5:1) to give the title compound as a white solid (25 g, 89%). ESI-MS (EI + , m / z):308.10.

[0232] Benzyl 4-hydroxy-2-phenylpiperidine-1-carboxylate and Benzyl 4-oxo-2-phenylpiperidine-1-carboxylate To a solution of benzyl 4-hydroxy-6-phenylpyridine-1(2H)-carboxylate (20.0 g, 65.15 mmol) in THF (400 mL) was added L-selectride (162.87 mL, 162.87 mmol) dropwise at −25° C. under N. The mixture was stirred at −25° C. under N for 3 h. The mixture was quenched with aqueous NaHCO (3%, 400 mL) at −25° C. and then further diluted with HO (100 mL). The aqueous phase was extracted with EtOAc (1.2 L). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography to give benzyl 4-hydroxy-2-phenylpiperidine-1-carboxylate as a yellow oil (15.6 g, 74%) and benzyl 4-oxo-2-phenylpiperidine-1-carboxylate as a yellow oil (4 g, 20%). ESI-MS (EI + , m / z):312.20.

[0233] To a solution of 4-hydroxy-2-phenylpiperidine-1-carboxylate (15.6 g, 50.16 mmol) in DMSO (90 mL) was added IBX (42.14 g, 150.50 mmol). The mixture was stirred at 60 °C for 16 h. The mixture was filtered, and the filtrate was diluted with HO (450 mL) and extracted with EtOAc (800 mL). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography to give benzyl 4-oxo-2-phenylpiperidine-1-carboxylate as a yellow oil (10.5 g, 68%). ESI-MS (EI + , m / z):310.15.

[0234] Benzyl 6-phenyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate To a solution of benzyl 4-oxo-2-phenylpiperidine-1-carboxylate (1.0 g, 3.24 mmol) in THF (45 mL) was added LiHMDS (9.27 mL, 9.27 mmol) dropwise at −78° C. under N. The mixture was warmed to 0° C., stirred for 1 h, and then cooled to −78° C. To the mixture was added N,N-bis(trifluoromethylsulfonyl)aniline (1.72 g, 3.55 mmol) in THF (45 mL). The reaction mixture was slowly warmed to room temperature and stirred for 16 h under N. The mixture was quenched with aqueous NH.sub.4Cl (saturated, 40 mL) at 0° C., diluted with HO (20 mL), and extracted with EtOAc (80 mL). The combined organic layers were concentrated, and the residue was purified by silica gel chromatography (petroleum ether: EtOAc = 20:1) to give the title compound as a yellow oil (0.5 g, 35%). ESI-MS(EI + , m / z):442.15.

[0235] Benzyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-6-phenyl-3,6-dihydropyridine-1(2H)-carboxylate To a solution of compound benzyl 6-phenyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (340 mg, 0.77 mmol) and 3-[3-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-isoindol-2-yl]piperidine-2,6-dione (238 mg, 0.64 mmol) in DMF (4 mL) was added Pd(t-BuP) (65 mg, 0.13 mmol) and EtNi-Pr (165 mg, 1.28 mmol). The reaction mixture was heated at 110° C. and stirred in a microwave reactor for 16 hours. The reaction mixture was then concentrated. The residue was suspended in DCM (30 mL) and then filtered. The filtrate was concentrated, and the residue was purified first by silica gel column chromatography (DCM:MeOH=99:1) and then by preparative thin-layer chromatography (DCM:MeOH=30:1) to give the title compound as a yellow solid (90 mg). ESI-MS (EI + , m / z):536.30.

[0236] 3-(1-oxo-5-(2-phenylpiperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (72) To a solution of benzyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-6-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.15 mmol) in THF (7 mL) was added 10% Pd / C (40 mg) and 10% Pd(OH) / C (40 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was then filtered, and the filtrate was concentrated to give the crude product as a yellow solid, which was purified by preparative HPLC to give the title compound as a white solid (4.3 mg, 7%). 1H NMR(400 MHz,DMSO-d6):δ 10.99(s,1H),9.12(d,J=8.0 Hz,1H),8.11(d,J=12.0 Hz,1H),7.71(d,J=8.0 Hz,1H),7.56(t,J=4.0 Hz,1H),7.43-7.50(m,3H),5.13-5.09(m,1H),4.48-4.39(m,3H),3.52(d,J=8.0 Hz,1H),3.24-3.20(m,1H),2.96-2.87(m,1H),2.67-2.58(m,1H),2.45-2.32(m,1H),2.18-1.96(m,5H).ESI-MS(EI + , m / z):404.25.

[0237] Example 4 Synthesis of 3-(1-oxo-5-(1-((2-phenoxypyridin-4-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (43)

[0238] [ka]

[0239] 2-phenoxyisonicotinonitrile Phenol (6.8 g, 72.2 mmol) and CsCO (35.3 g, 108.3 mmol) were added to a solution of 2-chloroisonicotinonitrile (10 g, 72.2 mmol) in NMP (50 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction was then partitioned between EtOAc (100 mL) and HO (100 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 50 / 1) to give the title compound as a white solid (8.2 g, 57.95%).

[0240] 2-phenoxyisonicotinaldehyde A solution of 2-phenoxyisonicotinonitrile (500 mg, 2.55 mmol) in toluene (10 mL) was stirred at −70° C. for 0.5 h, and then DIBAL-H (5 mL) was slowly added. The mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with NH4Cl (aq.) and water (50 mL) was added. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with DCM / MeOH=30 / 1) to give the title compound as a white solid (220 mg, 43.4%).

[0241] 3-(1-oxo-5-(1-((2-phenoxypyridin-4-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (43) A suspension of 2-phenoxyisonicotinaldehyde (50 mg, 0.25 mmol), 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (82 mg, 0.25 mmol), and NaBH(OAC) (159 mg, 0.75 mmol) in a 1:1 (v:v) solution of DMF (3 mL) and DCM (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and water (25 mL), and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phases were washed with water (25 mL), brine (25 mL), dried over NaSO, and then concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the title compound (3.0 mg, 2.4%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 10.98(s,1H),8.34(s,1H),8.08(d,J=5.2 Hz,1H),7.65(d,J=7.8 Hz,1H),7.51(s,1H),7.46-7.36(m,3H),7.21(t,J=7.4 Hz,1H),7.14-7.10(m,2H),6.98(s,1H),5.10(dd,J=13.4,4.8 Hz,1H),4.42(d,J=17.2 Hz,1H),4.29(d,J=17.2 Hz,1H),3.57(s,2H),2.68-2.56(m,3H),2.42-2.30(m,2H),2.18-2.09(m,2H),2.04-1.95(m,2H),1.82-1.67(m,4H).ESI-MS(EI + ,m / z):511.23.

[0242] Example 5: Synthesis of 3-(1-oxo-5-(1-(3-(pyridin-2-ylamino)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (42) - General Method C

[0243] [ka]

[0244] 3-(pyridin-2-ylamino)phenyl)methanol A solution of 2-bromopyridine (1.0 g, 6.3 mmol), (3-aminophenyl)methanol (0.8 g, 6.3 mmol), and 4-methylbenzenesulfonic acid hydrate (0.1 g, 0.6 mmol) in dioxane (5 mL) was heated in a microwave reactor at 130 °C for 5 min. The reaction was diluted with HO (50 mL) and extracted with EtOAc (100 mL). The phases were separated, the organic phase was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 20 / 1) to give the title compound (300 mg, 23.6%) as a yellow oil.

[0245] 3-(pyridin-2-ylamino)benzaldehyde Manganese(IV) oxide (208 mg, 24.4 mmol) was added to a solution of (3-(pyridin-2-ylamino)phenyl)methanol (240 mg, 1.2 mmol) in DCM (10 mL), and the reaction was stirred at room temperature for 16 h. The reaction was diluted with HO (50 mL) and extracted with EtOAc (2 x 50 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 20 / 1) to give the title compound as a yellow oil (180 mg, 75.6%). ESI-MS (EI+, m / z): 199.09.

[0246] 3-(1-oxo-5-(1-(3-(pyridin-2-ylamino)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (42) 3-(Pyridin-2-ylamino)benzaldehyde was converted to compound 42 using a procedure similar to that described for compound 43 (Example 5). 1 H NMR(400 MHz,DMSO-d6)δ 10.97(s,1H),8.99(s,1H),8.21-8.11(m,2H),7.72-7.67(m,1H),7.64(d,J=7.8 Hz,1H),7.55-7.52(m,2H),7.49(s,1H),7.40(dd,J=7.9,1.4 Hz,1H),7.20(t,J=7.8 Hz,1H),6.87-6.80(m,2H),6.74-6.71(m,1H),5.10(dd,J=13.3,5.1 Hz,1H),4.42(d,J=17.2 Hz,1H),4.28(d,J=17.2 Hz,1H),2.98(d,J=11.5 Hz,2H),2.94-2.84(m,1H),2.59(d,J=18.1 Hz,2H),2.39(dd,J=13.1,4.5 Hz,1H),2.09(t,J=11.3 Hz,2H),2.03-1.93(m,1H),1.80-1.67(m,4H).ESI-MS(EI + , m / z):510.35.

[0247] Example 6: Synthesis of 1-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)phenoxy)methyl)cyclopropane-1-carbonitrile (45) - General Method D

[0248] [ka]

[0249] (1-Cyanocyclopropyl)methyl methanesulfonate A solution of 1-(hydroxymethyl)cyclopropane-1-carbonitrile (680 mg, 5.15 mmol) in DCM (10 mL) was cooled to 0 °C and stirred for 10 min. TEA (1.56 g, 15.45 mmol) was added, and the reaction was then maintained at 0 °C for 1 h. MsCl (1.18 g, 10.3 mmol) was added slowly, and the reaction was stirred for 16 h. The reaction mixture was diluted with DCM (20 mL) and water (20 mL), and the organic phase was separated and washed with water (20 mL) and brine (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with 1:5 EtOAc / petroleum ether) to give the title compound (420 mg, 46.6%) as a white solid.

[0250] 1-((4-formylphenoxy)methyl)cyclopropane-1-carbonitrile To a solution of phenol (474 mg, 3.89 mmol), (1-cyanocyclopropyl)methyl methanesulfonate (680 mg, 3.89 mmol) in DMF (20 mL) was added KCO (1074 mg, 7.78 mmol), and the reaction was stirred at 100 °C for 16 hours. The reaction was then concentrated, and the residue was diluted with EtOAc (50 mL), and the organic phase was washed with water (20 mL) and brine (20 mL). The organic phase was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with EtOAc / petroleum ether = 1 / 3) to give the title compound (300 mg, 38.4%) as a yellow solid.

[0251] 1-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)phenoxy)methyl)cyclopropane-1-carbonitrile (45) 1-((4-formylphenoxy)methyl)cyclopropane-1-carbonitrile was converted to compound 45 using a procedure similar to that described for compound 43 (Example 5). 1 H NMR(400 MHz,DMSO-d6):δ 10.98(s,1H),8.13(s,1H),7.63(d,J=7.8 Hz,1H),7.48(s,1H),7.38(dd,J=7.9,1.3 Hz,1H),7.27(d,J=8.5 Hz,2H),6.97-6.87(m,2H),5.09(dd,J=13.2,5.1 Hz,1H),4.45-4.20(m,2H),4.00(s,2H),3.57(s,2H),3.07-2.82(m,3H),2.62(dd,J=28.5,14.3 Hz,3H),2.37(qd,J=13.4,4.6 Hz,1H),2.18(t,J=11.5 Hz,2H),2.03-1.91(m,1H),1.84-1.64(m,4H),1.40-1.33(m,2H),1.20-1.10(m,2H).ESI-MS(EI+,m / z):513.15.

[0252] Example 7: Synthesis of 3-(1-oxo-5-(1-(3-(phenylamino)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (46) - General Method E

[0253] [ka]

[0254] 3-(Phenylamino)benzaldehyde A solution of aniline (1.0 g, 10.7 mmol), 3-bromobenzaldehyde (2.0 g, 10.7 mmol), Pd(dba) (600 mg, 0.64 mmol), x-phos (600 mg, 1.2 mmol), and KCO (3.0 g, 21.4 mmol) in t-BuOH (50 mL) was stirred overnight at 80° C. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with petroleum ether / EtOAc = 5 / 1) to give the title compound (400 mg, 10%) as a yellow solid.

[0255] 3-(1-oxo-5-(1-(3-(phenylamino)benzyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (46) 3-(Phenylamino)benzaldehyde was converted to compound 46 using a procedure similar to that described for compound 43 (Example 5). 1 H NMR(400 MHz,DMSO-d6)δ 10.98(s,1H),8.15(s,1H),7.64(d,J=7.9 Hz,1H),7.49(s,1H),7.40(d,J=7.8 Hz,1H),7.20(dt,J=20.1,7.9 Hz,3H),7.07(d,J=7.9 Hz,3H),6.96(d,J=8.1 Hz,1H),6.85-6.74(m,2H),5.10(dd,J=13.3,5.0 Hz,1H),4.42(d,J=17.2 Hz,1H),4.28(d,J=17.3 Hz,1H),3.46(s,2H),2.96(d,J=11.3 Hz,2H),2.92-2.85(m,1H),2.69-2.55(m,2H),2.45-2.34(m,1H),2.08(t,J=12.0 Hz,2H),2.02-1.94(m,1H),1.84-1.64(m,4H).ESI-MS(EI+,m / z):509.25.

[0256] Example 8: Synthesis of 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)-N-phenylbenzamide (86) - General Method F

[0257] [ka]

[0258] 3-(chloromethyl)-N-phenylbenzamide To a solution of aniline (100 mg, 1.1 mmol) and 3-(chloromethyl)benzoyl chloride (203 mg, 1.1 mmol) in DCM (2 mL) was added pyridine (261 mg, 3.3 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the crude mixture was purified by silica gel column chromatography (eluted with petroleum ether / EtOAc = 10 / 1) to give the title compound (111 mg, 53.4%) as a white solid.

[0259] 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)methyl)-N-phenylbenzamide (86) A suspension of 3-(chloromethyl)-N-phenylbenzamide (100 mg, 0.41 mmol), 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (133 mg, 0.41 mmol), NaI (149 mg, 0.41 mmol), and EtN (414 mg, 4.1 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the title compound (25 mg) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 10.97(s,1H),10.28(s,1H),8.01-7.86(m,2H),7.77(d,J=8.0 Hz,2H),7.64(t,J=8.2 Hz,1H),7.59-7.48(m,2H),7.38(dt,J=15.6,7.9 Hz,3H),7.11(t,J=7.4 Hz,1H),5.09(dd,J=13.3,5.1 Hz,1H),4.42(d,J=17.3 Hz,1H),4.29(d,J=17.2 Hz,1H),3.86(s,1H),3.12(s,2H),2.88(d,J=12.8 Hz,2H),2.76(s,1H),2.59(d,J=18.2 Hz,1H),2.44-2.33(m,2H),2.02-1.92(m,1H),1.82(d,J=14.9 Hz,3H).ESI-MS(EI + ,m / z):537.24.

[0260] Example 9: Synthesis of 3-(1-oxo-5-(1-((1-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (105) - General Method G

[0261] [ka]

[0262] 2-phenyl-7-vinyl-3,4-dihydroisoquinolin-1(2H)-one A solution of 7-vinyl-3,4-dihydroisoquinolin-1(2H)-one (800 mg, 4.62 mmol), iodobenzene (1886 mg, 9.25 mmol), CuI (351 mg, 1.85 mmol), 1,10-phenanthroline (333 mg, 1.85 mmol), and KPO (2450 mg, 11.56 mmol) in toluene (20 mL) was stirred overnight at 110 °C under nitrogen. The reaction mixture was partitioned between EtOAc (50 mL) and water (20 mL), and the organic phase was washed with water (25 mL), brine (25 mL), dried over NaSO, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane / EtOAc = 10 / 1) to give the title compound (400 mg, 34.7%) as a yellow solid.

[0263] 1-Oxo-2-phenyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde A solution of 2-phenyl-7-vinyl-3,4-dihydroisoquinolin-1(2H)-one (400 mg, 1.60 mmol) in a mixture of DCM (4 mL) and MeOH (10 mL) was stirred at −78° C. for 5 minutes while ozone was bubbled through the reaction. The reaction mixture was then concentrated in vacuo, and the residue was purified by preparative silica gel TLC to afford the title compound as a yellow oil (240 mg, 24.8%).

[0264] 3-(1-oxo-5-(1-((1-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (105) A solution of 1-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinoline-7-carbaldehyde (100 mg, 0.39 mmol), 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (174 mg, 0.48 mmol), and NaBH(OAc) (169 mg, 0.79 mmol) in a mixture of DMF (2 mL) and DCM (2 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated to approximately 2 mL (removing most of the DCM) and filtered. The filtrate was purified by preparative HPLC to give the title compound as a white solid (30 mg, 13.3%). 1 H NMR(400 MHz,DMSO-d6)δ 10.96(s,1H),7.91(s,1H),7.65-7.61(m,1H),7.51-7.47(m,2H),7.41(q,J=6.3,4.8 Hz,6H),7.33(d,J=7.8 Hz,1H),7.26(tt,J=5.8,2.4 Hz,1H),5.09(dd,J=13.3,5.0 Hz,1H),4.45-4.23(m,2H),3.95(t,J=6.4 Hz,2H),3.56(s,2H),3.11(t,J=6.1 Hz,2H),2.91(dd,J=21.5,11.2 Hz,3H),2.70-2.55(m,2H),2.38(qd,J=13.1,4.3 Hz,1H),2.10(t,J=11.3 Hz,2H),2.03-1.94(m,1H),1.82-1.65(m,4H).ESI-MS(EI + ,m / z):549.28.

[0265] Example 10: Synthesis of 3-(5-(1-(3-((3-(dimethylphosphoryl)phenyl)amino)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (135) - General Method H

[0266] [ka]

[0267] 3-((3-(dimethylphosphoryl)phenyl)amino)benzaldehyde A solution of (3-aminophenyl)dimethylphosphine oxide (100 mg, 0.59 mmol), 3-iodobenzaldehyde (165 mg, 0.71 mmol), Pd(OAc) (6.6 mg, 0.03 mmol), Xantphos (17 mg, 0.03 mmol), and KPO (150 mg, 0.71 mmol) in DMF (2 mL) was stirred for 16 h at 70° C. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (eluted with petroleum ether / EtOAc = 4 / 1) to give the title compound as a white solid (50 mg, 26.4%).

[0268] 3-(5-(1-(3-((3-dimethylphosphoryl)phenyl)amino)benzyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (135) 3-((3-(dimethylphosphoryl)phenyl)amino)benzaldehyde was converted to compound 135 using a procedure similar to that described for compound 43 (Example 5). 1 H NMR:(400 MHz,DMSO-d6)δ 10.99(s,1H),8.39(s,1H),7.64(d,J=7.9 Hz,1H),7.49(s,1H),7.48-7.42(m,1H),7.40(m,1H),7.34(m,1H),7.21(t,J=7.8 Hz,2H),7.17-7.10(m,2H),6.99(m,1H),6.84(m,1H),5.10(m,1H),4.42(d,J=17.2 Hz,1H),4.28(d,J=17.2 Hz,1H),3.47(s,2H),2.96(d,J=10.7 Hz,2H),2.92-2.85(m,1H),2.61(t,J=16.2 Hz,2H),2.39(m,1H),2.13-2.05(m,2H),2.02-1.95(m,1H),1.74(d,J=16.2 Hz,4H),1.63(s,3H),1.60(s,3H).ESI-MS(EI + , m / z):585.26.

[0269] Example 11: Synthesis of 3-(1-oxo-5-(1-((3-oxo-2-phenylisoindolin-5-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (146) - General Method I

[0270] [ka]

[0271] Dimethyl 4-(bromomethyl)isophthalate A solution of dimethyl 4-methylisophthalate (15.3 g, 73.48 mmol), NBS (15.69 g, 88.18 mmol), and BPO (1.78 g, 7.35 mmol) in CCl4 (210 mL) was stirred for 16 h at 85° C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with petroleum ether / EtOAc = 80 / 1) to give the title compound as a yellow solid (10 g, 48%).

[0272] Methyl 3-oxo-2-phenylisoindoline-5-carboxylate A solution of dimethyl 4-(bromomethyl)isophthalate (10 g, 34.71 mmol), aniline (3.23 g, 34.71 mmol), and DBU (10.57 g, 69.42 mmol) in MeOH (200 mL) was stirred for 16 h at 70° C. The solvent was removed under reduced pressure to give the crude title compound as a yellow solid (5.07 g, 54.5%), which was used without further purification.

[0273] 6-(hydroxymethyl)-2-phenylisoindolin-1-one A solution of methyl 3-oxo-2-phenylisoindoline-5-carboxylate (5.07 g, 18.98 mmol) in THF (40 mL) was stirred at 0 °C, and then LiBH (37.96 mL, 75.92 mmol, 2 M) was slowly added. After stirring at 0 °C for 5 min, the reaction was warmed to room temperature and stirred overnight. The reaction mixture was partitioned with DCM / MeOH (200 mL, v:v, 20:1) and water (50 mL), and the organic phase was separated and washed with brine (40 mL). The organic phase was concentrated, and the residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 40 / 1) to give the title compound as a white solid (3 g, 66.6%).

[0274] 6-(chloromethyl)-2-phenylisoindolin-1-one Thionyl chloride (198.87 mg, 1.67 mmol) was added to a solution of 6-(hydroxymethyl)-2-phenylisoindolin-1-one (100 mg, 0.42 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give the crude title compound (100 mg) as a white solid, which was used without further purification.

[0275] 3-(1-oxo-5-(1-((3-oxo-2-phenylisoindolin-5-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (146) A solution of 6-(chloromethyl)-2-phenylisoindolin-1-one (80 mg, 0.31 mmol), 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (112.9 mg, 0.31 mmol), NaI (46.53 mg, 0.31 mmol) and TEA (314.12 mg, 3.1 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was then purified by preparative HPLC to give the title compound as a white solid (16.6 mg, 9.7%). 1H NMR(400 MHz,DMSO-d6)δ 11.00(s,1H),7.94(d,J=8.7 Hz,2H),7.76(s,1H),7.69-7.63(m,3H),7.54(s,1H),7.49-7.43(m,3H),7.20(t,J=7.4 Hz,1H),5.15-5.10(m,1H),5.04(s,2H),4.44(d,J=17.4 Hz,1H),4.30(d,J=17.2 Hz,1H),3.67(s,2H),2.98(d,J=11.6 Hz,2H),2.75-2.61(m,2H),2.58(d,J=11.8 Hz,1H),2.41(dd,J=11.4,5.1 Hz,1H),2.15(t,J=11.0 Hz,2H),2.05-1.97(m,1H),1.80(s,4H).

[0276] Example 12: Synthesis of 3-(1-oxo-5-(1-((1-oxo-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (183) - General Method J

[0277] [ka]

[0278] 7-Bromo-3,4-dihydronaphthalen-1(2H)-one oxime 7-Bromo-3,4-dihydronaphthalen-1(2H)-one (10.0 g, 44.43 mmol), NHOH in EtOH (200 mL) . A solution of HCl (3.4 g, 48.87 mmol) and KOAc (6.54 g, 66.64 mmol) was stirred under N at 80° C. for 2 h. The solution was concentrated and the solid residue was filtered, washed with water, and dried to give the crude title compound (14.3 g), which was used without further purification.

[0279] 8-Bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one A solution of 7-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (5.00 g, 20.83 mmol) in SOCl (37.5 mL) was stirred at 50 °C for 2 h. The reaction was concentrated, and the residue was cooled to 0 °C. Saturated aqueous NaHCO was added slowly, and then the aqueous suspension was extracted with EtOAc (200 mL). The layers were separated, and the organic phase was dried and concentrated under reduced pressure. Purification by silica gel column chromatography gave the title compound (3.6 g).

[0280] 8-Vinyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one A solution of 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (2.60 g, 10.9 mmol), trifluoro(vinyl)-borane-potassium salt (2.93 g, 21.8 mmol), N-cyclohexyl-N-methylcyclohexanamine (4.26 g, 21.8 mmol), and Pd(ddpf)Cl (798.6 mg, 1.09 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C under N for 16 h. The solution was partitioned with EtOAc (100 mL) and HO (30 mL). The organic phase was separated, washed with water (2 × 30 mL), dried over NaSO, and concentrated to give the crude product. Purification by silica gel column chromatography afforded the title compound (2.8 g).

[0281] 2-phenyl-8-vinyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one A solution of 8-vinyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (800.0 mg, 4.28 mmol), iodobenzene (4.36 g, 21.40 mmol), CuI (325.1 mg, 1.71 mmol), 1,10-phenanthroline (308.0 mg, 1.71 mmol), and KPO (2.72 g, 12.83 mmol) in 1,4-dioxane (16 mL) was stirred at 110 °C under N for 16 h. The solution was partitioned with EtOAc (100 mL) and HO (30 mL). The organic phase was separated, washed with water (2 × 30 mL), dried over NaSO, and concentrated to give the crude product. Purification by silica gel column chromatography afforded the title compound (600 mg).

[0282] 1-Oxo-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-8-carbaldehyde A solution of 2-phenyl-8-vinyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (300 mg, 1.14 mmol) in MeOH (5 mL) was stirred at −78° C., and ozone gas was bubbled into the reaction mixture for 10 minutes. The reaction was then warmed to room temperature and concentrated under reduced pressure to give a residue. Purification by silica gel preparative TLC (petroleum ether: EtOAc = 1:1) afforded the title compound (100 mg).

[0283] 3-(1-oxo-5-(1-((1-oxo-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (183) 1-Oxo-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-8-carbaldehyde was converted to compound 183 using a procedure similar to that described for compound 43 (Example 5). 1H NMR(400 MHz,DMSO-d6)δ 10.96(s,1H),7.63(d,J=7.8 Hz,1H),7.54(d,J=1.6 Hz,1H),7.52(s,1H),7.46-7.40(m,6H),7.30-7.26(m,2H),5.08(m,J=13.4,5.1 Hz,1H),4.42(d,J=17.3 Hz,1H),4.28(d,J=17.3 Hz,1H),3.56(s,2H),2.98-2.86(m,6H),2.68-2.58(m,2H),2.38(m,J=13.1,4.6 Hz,1H),2.16-1.92(m,6H),1.82-1.68(m,4H).ESI-MS(EI+,m / z):577.35.

[0284] Example 13: Synthesis of 3-(5-(4-hydroxy-1-((3-oxo-2-phenylisoindolin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200) - General Method K

[0285] [ka]

[0286] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate DIEA (4.8 g, 37.2 mmol) and bis(tri-t-butylphosphine)palladium (1.9 g, 3.72 mmol) were added to a solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (6 g, 18.6 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (22.92 g, 74.4 mmol) in 1,4-dioxane / HO (120 mL, v:v, 20 / 1). The reaction mixture was stirred at 110 °C under a N atmosphere for 4 hours. The reaction mixture was filtered to give a clear organic solution. The solution was concentrated to give a crude residue, which was triturated with DCM / petroleum ether (1:1) to give a solid, which was filtered and dried to give the crude title compound (7.2 g, 91.1%), which was used without further purification.

[0287] tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxypiperidine-1-carboxylate Phenylsilane (2.0 g, 18.3 mmol) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.9 g, 9.2 mmol) and Mn(dpm) (2.8 g, 4.6 mmol) in DCM / iPrOH / DMF (60 mL, v:v:v, 5 / 5 / 1). The reaction mixture was stirred at 0 °C under an O atmosphere for 16 h. A saturated aqueous solution of NaSO (20 mL) was then added, and the mixture was stirred at room temperature for 2 h. Brine (60 mL) was added, and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give the title compound as a yellow solid (1.5 g, 36.9%).

[0288] 3-(5-(4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxypiperidine-1-carboxylate (500 mg, 1.1 mmol) and HCl (4.0 M in 1,4-dioxane, 5 mL) were placed in a sealed flask. The suspension was stirred at room temperature for 2 hours. The reaction mixture was then concentrated to give the crude title compound as a yellow solid (480 mg, quantitative), which was used without further purification.

[0289] 3-(5-(4-hydroxy-1-((3-oxo-2-phenylisoindolin-5-yl)methyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200) A suspension of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-4-hydroxypiperidine-1-carboxylate (20.00 mg, 0.084 mmol), 3-(5-(4-hydroxypiperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (32.02 mg, 0.084 mmol), and sodium triacetoxyborohydride (53.60 mg, 0.25 mmol) in DMF (1 mL) was stirred at room temperature for 16 hours. Reaction monitoring by LC-MS showed 40% conversion. The suspension was filtered to give a clear organic phase, which was purified by preparative HPLC to give the title compound as a white solid (4.4 mg, 9.2%). 1 H NMR(400 MHz,DMSO-d6)δ 10.98(s,1H),7.92(s,2H),7.75(s,2H),7.66(s,4H),7.44(s,2H),7.18(s,1H),5.14-5.00(m,4H),4.44(d,J=20.8 Hz,1H),4.29(d,J=18.9 Hz,1H),3.66(s,2H),3.03-2.80(m,2H),2.66(s,2H),2.42-2.29(m,2H),2.00(d,J=4.5 Hz,4H),1.61(d,J=11.5 Hz,2H).ESI-MS(EI + , m / z):565.3.

[0290] Example 14: Liquid Chromatography Mass Spectrometry (LCMS) Data

[0291] Reaction monitoring and characterization of the final compounds were performed using a Shimadzu LC-20AD series (binary pump and diode array detector) equipped with an Agilent Poroshell 120 EC-C18 column (2.7 μm, 4.6 × 50 mm). Mobile phase: A: 0.05% formate (v / v) in water, B: 0.05% formate (v / v) in MeCN. Flow rate: 1 mL / min at 25 °C. MS: 2020, quadrupole LC / MS, ion source: API-ESI, TIC: 100–900 m / z; drying gas flow rate: 15 L / min; nebulizer pressure: 1.5 L / min; drying gas temperature: 250 °C; Vcap: 4500 V.

[0292] [Table 1-1]

[0293] [Table 1-2]

[0294] [Table 1-3]

[0295] Example 15: Cytolytic GFP assay

[0296] IKZF1, IKZF2, and GSPT1 were subcloned into the mammalian pcDNA5 / FRT vector (ampicillin and hygromycin B resistance) modified to contain MCS-eGFP-P2A-mCherry. Stable cell lines expressing the eGFP-protein fusions and mCherry reporter were generated using the Flip-In 293 system. Plasmid (0.3 μg) and pOG44 (4.7 μg) DNA were preincubated for 20 minutes in 100 μL of Opti-MEM I (Gibco®, Life Technologies™) medium containing 0.05 mg / mL Lipofectamine 2000 (Invitrogen™) and then added to Flip-In 293 cells in 1.9 mL of DMEM medium (Gibco®, Life Technologies™) per well in a 6-well plate format (Falcon®, 353046). Cells were grown for 48 hours and then plated in 10 cm of DMEM medium containing 50 μg / mL hygromycin B (REF10687010, Invitrogen™) as a selection marker. 2 After 2-3 passages, cells expressing eGFP and mCherry were enriched using cycle FACS (FACSAria™ II, BD).

[0297] Cells stably expressing IKZF1, IKZF2, or GSPT1 GFP fusions with an mCherry reporter were seeded at 30-50% confluency into 384-well plates containing 50 μL of FluoroBrite™ DMEM medium (Thermo Fisher Scientific A 18967) containing 10% FBS per well the day before compound treatment. Compound titrations were dispensed using a D300e Digital Dispenser® (HP), standardized to 0.5% DMSO, and incubated with the cells for 5 hours.

[0298] Assay plates were immediately imaged using an Acumen® High-Content Imager (TTP Labtech) equipped with 488 nm and 561 nm lasers in a 2 μm x 1 μm grid / well format. The resulting images were analyzed using CellProfiler™. A series of image analysis steps (the "image analysis pipeline") was constructed. First, the red and green channels were aligned and cropped to target the center of each well (to avoid analysis of cells that were largely clumped at the edges). Background illumination effects were calculated separately for both the red and green channels for each well and subtracted to correct for illumination variations across the 384-well plate from various error sources. Further steps were then applied to the green channel to suppress analysis of large autofluorescence artifacts and enhance analysis of cell-specific fluorescence by selecting objects with a given size, less than 30 AU, and a given speckle shape. mCherry-positive cells were then identified in the red channel filtering for objects between 8 and 60 pixels in diameter, and their intensity was used to distinguish between clumped objects. The green channel was then segmented into GFP-positive and GFP-negative regions, and objects were labeled as GFP-positive if at least 40% of them overlapped with the GFP-positive region. The percentage of GFP-positive / mCherry-positive cells in each well was then calculated, and the green and red images were rescaled for visualization. A nonlinear fit variable slope model (GraphPad Software) was used to calculate the concentration resulting in half-degradation at 5 h (DC 50 , 5h) was calculated.

[0299] The results are shown in Figures 1A to 1C, which demonstrate that the tested compounds of the present invention potently degraded IKZF2 in cells.

[0300] Example 16: HiBit-IKZF2 assay

[0301] The HiBiT protein tagging system was applied to MOLT4 cells by CRISPR / Cas9-mediated insertion of a HiBiT peptide tag (Promega™) into the N-terminus of the IKZF2 locus (Neon™ Transfection System). The resulting HiBiT-Helios stable cell line was treated in triplicate with the following compounds 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 utilized to detect bioluminescence of the HiBiT tag in treated cells. The abundance of the tag is proportional to the level of luminescence. After normalization to DMSO, dose-response curves were plotted (GraphPad Prism) to determine the concentration point at which each compound achieved 50% HiBiT-Helios degradation. The extent of degradation (range of luminescence) from the highest to lowest concentration point was calculated to obtain the D max It was decided that:

[0302] [Table 2-1]

[0303] [Table 2-2]

[0304] [Table 2-3]

[0305] All patent and non-patent publications are indicative of the level of skill of those skilled in the art to which this invention pertains. All these publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0306] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that many modifications can be made to the exemplary embodiments and that other arrangements can be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. Structure of Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, During the ceremony, R ２ is hydrogen, amino, cyano, halo, (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl; R ３ is amino, hydroxyl, cyano, halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl; or R ３ and R ４ together with the atoms to which they are bonded, (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ３ and R ２ together with the atoms to which they are bonded, (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein the cycloalkyl, heterocycloalkyl group is one or more of the same or different R １５ optionally further independently substituted with groups; R ４ and R ４ ' is hydrogen, hydroxyl, amino, amide, carbonyl, cyano, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, and (C ２ -C ６ ) alkynyl, wherein said alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ or R ４ and R ４ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ４ and R ４ If the ' are on different carbon atoms, then together with the atoms to which they are attached, (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ４ and R ４ If ' are on adjacent atoms, together with the atoms to which they are attached, (C ６ -C １０ ) aryl or 5- or 6-membered heteroaryl; wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be one or more of the same or different R １５ optionally further independently substituted with groups; R ５ and R ５ ' is hydrogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R ６ But, R ７ Substituted aryl or R ７ substituted heteroaryl; wherein R ７ Substituted aryl or R ７ The substituted heteroaryl may be one or more of the same or different R １５ optionally further substituted independently by groups; R ７ が、-C(O)NR ８ R ９ 、-SO ２ NR ８ R ９ 、-S(O)(=NH)R ９ 、-OR ８ 、-N(R ８ R ９ )、-N(R ９ )C(O)R ８ 、-N(R ９ )SO ２ R ９ 、-N(R ９ )C(O)N(R ９ ) ２ 、-P(O)(R ９ ) ２ 、-N(R ９ )S(O) ２ N(R ９ ) ２ 、 【Chemistry 3】 selected from the group consisting of: R ８ However, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R ９ is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R １０ and R １０ ' is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ )aryl, monocyclic or bicyclic 5-10 membered heteroaryl, 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 ) alkynyl, provided that at least one R １０ and one R １０ ', when attached to the same carbon atom, form a spiro 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, or when attached to different carbon atoms, form a heterocycle or carbocycle, wherein said alkyl, heterocycle or carbocycle may be joined by one or more of the same or different R １５ optionally further substituted independently by groups; R １１ and R １１ ' is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ )aryl, monocyclic or bicyclic 5-10 membered heteroaryl, 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 ) alkynyl; said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be selected from the group consisting of one or more of the same or different R １５ and optionally further independently substituted by groups, or R １１ and R １１ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R １１ and R １１ If the ' are on different carbon atoms, then together with the atoms to which they are attached, (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; wherein said cycloalkyl or heterocycloalkyl group is selected from one or more of the same or different R １５ optionally further substituted independently by groups; R １２ and R １３ together with the carbon atoms to which they are attached, (C ６ -C １０ ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl, wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R １４ and R １４ ', taken together with the same carbon atom to which they are attached, form a spiro 4- to 7-membered heterocycloalkyl, or (C ３ -C ７ ) form a cycloalkyl; wherein said cycloalkyl or heterocycloalkyl may be one or more of the same or different R １５ optionally further substituted independently by groups; R １５ is alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-hetero arylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkynylcarbonyloxy, 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, azido, phosphinyl, phosphoryl including phosphine oxide and phosphonate, cyclic acetal,independently selected from the group consisting of 4-7 membered heterocycloalkyl, aryl, and heteroaryl containing at least one nitrogen atom and linked via said nitrogen atom, or two adjacent R, １５ are taken together with the atoms to which they are attached to form an aryl, or heteroaryl, or a 5- to 8-membered cycloalkyl or a 5- to 8-membered heterocycloalkyl; W １ is —O—, —S—, and —NR ９ - selected from the group consisting of; W ３ But nitrogen, CR １１ and a carbon atom which is the point of attachment; Y is -SO ２ - and -C(O)-; n １ is 1, n ２ is 0, 1, 2 or 3, n ３ are independently 1, 2 or 3, or Structure of Formula II: 【Chemistry 6】 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, During the ceremony, L, 【Chemistry 7】 selected from the group consisting of: R ２ is hydrogen, amino, cyano, halo, (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl; R ３ is amino, hydroxyl, cyano, halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) haloalkyl; R ３ and R ４ together with the atoms to which they are bonded (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ３ and R ２ together with the atoms to which they are bonded (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein the cycloalkyl, heterocycloalkyl group is one or more of the same or different R １５ optionally further independently substituted with groups; R ４ and R ４ ' is hydrogen, hydroxyl, amino, amide, carbonyl, cyano, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ２ -C ６ ) alkenyl, and (C ２ -C ６ ) alkynyl; wherein said alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ or R ４ and R ４ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ４ and R ４ If the ' are on different carbon atoms, then together with the atom to which they are attached (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ４ and R ４ When ' are on adjacent atoms, together with the atom to which they are attached, (C ６ -C １０ ) aryl or 5- or 6-membered heteroaryl; wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are each independently selected from one or more of the same or different R １５ optionally further substituted independently by groups; R ５ and R ５ ' is hydrogen, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) hydroxyalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ optionally further independently substituted with groups; R ６ is R ７ Substituted aryl or R ７ substituted heteroaryl; wherein R ７ Substituted aryl or R ７ The substituted heteroaryl may be one or more of the same or different R １５ optionally further independently substituted with groups; R ７ が、-C(O)NR ８ R ９ 、-SO ２ NR ８ R ９ 、-S(O)(=NH)R ９ 、-OR ８ ,-N(R ８ R ９ )、-N(R ９ )C(O)R ８ 、-N(R ９ )SO ２ R ９ 、-N(R ９ )C(O)N(R ９ ) ２ 、-P(O)(R ９ ) ２ 、-N(R ９ )S(O) ２ N(R ９ ) ２ 、 【Chemistry 9】 selected from the group consisting of: R ８ However, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R ９ is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R １０ and R １０ ' is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ )aryl, monocyclic or bicyclic 5-10 membered heteroaryl, 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 ) alkynyl, provided that at least one R １０ and one R １０ ', when attached to the same carbon atom, form a spiro 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, or when attached to different carbon atoms, form a heterocycle or carbocycle, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be joined by one or more of the same or different R １５ optionally further substituted independently by groups; R １１ and R １１ ' is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ )aryl, monocyclic or bicyclic 5-10 membered heteroaryl, 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 ) alkynyl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ and optionally further substituted independently by a group; or R １１ and R １１ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; or R １１ and R １１ When the carbon atoms are on different carbon atoms, together with the atoms to which they are attached, ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is one or more of the same or different R １５ optionally further substituted independently by groups; R １２ and R １３ together with the carbon atoms to which they are attached (C ６ -C １０ ) form an aryl or a monocyclic or bicyclic 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl is selected from one or more of the same or different R １５ may be further substituted independently by groups; R １４ and R １４’ together with the same carbon atom to which they are attached form a spiro 4- to 7-membered heterocycloalkyl, or (C ３ -C ７ ) form a cycloalkyl; wherein said cycloalkyl or heterocycloalkyl is selected from one or more of the same or different R １５ may be further substituted independently by groups; R １５ is alkyl, alkenyl, alkynyl, halo, haloalkyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, 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-hetero arylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, alkynylcarbonyloxy, 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, azido, phosphinyl, phosphoryl including phosphine oxide and phosphonate, cyclic acetal,independently selected from the group consisting of 4-7 membered heterocycloalkyl, aryl, and heteroaryl containing at least one nitrogen atom and linked via said nitrogen atom, or two adjacent R, １５ are taken together with the atoms to which they are attached to form an aryl, or heteroaryl, or a 5- to 8-membered cycloalkyl or a 5- to 8-membered heterocycloalkyl; R ２１ But, R ６ , (C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R ２５ may be independently substituted by groups; R ２３ is amino, hydroxyl, cyano, halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; or R ２３ and R ４ together with the atoms to which they are bonded (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ２３ and R ２ together with the atoms to which they are bonded (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, wherein the cycloalkyl, heterocycloalkyl group is one or more of the same or different R １５ may be further substituted independently by groups; R ２５ However, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, —C(O)R ２６ , -(CH ２ ) ０－３ C(O)OR ２６ , —C(O)NR ２６ R ２７ , -NR ２６ C(O)R ２７ , -NR ２６ C(O)OR ２７ , -S(O)pNR ２６ R ２７ , -S(O)pR ２８ , (C １ -C ６ ) hydroxyalkyl, halogen, —OH, —O(CH ２ ) １－３ CN, -(CH ２ ) １－３ CN, -(CR ２９ R ２９ ')CN, -NH ２ , CN, —O(CH ２ ) ０－３ (C ６ -C １０ ) aryl, adamantyl, -O(CH ２ ) ０－３ - 5- or 6-membered heteroaryl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ３ -C ７ ) cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is / are independently selected from the group consisting of one or more of the same or different R １５ may be further substituted independently by groups, or Two R's ２５ If groups are on adjacent atoms, then together with the atoms to which they are attached, one or more R １５ forming an aryl or a 5- or 6-membered heteroaryl optionally substituted by a group, or Two R's ２５ Groups, together with the atoms to which they are attached, can be one or more R １５ may be substituted by a group (C ５ -C ７ ) forming a cycloalkyl ring or a 5- to 7-membered heterocycloalkyl ring; R ２６ and R ２７ are independently selected from the group consisting of hydrogen and alkyl; R ２８ However, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are selected from the group consisting of one or more of the same or different R １５ may be further substituted independently by groups; R ２９ and R ２９ ', R ４ and independently selected from the group consisting of: ２９ and R ２９ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl, or R ２９ and R ２９ If ' are on adjacent carbon atoms, then together with the atoms to which they are attached, (C ３ -C ７ ) form a cycloalkyl; wherein said cycloalkyl is selected from one or more of the same or different R １５ may be further substituted independently by groups; W １ is —O—, —S—, and —NR ９ - selected from the group consisting of; W ３ But nitrogen, CR １１ and a carbon atom which is the point of attachment; Y is -SO ２ - and -C(O)-; n １ is 1, n ２ is 0, 1, 2 or 3, n ３ is independently 1, 2 or 3; p is 0, 1 or 2; The compound, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

2. The compound is represented by the structure of Formula I: R ２ is hydrogen, halo or (C １ -C ６ ) alkyl; R ３ is halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; R ４ and R ４ ' is hydrogen, amide, halogen, (C １ -C ６ ) alkyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, and (C ２ -C ６ ) alkynyl; wherein said alkyl, alkynyl, aryl or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ or R ４ and R ４ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, or R ４ and R ４ If the ' are on different carbon atoms, then together with the atom to which they are attached (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; wherein said cycloalkyl or heterocycloalkyl group is selected from one or more of the same or different R １５ optionally further independently substituted with groups; R ５ and R ５ ' is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl and (C １ -C ６ ) hydroxyalkyl; wherein said alkyl is independently selected from the group consisting of one or more of the same or different R １５ optionally further independently substituted with groups; R ７ が、-C(O)NR ８ R ９ 、-SO ２ NR ８ R ９ 、-S(O)(=NH)R ９ 、-OR ８ 、-N(R ８ R ９ )、-N(R ９ )C(O)R ８ 、-N(R ９ )SO ２ R ９ 、-N(R ９ )C(O)N(R ９ ) ２ 、-P(O)(R ９ ) ２ 、-N(R ９ )S(O) ２ N(R ９ ) ２ 、 【Chemistry 5】 selected from the group consisting of: R ９ is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more of the same or different R １５ optionally further substituted independently by groups; R １０ and R １０ ' is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ６ -C １０ ) independently selected from the group consisting of aryl, monocyclic or bicyclic 5-10 membered heteroaryl, and halo, provided that at least one R １０ and one R １０ ', when attached to the same carbon atom, form a spiro 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, or when attached to different carbon atoms, form a 4- to 7-membered heterocycle or a 3- to 7-membered carbocycle, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be selected from one or more of the same or different R １５ optionally further substituted independently by groups; R １１ and R １１ ' is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ６ -C １０ ) independently selected from the group consisting of aryl, monocyclic or bicyclic 5- to 10-membered heteroaryl, and halo; wherein said alkyl, aryl, or heteroaryl is selected from the group consisting of one or more of the same or different R １５ and optionally further substituted independently by a group; or R １１ and R １１ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; or R １１ and R １１ If the ' are on different carbon atoms, then together with the atom to which they are attached (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is one or more of the same or different R １５ may be further substituted independently by groups; or The compound is represented by the structure of Formula II: R ２ is hydrogen, halo or (C １ -C ６ ) alkyl; R ３ is halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; R ４ and R ４ ' is hydrogen, amide, halogen, (C １ -C ６ ) alkyl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl and (C ２ -C ６ ) alkynyl; wherein said alkyl, alkynyl, aryl or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ or R ４ and R ４ ', together with the same carbon atom to which they are attached, form a spiro (C ３ -C ７ ) forming a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; or R ４ and R ４ If ', ', and ' are on different carbon atoms, then together with the atom to which they are attached, they form (C ３ -C ７ ) form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group; wherein the cycloalkyl, heterocycloalkyl group is one or more of the same or different R １５ optionally further independently substituted with groups; R ５ and R ５ ' is hydrogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl and (C １ -C ６ ) hydroxyalkyl; wherein said alkyl is independently selected from the group consisting of one or more of the same or different R １５ optionally further independently substituted with groups; R ９ is hydrogen, (C １－ C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl, 4- to 7-membered heterocycloalkyl, (C ６ -C １０ ) aryl, and monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are selected from the group consisting of one or more of the same or different R １５ may be further substituted independently by groups; R ２３ is halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; R ２５ However, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkyl, —C(O)NR ２６ R ２７、 -NR ２６ C(O)R ２７ , -S(O)pNR ２６ R ２７ , -S(O)pR ２８ , halogen, —O(CH ２ ) １－３ CN, -NH ２ , CN, -(CR ２９ R ２９ ') -O(CH ') containing 1 to 3 heteroatoms selected from CN, O, N, and S ２ ) ０－３ - 5- or 6-membered heteroaryl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ３ -C ７ ) cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ or Two R's ２５ When groups are on adjacent atoms, together with the atoms to which they are attached, one or more R １５ or forming an optionally substituted aryl, or a 5- or 6-membered heteroaryl, Two R's ２５ Groups, together with the atoms to which they are attached, can be one or more R １５ optionally substituted with a group (C ５ -C ７ ) forming a cycloalkyl or a 5- to 7-membered heterocycloalkyl; R ２６ and R ２７ are independently selected from the group consisting of hydrogen and alkyl; R ２８ However, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ３ -C ７ ) cycloalkyl and (C ６ -C １０ ) aryl; wherein said alkyl, cycloalkyl or aryl is selected from the group consisting of one or more of the same or different R １５ optionally further independently substituted with groups; W １ is —O— and —NR ９ - selected from the group consisting of 2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. n ２ is 0, 1 or 2, or n ３ is 1 or 2, or 3. The compound of claim 1 or 2, wherein the compound is represented by formula II and p is 2.

4. The compound is represented by formula I, ５ and R ５ ' are independently hydrogen or methyl, or R ７ が、-C(O)NR ８ R ９ 、-SO ２ NR ８ R ９ 、-OR ８ 、-N(R ８ R ９ )、-N(R ９ )C(O)R ８ 、-N(R ９ )SO ２ R ９ 、-N(R ９ )C(O)N(R ９ ) ２ 、-P(O)(R ９ ) ２ 、 【Chemistry 10】 2. The compound of claim 1, wherein

5. The compound is represented by formula I: R ３ is amino, hydroxyl, cyano, halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; In some cases, R ２ is hydrogen, R ３ is hydroxyl, R ４ and R ４ ' are each hydrogen, halo, or (C １ -C ６ ) alkyl, R ５ and R ５ ' are hydrogen, The compound of claim 1.

6. The compound is represented by formula II, wherein R ２３ is amino, hydroxyl, cyano, halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; Optionally, L is 【Chemistry 14】 and R ２ is hydrogen, R ４ and R ４ ' are each hydrogen, halo, or (C １ -C ６ ) alkyl, R ５ and R ５ ' may each be hydrogen; In some cases, R ２３ is hydroxyl, In some cases, R ２１ is substituted C ６ aryl, provided that said aryl is at least two R ２５ and R ２５ are on adjacent atoms, at least one (C ６ -C １０ ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R １５ forming a monocyclic or bicyclic 5-10 membered heteroaryl optionally independently substituted with R ２１ is a substituted 5- or 6-membered heteroaryl, provided that said heteroaryl is substituted with at least two R ２５ is substituted with R ２５ If two of these are on adjacent atoms, C ６ aryl, or at least one (C ６ -C １０ ) a 5- or 6-membered heteroaryl substituted with an aryl, or one or more R １５ forming a monocyclic or bicyclic 5-10 membered heteroaryl optionally independently substituted with R ２１ However, (C ６ -C １０ ) aryl, or monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is selected from the group consisting of one or more of the same or different R ２５ optionally substituted independently by groups; R ２５ However, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) haloalkyl, (C １ -C ６ ) haloalkoxy, halogen, CN, —O(CH ２ ) (C ６ -C １０ ) aryl, —O(CH ２ )-5- or 6-membered heteroaryl, (C ６ -C １０ ) aryl, monocyclic or bicyclic 5-10 membered heteroaryl, (C ３ -C ７ ) cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently selected from the group consisting of one or more of the same or different R １５ and optionally further substituted independently by groups, The compound of claim 1.

7. Each R １５ However, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, halo, CF ３ , (C ５ -C １０ ) cycloalkyl, 3- to 12-membered heterocycloalkyl, hydroxy, (C １ -C ６ ) alkoxy, 3- to 12-membered cycloalkoxy, 3- to 12-membered heterocycloalkoxy, haloalkoxy, (C ６ -C １２ ) aryloxy, 5- to 6-membered heteroaryloxy, aralkyloxy, (C ２ -C ６ ) alkenyloxy, (C ２ -C ６ ) alkynyloxy, amino, (C １ -C ６ ) alkylamino, (C ５ -C １０ ) cycloalkylamino, 3- to 12-membered heterocycloalkylamino, (C ６ -C １２ ) arylamino, 5- to 6-membered 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 ) alkylsulfonyl, haloalkylsulfonyl, (C ５ -C １０ ) cycloalkylsulfonyl, 3- to 12-membered heterocycloalkylsulfonyl, (C ６ -C １２ ) arylsulfonyl, 5- to 6-membered heteroarylsulfonyl, aminosulfonyl, (C １ -C ６ ) alkylaminosulfonyl, (C ５ -C １０ ) cycloalkylaminosulfonyl, 3- to 12-membered heterocycloalkylaminosulfonyl, (C ６ -C １２ ) arylaminosulfonyl, 5-6 membered 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, carboxy, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkynylcarbonyloxy, amino, (C １ -C ６ ) alkylsulfonylamino, haloalkylsulfonylamino, (C ５ -C １０ ) cycloalkylsulfonylamino, 3- to 12-membered heterocycloalkylsulfonylamino, (C ６ -C １２ ) arylsulfonylamino, 5- to 6-membered heteroarylsulfonylamino, aralkylsulfonylamino, (C １ -C ６ ) alkylcarbonylamino, haloalkylcarbonylamino, (C ５ -C １０ ) cycloalkylcarbonylamino, 3- to 12-membered heterocycloalkylcarbonylamino, (C ６ -C １２ ) arylcarbonylamino, 5- to 6-membered heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, (C １ -C ６ ) alkylaminocarbonyl, (C ５ -C １０ ) cycloalkylaminocarbonyl, 3- to 12-membered heterocycloalkylaminocarbonyl, (C ６ -C １２ ) arylaminocarbonyl, 5- to 6-membered 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, azido, phosphinyl, phosphoryl including phosphine oxide and phosphonate, cyclic acetal, 4 to 7-membered heterocycloalkyl containing at least one nitrogen atom and linked via said nitrogen atom, (C ６ -C １２ ) aryl, and 5- to 6-membered heteroaryl, or two adjacent R １５ together with the atoms to which they are bonded (C ６ -C １２ ) forming an aryl, a 5- to 6-membered heteroaryl, a 5- to 8-membered cycloalkyl, or a 5- to 8-membered heterocycloalkyl; The compound according to any one of claims 1 to 6.

8. 【Catalog 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical 29】 【Chemistry 30】 【Chemical Formula 31】 【Chemical Formula 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemical 54】 【Chemistry 55】 【Chemical Formula 56】 【Chemical 57】 【Chemistry 58】 【Chemical Formula 59】 【Chemistry 60】 【Hua 61】 【Hua 62】 【Chemistry 63】 【Hua 64】 a compound selected from the group consisting of or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier; Optionally, the pharmaceutical composition, wherein the compound is in the form of a co-crystal.

10. 10. The pharmaceutical composition of claim 9 for treating a disease or disorder in a subject in which IKZF2 (Helios) is involved and which would benefit from IKZF2 degradation, optionally wherein the disease or disorder is cancer; Optionally, the cancer may be T-cell leukemia, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, or gastrointestinal stromal tumor (GIST).

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