Low Molecular Weight Degradation Inducing Agent of HELIOS and Method of Use

Abstract

Disclosed are compounds capable of causing degradation of various proteins, such as IKZF2 (Helios), and pharmaceutically acceptable salts and stereoisomers thereof. Also disclosed are pharmaceutical compositions containing the compounds, and methods for preparing and using the compounds to treat diseases and disorders characterized by or mediated by aberrant protein activity.

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 / 774,482, filed Dec. 3, 2018, and U.S. Provisional Patent Application No. 62 / 938,410, filed Nov. 21, 2019, each of which is hereby incorporated by reference in its entirety.

[0002] Government Licensing Rights This invention was made with government support under Grant No. R01 CA214608 awarded by the National Institutes of Health. The government has certain rights in this invention.

Background Art

[0003] The discovery of immune checkpoint receptors such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), which suppress the activity of anti-tumor T cells (Leach et al., Science 271:1734-1736 (1996); Phan et al., Proc. Natl. Acad. Sci. 100:8372-8377 (2003); Nishimura et al., Immunity 11:141-151 (1999); Dong et al., Nat. Med. 8:793-800 (2002); Brahmer et al., J. Clin. Oncol. 28:3167-3175 (2010)) has led to the development of blocking antibodies against these receptors or their ligands, including ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), and nivolumab (anti-PD-1). Surprisingly, some patients treated with checkpoint inhibitors experienced sustained tumor regression, in contrast to targeted small molecule therapies where tumor recurrence is common (Sharma et al., Cell 161:205-214 (2015)). This remarkable response has led to the rapid approval of these therapies for patients and extraordinary optimism in the field. However, checkpoint blockade therapy has been successful only in a subset of patients, with certain tumor types responding more favorably than others (Mahoney et al., Nat. Rev. Drug Discov. 14:561-584 (2015)). Therefore, it is important to more fully understand the mechanisms underlying tumor-induced immune dysfunction, expand the types of tumors that can be treated, and develop complementary therapies that increase the anti-tumor activity of existing approaches while reducing autoimmune side effects.

[0004] One such approach is to target regulatory T cells (Tregs). These T cells have important functions in maintaining normal immune tolerance and homeostasis (Sakaguchi et al., Cell 133:775-787 (2008)), but also play a harmful role in suppressing the anti-tumor immune response (Tanaka et al., Cell Res. 27:109-118 (2017)). They are a special subset of the Foxp3-expressing cluster of differentiated 4+ T (CD4+) cells. The observed accumulation of Tregs in the tumor microenvironment may be due to the efficient recruitment and proliferation of Tregs. Furthermore, most Tregs develop in the thymus as an alternative to elimination by negative selection of CD4+ T cells expressing self-reactive T cell receptors (TCRs) (Hogquist et al., Nat. Rev. Immunol. 5:772-782 (2005)); thus, the accumulation of Tregs in tumors may also reflect an increase in Treg self-reactivity, including the recognition of tumor-associated antigens (Scanlan et al., Immunol. Rev. 188:22-32 (2002); Nishikawa et al., Curr. Opin. Immunol. 27:1-7 (2014)). Due to the prevalence of self-reactive TCRs, the mechanisms ensuring the stability of the suppressive phenotype of Tregs seem to be important for preventing the development of autoimmunity.

[0005] The zinc finger transcription factor Helios (also known as Ikaros family zinc finger protein 2 (IKZF2)) has been identified as an important regulator of Treg suppressive activity. Although not all Tregs express Helios, higher Helios expression has been shown to correlate with increased suppressive function in Tregs from both mice (Sugita et al., Exp. Dermatol. 24:554-556 (2015); Zabransky et al., PLoS One 7:e34547 (2012)) and humans (Bin Dhuban et al., J. Immunol. 194:3687-3696 (2015)). Consistent with this, Helios has recently been identified as an important factor for maintaining a stable Treg phenotype in the inflammatory tumor microenvironment (Nakagawa et al., Proc. Natl. Acad. Sci. 113:6248-6253 (2016); Kim et al., Science 350:334-339 (2015); Yates et al., Proc. Natl. Acad. Sci. 115:2162-2167 (2018)). Genetic deletion of Helios in Tregs results in loss of suppressive activity and acquisition of effector T cell functions (i.e., secretion of type II interferon (IFNγ) and tumor necrosis factor-α (TNFα)), indicating that loss of Helios enables conversion of Tregs into effector-like T cells (Nakagawa et al., Proc. Natl. Acad. Sci. 113:6248-6253 (2016); Kim et al., Science 350:334-339 (2015)).

[0006] Targeting transcription factors with small molecules is difficult, but proteolysis strategies have expanded the range of targets that could lead to the development of new drugs. In particular, recent studies have shown that immunomodulatory imide (IMiD) molecules such as thalidomide and its analogs bind to the ubiquitously expressed E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (CRL4 CRBN) was found to bind to cereblon (CRBN), a substrate adapter (Ito et al., Science 327:1345-1350 (2010)). Binding of these imide molecules to CRBN does not inhibit the activity of CRL4 CRBN but rather creates a novel surface that results in new interactions between CRBN and other proteins, particularly Ikaros (IKZF1) and Aiolos (IKZF3). Treatment with thalidomide or its analogs was found to result in CRBN-dependent ubiquitination and subsequent proteasomal degradation of Ikaros and Aiolos (Kronke et al., Science 343:301-305 (2014); Lu et al., Science 343:305-309 (2014)).

PRIOR ART DOCUMENTS

NON-PATENT LITERATURE

[0007]

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Summary of the Invention

Means for Solving the Problems

[0008] The first aspect of the present invention relates to a compound represented by the structure of formula (I):

Chemical Formula

Chemical Formula

[0009] The second aspect of the present invention relates to a compound represented by the structure of formula (II):

Chemical Formula

Chemical Formula

[0010] The third aspect of the present invention relates to a compound represented by the structure of formula (III):

Chemical Formula

[0011] Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I, II or III) or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

[0012] Another aspect of the invention is a method of treating a disease or disorder characterized by or mediated by abnormal (e.g., dysregulated) activity of a protein that is a substrate of a complex of cereblon (CRBN) and a compound of the invention, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I, II or III) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0013] Such protein substrates include, for example, Family with sequence similarity 83 member F (FAM83F), DTW domain-containing 1 (DTWD1), Zinc finger protein 62 (ZFP62), ZFP91, Ring finger protein 166 (RNF166), Ikaros family zinc finger protein 1 (IKZF1), IKZF2 (Helios), IKZF3, IKZF4, IKZF5, Casein kinase 1 isoform alpha (CK1α) Zinc finger protein 653 (ZN653), ZN654, ZN827, ZN692, zinc finger and BTB domain-containing protein 2 (ZBTB2), ZBTB39, RAB28, glutathione S-transferase P1 (GSTP1), ZFP36 ring finger protein-like 2 (ZFP36L2), glial cell line-derived neurotrophic factor (GDNF)-inducible zinc finger protein 1 (GZF1), G1 to S transition 2 protein (GSPT2), early growth response protein 1 (EGR1), hypermethylated in cancer 1 protein (HIC1), HIC2, insulinoma-associated protein 2 (INSM2), odd skipped-related 1 protein (OSR1), OSR2, positive regulatory domain zinc finger protein 15 (PRD15), Sal-like protein 1 (SALL1), SALL3, SALL4, wide-interval zinc finger-containing protein (WIZ), zinc finger protein 324B (Z324B), zinc finger and BTB domain-containing protein 17 (ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, zinc finger protein that interacts with protein K (ZIK1), zinc finger protein 3 (ZNF3), ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, zinc finger and SCAN domain-containing protein 10 (ZSC10), ZSC22, zinc finger with UFM1-specific peptidase domain protein (ZUFSP), E4F1, B-cell lymphoma 6 protein (BCL6), BCL6B, POZ / BTB and AT hook-containing zinc finger 1 (PATZ1), and zinc finger protein with Krueppel-associated box (KRAB) and SCAN domain 5 (ZKSC5) may be included.

[0014] In some embodiments, the disease or disorder is characterized by or mediated by abnormal IKZF2 (Helios) activity, such as coronary heart disease. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is T cell leukemia, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC) or nasopharyngeal cancer (NPC).

[0015] In some embodiments, the abnormal protein contains one or more sequence motifs, such as the CxxCG motif present in ZFP62, GZF1, EGR1, HIC1, HIC2, INSM2, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF316, ZNF335, ZNF407, ZNF408, ZNF462, ZNF483, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, ZSC10, ZSC22, ZN654 and ZUFSP.

[0016] A further aspect of the invention relates to a method of treating a disease or disorder that develops due to a decrease in TXNIP protein levels. The method involves administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I, II or III) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0017] As demonstrated in the examples, the compounds of the invention exhibit potent and selective degradation of IKZF1 (Ikaros) and IKZF2 (Helios). BRIEF DESCRIPTION OF THE DRAWINGS

[0018]

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[0027] 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 otherwise specified, the following terms have the meanings set forth below for the purpose of facilitating understanding of the invention.

[0028] As used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a", "an" and "the" include plural referents. Thus, for example, a reference to "a composition" includes mixtures of two or more such compositions, a reference to "an inhibitor" includes mixtures of two or more such inhibitors, and the like.

[0029] Unless otherwise specified, the term "about" means within 10% of a particular value modified by the term "about" (e.g., within 5%, 2% or 1%).

[0030] The transitional term "comprising", which is synonymous with "including", "containing" or "characterized by", is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes elements, steps or components not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps and those that do not substantially affect the "basic and novel characteristics" of the claimed invention.

[0031] For the compounds of the present invention, and to the extent that the following terms are used herein to further describe them, the following definitions apply.

[0032] As used herein, the term "aliphatic" refers to acyclic hydrocarbon groups and includes branched and unbranched alkyl, alkenyl or alkynyl groups.

[0033] As used herein, the term "alkyl" refers to saturated straight-chain or branched-chain monovalent hydrocarbon groups. In one embodiment, the alkyl group is C1-C 18is a base. In other embodiments, the alkyl group is C0-C6, C0-C5, C0-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.

[0034] As used herein, the term "alkylene" consists of only carbon and hydrogen, contains no unsaturation, has 1 to 12 carbon atoms, and is a straight-chain or branched divalent hydrocarbon chain that links the remainder of its molecule to a radical group, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain can be bonded to the remainder of the molecule via a single bond and to the radical group via a single bond. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0035] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with one or more (e.g., 1, 2, 3, or 4) halo groups.

[0036] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group having at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations, or "E" and "Z" orientations. In one example, the alkenyl group is a C2-C 18 group. In other embodiments, the alkenyl group is a C2-C 12 , C2-C 10 , C2-C8, C2-C6, or C2-C3 group. 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-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0037] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined above to which an oxygen group is attached. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. "Ether" is two hydrocarbons covalently linked by oxygen. Thus, the alkyl substituent that makes an alkyl an ether can be an alkoxyl such that it can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl, or is similar to an alkoxyl.

[0038] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0039] As used herein, the term "carbamate" is represented by the formula -O-C(O)NH2.

[0040] As used herein, the term "carbamide" is represented by the formula -NH-C(O)NH2.

[0041] As used herein, the term "cyclic group" is used alone or as part of a larger moiety and broadly refers to any group containing a saturated, partially saturated or aromatic ring system, such as a carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaryl group. The cyclic group can have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group can contain one or more carbocyclic groups, heterocyclic groups, aryl or heteroaryl groups.

[0042] As used herein, the term "carbocyclic" (also referred to as "carbocyclyl") is used alone or as part of a larger moiety and refers to a group containing a saturated, partially unsaturated or aromatic ring system having 3 to 20 carbon atoms that is alone or part of a larger moiety (e.g., an alk carbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused rings, bridged rings and spiro ring systems, and combinations thereof. In one embodiment, the carbocyclyl contains 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 contains C3 - C8, C3 - C 10 or C5 - C 10 . In another embodiment, the carbocyclyl as a monocyclic ring contains C3 - C8, C3 - C6 or C5 - C6. In some embodiments, the carbocyclyl as a bicyclic ring contains C7 - C 12 . In another embodiment, the carbocyclyl as a spiro system contains C5 - C 12It includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, perdeuterocyclohexyl, 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, for example, [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 carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic or spiro-carbon rings). The term carbocyclic group also includes a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl or heterocyclic ring) where the group or point of attachment is on the carbocyclic ring.

[0043] Accordingly, the term carbocyclic also, when used herein, refers to a group of the formula -R c -carbocyclyl (wherein R c is an alkylene chain), also encompassing a carbocyclylalkyl group. The term carbocyclic also, when used herein, refers to a group of the formula -O-R c -carbocyclyl (wherein R c is an alkylene chain), also encompassing a carbocyclylalkoxy group which is attached via an oxygen atom.

[0044] As used herein, the term "aryl", alone or as part of a larger moiety (e.g., "aralkyl" where the terminal carbon atom of the alkyl group is the point of attachment, such as a benzyl group, "aralkoxy" where the oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an alkyl group), refers to a group comprising a monocyclic, bicyclic or tricyclic carbocyclic system including fused rings, wherein at least one ring of the system is aromatic. In some embodiments, the aralkoxy group is a benzyloxy group. The term "aryl" may be used interchangeably with the term "aryl ring". In one embodiment, aryl comprises a group having 6 to 18 carbon atoms. In another embodiment, aryl comprises a group 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, etc., which may be substituted or independently substituted by one or more substituents described herein. A particular aryl is phenyl. In some embodiments, the aryl group comprises an aryl ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring) where the group or point of attachment is on the aryl ring.

[0045] Thus, the term aryl, as disclosed above, refers to a group of the formula -R c -aryl, where R c is an alkylene chain such as methylene or ethylene), and includes aralkyl groups (e.g., benzyl). In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, also includes an aralkoxy group, which refers to a group bonded through an oxygen atom of the formula -O-R c -aryl, where R c is an alkylene chain such as methylene or ethylene).

[0046] As used herein, the term "heterocyclyl" is used alone or as part of a larger moiety and refers to a "carbocyclyl" containing a saturated, partially unsaturated or aromatic ring system in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, N(O), S, S(O) or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged and spiro ring systems, as well as 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 is a saturated or partially unsaturated monocyclic, bicyclic or spiro ring system containing 3 to 8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

[0047] In some embodiments, the heterocyclyl group includes monocyclic, bicyclic, tricyclic, and spiro ring systems having 3 to 12 ring atoms, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes a 3-membered monocyclic ring. In some embodiments, the heterocyclyl includes a 4-membered monocyclic ring. In some embodiments, the heterocyclyl includes a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group includes 0 to 3 double bonds. In any of the above embodiments, the heterocyclyl contains 1, 2, 3, or 4 heteroatoms. Nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2), and nitrogen heteroatoms may optionally be quaternized (e.g., [NR4] + 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-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 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]decan-2-one only (1-azaspiro[4.5]decan-2-only), azaspiro[5.5] Examples include undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyl containing a sulfur or 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 ring heterocyclyl containing 2 to 4 nitrogen atoms include imidazolyl such as imidazol-2-yl; triazolyl such as 1,3,4-triazol-5-yl; tetrazolyl such as 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyl are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyl contain 1 to 3 nitrogen atoms and optionally a sulfur or oxygen atom, for example, pyridyl such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl; triazinyl such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, particularly 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, the heterocyclic group includes a heterocyclic ring having a group or a bonding point on the heterocyclic ring, and in some embodiments, the bonding point is a heteroatom contained in the heterocyclic ring, and is condensed with one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring).

[0048] Accordingly, the term heterocyclic, as used herein, refers to a heterocyclyl group containing at least one nitrogen, and includes N - heterocyclyl groups where the heterocyclyl group and the remaining attachment point of the molecule are through a nitrogen atom of the heterocyclyl group. Representative examples of N - heterocyclyl groups include 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. The term heterocyclic, as used herein, also refers to a heterocyclyl group containing at least one heteroatom, and includes C - heterocyclyl groups where the heterocyclyl group and the remaining attachment point of the molecule are through a carbon atom of the heterocyclyl group. Representative examples of C - heterocyclyl groups include 2 - morpholinyl, 2 - or 3 - or 4 - piperidinyl, 2 - piperazinyl, and 2 - or 3 - pyrrolidinyl. The term heterocyclic, as used herein, also includes, as disclosed above, a heterocyclylalkyl group that refers to a group of the formula - R c - heterocyclyl (wherein R c is an alkylene chain).

[0049] The term heterocyclic, as used herein, also includes a heterocyclylalkoxy group that refers to a group attached through an oxygen atom of the formula - O - R c - heterocyclyl (wherein R c is an alkylene chain).

[0050] As used herein, the term "heteroaryl," whether used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl") or "heteroarylalkoxy" (also referred to as "heteroaralkoxy")), refers to a monocyclic, bicyclic, or tricyclic system having 5 to 14 ring atoms, wherein 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 of the ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, imidazopyridyl, 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., carbocyclic or heterocyclic) rings, where the group or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, 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. The heteroaryl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group has a group or point of attachment on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring, and includes a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring). Thus, the term heteroaryl, as used herein, refers to a heteroaryl group defined as containing at least one nitrogen, and includes an N-heteroaryl group where the heteroaryl group and the remaining point of attachment of the molecule are through a nitrogen atom of the heteroaryl group. The term heteroaryl also, as used herein, refers to a heteroaryl group as defined above, and also includes a C-heteroaryl group where the heteroaryl group and the remaining point of attachment of the molecule are through a carbon atom of the heteroaryl group. The term heteroaryl also, as disclosed above, refers to the formula -R. c -heteroaryl (wherein R c is an alkylene chain as defined above) also includes a heteroarylalkyl group referring to a group. The term heteroaryl also, as used herein, refers to the formula -O-R c -heteroaryl (wherein R c is an alkylene group as defined above) also includes a heteroaralkoxy (or heteroarylalkoxy) group referring to a group bonded through an oxygen atom.

[0051] Any of the groups described in this specification may or may not be substituted. As used herein, the term "substituted" refers broadly to all acceptable substituents, provided that such substitution conforms to the acceptable valences of the atoms being substituted and the substituents, and under the implicit condition that a stable compound is obtained by the substitution, i.e., a compound that does not undergo spontaneous conversion, such as rearrangement, cyclization, elimination, etc. Representative substituents include halogen, hydroxyl groups, and any other organic group that may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms such as oxygen, sulfur, and nitrogen atoms, which contain any number of carbon atoms, e.g., from 1 to 14 carbon atoms, grouped in linear, branched, or cyclic structural forms.

[0052] Thus, representative examples of substituents include alkyl, substituted alkyl (e.g., C1-C6, C1-5, C1-4, C1-3, C1-2, C1), alkoxy (e.g., C1-C6, C1-5, C1-4, C1-3, C1-2, C1), substituted alkoxy (e.g., C1-C6, C1-5, C1-4, C1-3, C1-2, C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-5, C2-4, C2-3, C2), substituted alkenyl (e.g., C2-C6, C2-5, C2-4, C2-3, C2), alkynyl (e.g., C2-C6, C2-5, C2-4, C2-3, C2), substituted alkynyl (e.g., C2-C6, C2-5, C2-4, C2-3, C2), cyclic (e.g., C3-C12, C5-C6), substituted cyclic (e.g., C3-C12, C5-C6), carbocyclic (e.g., C3-C12, C5-C6), substituted carbocyclic (e.g., C3-C12, C5-C6), heterocyclic (e.g., C3-C12, 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-C12, C6), substituted aryloxy (e.g., C6-C12, C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C12, C6), substituted arylthio (e.g., C6-C12, C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acids and peptide groups may be mentioned.

[0053] In one aspect, the compound of the present invention has the formula (I):

Chemical formula

[0054] In some embodiments, Q is C=O.

[0055] In some embodiments, Q is CH2.

[0056] In some embodiments, X is NH.

[0057] In some embodiments, X is NMe.

[0058] In some embodiments, X is O.

[0059] In some embodiments, X is S.

[0060] In some embodiments, M is cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl and benzene.

[0061] In some embodiments,

Chemical formula

Chemical formula

[0062] In some embodiments, Y represents an optionally substituted N-aryl, wherein Y is, for example, optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, optionally substituted tetrazolyl, optionally substituted thiazolyl, optionally substituted quinolinyl, optionally substituted indolyl, or optionally substituted indazolyl.

[0063] In some embodiments, Y represents optionally substituted C1-C5 alkyl.

[0064] In some embodiments, Y represents optionally substituted phenyl or optionally substituted benzyl.

[0065] In some embodiments where the compound is represented by Formula Ia, Y is phenyl, benzyl,

Chemical formula

Chemical formula

[0066] In some embodiments, R1 is ethyl, isopropyl, tert-butyl, phenyl, benzyl, pyrazolyl, imidazolyl, tetrazolyl, pyridinyl or pyrimidinyl.

[0067] In some embodiments, any substituent of any of the groups in the compound of Formula Ia is methyl, chloro, fluoro, phenyl, benzyl,

Chemical formula

[0068] In some embodiments, Y is absent and the compound of the present invention has the structure represented by Formula (Ib):

Chemical formula

[0069] In some embodiments,

Chemical formula

[0070] In some embodiments,

Chemical formula

Chemical formula

[0071] In some embodiments,

Chem.

[0072] In some embodiments,

Chem.

Chem.

[0073] In some embodiments, Z is

Chem.

[0074] In some embodiments, Ar is optionally substituted phenyl, for example,

Chem.

[0075] In some embodiments, R3 independently represents methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, chloro or fluoro.

[0076] In some embodiments, any substituent of the groups in the compound of formula Ib is methyl, chloro, fluoro, phenyl, benzyl,

Chem.

[0077] Representative embodiments of the compound of formula (I) are as follows:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0078] A second aspect of the present invention is a compound represented by the structure of formula II:

Chemical formula

Chemical formula

Chemical formula

Chem.

[0079]

Chem.

Chem.

[0080] In some embodiments, R4 is alkyl, halo, hydroxyl, amino, amide, substituted carbamate or substituted carbamide.

[0081] In some embodiments, Ar1 is optionally substituted phenyl.

[0082] Representative embodiments of the compound of formula (II) are as follows:

Chem.

Chem.

Chem.

Chem.

Chem.

[0083] The third aspect of the present invention relates to a compound represented by the structure of formula III:

Chemical formula

[0084] In some embodiments, both W5 and W6 are -NH-.

[0085] In some embodiments, Ar2 is phenyl substituted with one or more groups selected from alkyl, halo, and haloalkyl.

[0086] Representative embodiments of the compound of formula (III) are as follows:

Chemical formula

[0087] The compounds of the present invention can be in the form of free acids or free bases, or pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not inactivate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material 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 components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to a product obtained by the reaction of 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 are 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, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate, etc. Certain compounds of the present invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.

[0088] The compounds of the present invention may have at least one chiral center and thus, as used herein, may be in the form of stereoisomers encompassing all isomers of the individual compounds that differ only in the orientation of their atoms in space. The term stereoisomers includes enantiomers (including (R-) or (S-) configurations of the compound), mixtures of enantiomers of the compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of the compound, and isomers of the compound having two or more chiral centers that are not mirror images of each other (diastereoisomers). Since the chiral centers of the compounds may undergo epimerization in vivo, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Thus, the compounds of the present invention may be prepared and used in the form of the individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0089] In some embodiments, the compounds are isotope derivatives in that they have at least one desired isotope substitution of an atom in an amount that exceeds the natural abundance of the isotope, i.e., in an enriched amount. In one embodiment, the compounds contain deuterium or multiple deuterium atoms. Substitution with deuterium, i.e., 2 substitution with a heavier isotope such as 2H, can result in certain therapeutic advantages obtained from higher metabolic stability, such as an increase in in vivo half-life or a decrease in dosage requirements, and thus can be advantageous depending on the situation.

[0090] The compounds of the present invention can be prepared by crystallization under different conditions and can exist as one or a combination of polymorphs of the compound. For example, by using various solvents or various solvent mixtures for recrystallization, performing crystallization at various temperatures, or using various cooling modes ranging from very fast cooling to very slow cooling during crystallization, various polymorphs can be identified and / or prepared. Polymorphs can also be obtained by heating or melting the compound and subsequently cooling it slowly or rapidly. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction patterns, and / or other known techniques. Accordingly, the term "compound" includes its isotopic derivatives, tautomeric forms, polymorphs, pharmaceutically acceptable solvates and hydrates, and pharmaceutically acceptable prodrugs.

[0091] In some embodiments, the pharmaceutical composition comprises a co-crystal of the compound of the present invention. As used herein, the term "co-crystal" refers to a stoichiometric multi-component system comprising the compound of the present invention and a co-crystal former, wherein the compound of the present invention and the co-crystal former are bound by non-covalent interaction. As used herein, the term "co-crystal former" refers to a compound that can form an intermolecular interaction with the 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-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl-4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital. Synthesis method

[0092] In another aspect, the present invention relates to a method for preparing a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof. Broadly speaking, the compounds of the present invention or pharmaceutically acceptable salts or stereoisomers thereof can be prepared by any method known to be applicable to the preparation of chemically related compounds. The compounds of the present invention are described in various examples and will be better understood in connection with synthetic schemes that illustrate non-limiting methods by which the compounds of the present invention can be prepared. Pharmaceutical composition

[0093] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention of formula (I, II or III) or a pharmaceutically acceptable salt or stereoisomer 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 the compounds of the present invention to mammals. 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 that function to carry or transport the compound from one organ or part of the body to another. The carrier is "acceptable" in the sense that it is physiologically inert with respect to the other components of the formulation, compatible with the other components of the formulation, and not harmful to the subject or patient. Depending on the type of formulation, the composition may further comprise one or more pharmaceutically acceptable excipients.

[0094] Generally, the compounds of the present invention, as well as their pharmaceutically acceptable salts and stereoisomers, can be formulated into a given type of composition according to conventional pharmaceutical operations such as conventional mixing, dissolving, granulating, sugar coating, wet milling, emulsifying, encapsulating, entrapping, and compression processes (see, e.g., 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 (s.c.), intravenous (i.v.), intramuscular (i.m.), and intrasternal injection, or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). Generally, the most appropriate route of administration depends on various factors including, for example, the nature of the agent (e.g., its stability in the gastrointestinal tract environment), and / or the condition of the subject (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 rapidly, such as in the case of single-dose treatment and / or acute conditions.

[0095] In some embodiments, the compound is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0096] Accordingly, the compounds of the present invention can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets, and suppositories), liquid compositions (e.g., solutions 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 immediate release, intermediate release, or extended release.

[0097] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with carriers such as sodium citrate or dicalcium phosphate, and a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone (crospovidone), sodium cross-linked carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), e) solution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and additional carriers or excipients. In the case of capsules, tablets, and pills, the dosage form may also include buffering agents. Excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol can also be used to fill soft and hard gelatin capsules with the same type of solid composition as a filler. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings. These may further contain opacifying agents.

[0098] In some embodiments, the compounds of the 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, lactose anhydrous, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell can contain gelatin, titanium dioxide, iron oxide, and colorants.

[0099] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to the compound, the liquid dosage form can contain an aqueous or non-aqueous carrier (depending on the solubility of the compound) commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions can also contain excipients such as wetting agents, suspending agents, coloring agents, sweetening agents, flavoring agents, and fragrances.

[0100] Injectable preparations may contain sterile aqueous solutions or oily suspensions. These can be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable formulations may be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, United States Pharmacopeia and isotonic sodium chloride solution. Furthermore, sterile fixed oils have conventionally been used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacteria - 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 before use. The effect of the compound can be prolonged by delaying its absorption, which can be achieved by using a liquid suspension or a crystalline or amorphous material of low water solubility. Prolonged absorption of the compound from parenteral formulations can also be achieved by suspending the compound in an oily vehicle.

[0101] In certain embodiments, the compounds of the invention can often be administered locally rather than systemically in depot or sustained release formulations, for example, via direct injection of the conjugate into an organ. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). By varying the ratio of the compound to the polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Depot injection formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues. Further, in other embodiments, the compounds are delivered in a targeted drug delivery system, for example, liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ.

[0102] The compounds of the invention can be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0103] The compounds can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists, or powders. The pharmaceutical compositions can be delivered in the form of an aerosol spray presentation from a pressurized pack or a 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 a powder mixture of the compound and a suitable powder base such as lactose or starch and including gelatin for use in, for example, an inhaler or insufflator can be formulated.

[0104] The compounds of the present invention, as used herein, can be formulated for topical administration, which refers to intradermal administration by application of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0105] Representative examples of carriers useful for formulating compositions for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). Creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl or oleyl alcohol. Creams can also contain nonionic surfactants such as polyoxy-40-stearate.

[0106] In some embodiments, the topical formulation may also include excipients, examples of which are penetration enhancers. These agents can transport pharmacologically active compounds through the stratum corneum to the epidermis or dermis, preferably with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the rate of drug penetration through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H.I. and Smith H.E. (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys 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 T.K., Pfister W.R., Yum S.I. (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, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerin monooleate and propylene glycol monooleate), and N-methylpyrrolidone.

[0107] Representative examples of other excipients that can be included in topical and other types of formulations (to the extent they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citric acid. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactate buffers. Suitable solubilizers include quaternary ammonium chlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0108] Transdermal formulations typically use a transdermal delivery device and a transdermal patch in which the compound is formulated in a lipophilic emulsion or buffered aqueous solution and dissolved and / or dispersed in a polymer or adhesive. The patch can be configured for continuous, pulsatile, or on-demand delivery of the pharmaceutical. Transdermal delivery of the compound can be achieved by an iontophoresis patch. Transdermal patches can provide controlled delivery of compounds with a delayed absorption rate by using a rate-controlling membrane or by trapping the compound within a polymer matrix or gel. An absorption enhancer may be used to increase absorption, examples of which include pharmaceutically acceptable solvents that are absorbable and assist in passage through the skin.

[0109] Ophthalmic formulations include eye drops.

[0110] Formulations 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, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. Compositions for rectal or vaginal administration can also be formulated as suppositories by mixing the compound with a suitable non-irritating carrier and excipient that are all solid at ambient temperature but liquid at body temperature, so that they melt in the rectal or vaginal cavity and release the compound, for example, cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof. Dosage

[0111] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of the invention or a pharmaceutically acceptable salt or stereoisomer thereof that is effective to produce a desired therapeutic response in a particular patient afflicted with a disease or disorder characterized by or mediated by abnormal activity of a protein (e.g., IKZF2 (Helios)) that can be a substrate of the complex of the compound of the invention and cereblon. Thus, the term "therapeutically effective amount" includes an amount of a compound of the invention or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, induces a positive modification in the disease or disorder being treated, or prevents the onset or progression of the disease or disorder, or reduces to some extent one or more symptoms of the disease or disorder being treated in the subject, or simply kills or inhibits the growth of diseased (e.g., cancer) cells, or reduces the amount of abnormal protein in diseased cells.

[0112] The total daily dosage of the compounds of the present invention and their use can be determined by the attending physician in accordance with standard medical practice, for example, using sound medical judgment. The specific therapeutically effective dosage for any particular patient will depend on any one or more of a variety of factors, including the disease or disorder being treated and its severity (e.g., its current state) well known in the medical art; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and rate of excretion of the specific compound being used; the duration of the treatment; drugs used in combination with or simultaneously with the specific compound being used, etc. (see, e.g., Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173 (2001)).

[0113] The compounds of the present invention, as well as their pharmaceutically acceptable salts and stereoisomers, can be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for an adult) can be 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 - 400 mg / day, about 1 to about 50 mg / day, and about 5 to about 40 mg / day, and in still other embodiments, can range from about 10 to about 30 mg / day. By way of example, capsules can be formulated with from about 1 to about 200 mg of the compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150 and 200 mg). Some embodiments can be formulated such that the individual dosage contains the desired dosage depending on the number of times the compound is administered per day. Method of Use

[0114] In another aspect, the compounds of the invention, as well as their pharmaceutically acceptable salts and stereoisomers, are substrates of the complex of CRBN and the compound of the invention, and are useful for the treatment of diseases and disorders characterized by or mediated by abnormal (e.g., dysregulated) activity of proteins involved in the onset of a disease or disorder, the expression, severity or progression of one or more symptoms or markers, and where degradation of the targeted protein may provide a therapeutic benefit. These proteins may include FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1α, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1 or ZKSC5. The method involves administration to a subject in need thereof of a therapeutically effective amount of a compound of formula (I, II or III) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0115] In some embodiments, the malfunctioning protein contains one or more sequence motifs, such as the CxxCG motif present in ZFP62, GZF1, EGR1, HIC1, HIC2, INSM2, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF316, ZNF335, ZNF407, ZNF408, ZNF462, ZNF483, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, ZSC10, ZSC22, ZN654, and ZUFSP.

[0116] The compounds of the present invention may also be useful for the treatment of diseases or disorders caused by a decrease in the TXNIP protein level. The method involves administering a therapeutically effective amount of a compound of formula (I, II, or III), or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need thereof.

[0117] A "disease" is generally regarded as the health condition of a subject where the subject is unable to maintain homeostasis, and if the disease is not improved, the subject's health continues to deteriorate. In contrast, a "disorder" of a subject is a condition where the subject can maintain homeostasis, but the subject's health condition is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily further deteriorate the subject's health condition.

[0118] In some embodiments, the compounds of the present invention may be useful for the treatment of 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 deregulated cell proliferation, abnormal cell proliferation, or both, including non-cancerous conditions such as neoplasms, pre-cancerous states, benign tumors, and cancer.

[0119] As used herein, the term "subject" (or "patient") includes all members of the animal kingdom that are 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 methods are applicable to companion animals such as dogs and cats, as well as livestock such as cows, horses, sheep, goats, pigs, and other domesticated and wild animals. A subject "in need of" treatment according to the invention is one that is "suffering from or suspected of suffering from" a specific disease or disorder, or in which a sufficient number of risk factors or a sufficient number or combination of signs or symptoms are present such that a medical professional can diagnose or suspect that the subject is suffering from a disease or disorder. Thus, subjects suffering from and suspected of suffering from a specific disease or disorder are not necessarily two different groups.

[0120] Exemplary types of non-cancerous (e.g., cell proliferative) diseases or disorders that can be treated with the compounds of the invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, as well as allergic and genetic diseases.

[0121] 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, polycythemia vera, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndrome (CAPS), endotoxin shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic lung inflammation, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behcet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, juvenile-onset diabetes, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, Hashimoto's disease, Sjogren's syndrome, vitiligo, Wegener's granulomatosis, testicular sarcoidosis, 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 renal diseases, irritable bowel syndrome, heartburn, restenosis, cervicitis, stroke and ischemic injury, nerve trauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, hernia, ruptured or herniated disc syndrome, osteoporosis, rhinitis, thrombosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, fibromyalgia, AIDS and other viral diseases, e.g., herpes zoster, herpes simplex type I or II, influenza virus, and cytomegalovirus, type I and type II diabetes, obesity, insulin resistance, and diabetic retinopathy, 22q11.22q11.2 deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, color vision deficiency, cat cry 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 disorder, thalassemia, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, arteriosclerosis, atherosclerotic arteriosclerosis, amyotrophic lateral sclerosis, asociality, aneurysm, vaginitis, depression, and sudden infant death syndrome are exemplified.

[0122] Some embodiments are such that the compounds of the invention can be used to treat gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, non-alcoholic steatohepatitis, atherosclerotic arteriosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy or diabetic cardiomyopathy.

[0123] In other embodiments, the method is directed to treating a subject having cancer. Generally, the compounds of the invention can be effective in the treatment of carcinomas (solid tumors including both primary and metastatic tumors), sarcomas, melanomas, and blood cancers (cancers that develop in 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 an angiogenic tumor, a tumor that is not yet substantially angiogenic, or a non-angiogenic tumor.

[0124] Typical examples of cancer include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's sarcoma and AIDS-related lymphomas), appendiceal cancer, pediatric cancers (e.g., pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma), basal cell carcinoma, cutaneous cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladdercancer), brain cancer (e.g., glioma and glioblastoma, e.g., brainstem glioma, gestational choriocarcinoma glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic 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), lymphoid neoplasms, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., stomach cancer, small intestine cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST)), germ cell tumor, ovarian germ cell tumor, head and neck cancer, Hodgkin lymphoma, leukemia, lymphoma, multiple myeloma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), kidney cancer (e.g., Wilms tumor, clear cell renal carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenström macroglobulinemia, melanoma, intraocular (ocular) melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer of unknown primary, multiple endocrine neoplasia (MEN), myelodysplastic syndrome, myelodysplasia / myeloproliferative disease, nasopharyngeal cancer, neuroblastoma, oral cancer (e.g., oral cavity cancer, lip cancer, oral cavity cancer, tongue cancer, oropharyngeal cancer, pharyngeal cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, 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 / multiple myeloma, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, corpus uterine cancer), squamous cell carcinoma, thymoma, thymic carcinoma, thyroid cancer, renal pelvis and ureter and other urothelial cancer of the urinary tract, urethral cancer, gestational choriocarcinoma, vaginal cancer and vulvar cancer.

[0125] Sarcomas that may be treatable with the compounds of the present invention include both soft tissue and bone cancers, and representative examples thereof include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelioma or mesothelioma (lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), and mesenchymal or mixed mesodermal tumors (mixed connective tissue type).

[0126] In some embodiments, the methods of the present invention involve treating a subject having a cell proliferative disease or disorder of the hematopoietic system, liver, brain, lung, colon, pancreas, prostate, ovary, breast, skin, and endometrium.

[0127] As used herein, "hematopoietic cell proliferative disease or disorder" includes lymphoma, leukemia, myeloid neoplasm, mast cell neoplasm, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, myelofibrosis with myeloid metaplasia, and essential thrombocythemia. Thus, representative examples of blood cancers include multiple myeloma, lymphoma (T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma (diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and ALK+ anaplastic large cell lymphoma (e.g., diffuse large B cell lymphoma (e.g., germinal center B cell-like diffuse large B cell lymphoma or activated B cell-like diffuse large B cell lymphoma), Burkitt lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B cell non-Hodgkin lymphoma, and relapsed B cell non-Hodgkin lymphoma), B cell non-Hodgkin lymphoma selected from the group consisting of pediatric lymphoma, and lymphomas of lymphocytic and cutaneous origin, e.g., small lymphocyte lymphoma), leukemia (pediatric leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocyte leukemia, chronic myelogenous leukemia (chronic myelocytic leukemia), chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0128] As used herein, "proliferative disease or disorder of the liver" includes all forms of proliferative disorders that develop in the liver. Proliferative disorders of the liver can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and hepatoblastoma), pre-cancer or pre-cancerous conditions of the liver, benign proliferations or lesions of the liver, as well as malignant proliferations or lesions of the liver, and metastatic lesions in tissues and organs of the body other than the liver. Proliferative disorders of the liver can include hyperplasia, metaplasia, dysplasia, hepatocellular carcinoma, intrahepatic cholangiocarcinoma (bile duct cancer), angiosarcoma, hemangiosarcoma, hepatoblastoma, and secondary liver cancer (metastatic liver cancer). In some embodiments, the compounds of the present invention can be effective in the treatment of biliary tract cancer (BTC). In some embodiments, BTC is intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC).

[0129] As used herein, "proliferative disease or disorder of the brain" includes all forms of proliferative disorders that develop in the brain. Proliferative disorders of the brain can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and undifferentiated neuroectodermal tumor (medulloblastoma)), pre-cancer or pre-cancerous conditions of the brain, benign proliferations or lesions of the brain, as well as malignant proliferations or lesions of the brain, and metastatic lesions in tissues and organs of the body other than the brain. Proliferative disorders of the brain can include hyperplasia, metaplasia, and dysplasia of the brain.

[0130] As used herein, "pulmonary cell proliferative disease or disorder" includes all forms of cell proliferative disorders that develop in lung cells. Pulmonary cell proliferative disorders include lung cancer, pre-cancer and pre-cancerous conditions of the lung, benign proliferation or lesions of the lung, hyperplasia, metaplasia and dysplasia of the lung, and metastatic lesions in tissues and organs of the body other than the lung. Lung cancer includes all forms of cancer of the lung, for example, 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", bronchioveolar carcinoma, giant cell carcinoma, spindle cell carcinoma and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms having histological and ultrastructural heterogeneity (e.g., mixed cell type). In some embodiments, the compounds of the present invention may be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC having ROS1 rearrangement, lung adenocarcinoma, and lung squamous cell carcinoma). In some embodiments, the compounds of the present invention may be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC having ROS1 rearrangement, lung adenocarcinoma, and lung squamous cell carcinoma).

[0131] As used herein, "colonic cell proliferative disease or disorder" includes all forms of cell proliferative disorders that develop in colonic cells, including colon cancer, pre-cancer or pre-cancerous 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 and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma and squamous cell carcinoma. Colon cancer may be associated with hereditary syndromes such as hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, MYH-related polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome and juvenile polyposis. The cell proliferative disorder of the colon may also be characterized by hyperplasia, metaplasia or dysplasia of the colon.

[0132] As used herein, "pancreatic cell proliferative disease or disorder" includes all forms of cell proliferative disorders that develop in pancreatic cells. Pancreatic cell proliferative disorders can include pancreatic cancer, pre-cancer or pre-cancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign proliferation or lesions of the pancreas, as well as malignant proliferation or lesions of the pancreas, and metastatic lesions in tissues and organs of the body other than the pancreas. Pancreatic cancer includes all forms of pancreatic cancer, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, unclassified, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, as well as pancreatic neoplasms having histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0133] As used herein, "prostate cell proliferative disease or disorder" includes all forms of cell proliferative disorders that develop in prostate cells. Prostate cell proliferative disorders can include prostate cancer, pre-cancer or pre-cancerous conditions of the prostate, benign proliferation or lesions of the prostate, as well as malignant proliferation or lesions of the prostate, and metastatic lesions in tissues and organs of the body other than the prostate. Prostate cell proliferative disorders can include prostate hyperplasia, metaplasia, and dysplasia.

[0134] As used herein, "ovarian cell proliferative disease or disorder" includes all forms of cell proliferative disorders that develop in ovarian cells. Ovarian cell proliferative disorders can include pre-cancer or pre-cancerous conditions of the ovary, benign proliferation or lesions of the ovary, ovarian cancer, as well as metastatic lesions in tissues and organs of the body other than the ovary. Ovarian cell proliferative disorders can include ovarian hyperplasia, metaplasia, and dysplasia.

[0135] As used herein, "mammary cell proliferative disease or disorder" includes all forms of cell proliferative disorders that occur in mammary cells. Mammary cell proliferative disorders can include breast cancer, pre-cancerous or pre-cancerous conditions of the breast, benign proliferations or lesions of the breast, as well as metastatic lesions in tissues and organs of the body other than the breast. Mammary cell proliferative disorders can include hyperplasia, metaplasia, and dysplasia of the breast.

[0136] As used herein, "cutaneous cell proliferative disease or disorder" includes all forms of cell proliferative disorders that occur in cutaneous cells. Cutaneous cell proliferative disorders can include pre-cancerous or pre-cancerous conditions of the skin, benign proliferations or lesions of the skin, melanoma, malignant melanoma or other malignant proliferations or lesions of the skin, as well as metastatic lesions in tissues and organs of the body other than the skin. Cutaneous cell proliferative disorders can include hyperplasia, metaplasia, and dysplasia of the skin.

[0137] As used herein, "endometrial cell proliferative disease or disorder" includes all forms of cell proliferative disorders that occur in endometrial cells. Endometrial cell proliferative disorders can include pre-cancerous or pre-cancerous conditions of the endometrium, benign proliferations or lesions of the endometrium, endometrial cancer, as well as metastatic lesions in tissues and organs of the body other than the endometrium. Endometrial cell proliferative disorders can include hyperplasia, metaplasia, and dysplasia of the endometrium.

[0138] In some embodiments, the compounds of the present invention can be used to treat coronary heart disease.

[0139] In some embodiments, the compounds of the present invention can be used to treat T-cell leukemia or T-cell lymphoma.

[0140] In some embodiments, the compounds of the present invention can be used to treat Hodgkin lymphoma or non-Hodgkin lymphoma.

[0141] In some embodiments, the compounds of the present invention can be used to treat myeloid leukemia.

[0142] In some embodiments, the compounds of the present invention can be used to treat non-small cell lung cancer (NSCLC).

[0143] In some embodiments, the compounds of the present invention can be used to treat melanoma.

[0144] In some embodiments, the compounds of the present invention can be used to treat triple-negative breast cancer (TNBC).

[0145] In some embodiments, the compounds of the present invention can be used to treat nasopharyngeal carcinoma (NPC).

[0146] In some embodiments, the compounds of the present invention can be used to treat microsatellite stable colorectal cancer (mssCRC).

[0147] In some embodiments, the compounds of the present invention can be used to treat thymoma.

[0148] In some embodiments, the compounds of the present invention can be used to treat carcinoid.

[0149] In some embodiments, the compounds of the present invention can be used to treat gastrointestinal stromal tumor (GIST).

[0150] The compounds of the present invention can be administered to patients, such as cancer patients, as monotherapy, or by combination therapy, and as a subsequent therapy for patients who are non-responsive to first-line therapy or first-line therapy. The therapy can be "first-line", i.e., as the first treatment in patients who have not previously received an anticancer treatment regimen, either alone or in combination with other treatments; or it can be "second-line", i.e., as a treatment in patients who have previously received an anticancer treatment regimen, either alone or in combination with other treatments; or it can be "third-line", "fourth-line", etc., as a treatment, either alone or in combination with other treatments. The therapy can also be given to patients who have received a previous treatment that has been partially successful but are intolerant to a specific treatment. The therapy can also be given as an adjuvant therapy, i.e., in patients who do not currently have a detectable disease, or to prevent cancer recurrence after surgical removal of a tumor. Thus, in some embodiments, the compounds can be administered to patients who have received another therapy such as chemotherapy, radioimmunotherapy, surgery, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0151] The methods of the present invention can involve administering the compounds of the present invention or pharmaceutical compositions 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 a day to about once every 8 weeks. In some embodiments, the dosing frequency ranges from 1, 2, 3, 4, 5 or 6 weeks, about once a day, and in other embodiments, it involves a 28-day cycle that includes daily dosing for 3 weeks (21 days) followed by a 7-day drug-free period. In other embodiments, the compound can be administered twice a day (BID) for 2.5 days (total of 5 doses), or once a day (QD) for 2 days (total of 2 doses). In other embodiments, the compound can be administered once a day (QD) for 5 days. Combination therapy

[0152] The compounds of the invention, as well as their pharmaceutically acceptable salts and stereoisomers, can be used in the treatment of diseases and disorders in combination with or simultaneously with at least one other active agent, such as an anti-cancer agent or regimen. The terms "in combination" and "simultaneously" in this context mean that the agents are administered concurrently, which includes substantially concurrent administration by the same or different dosage forms and by the same or different modes of administration, or sequentially, for example, as part of the same treatment regimen or as a continuous treatment regimen. Thus, when administered sequentially, at the start of administration of the second compound, the first compound of the two compounds can still be detectably present at an effective concentration, in some cases at the site of treatment. The order and time interval can be determined such that they can act together (e.g., synergistically to provide an effect greater than if they were administered by other means). For example, the therapeutic agents can be administered simultaneously or sequentially in any order at different times; however, if not administered simultaneously, they can be administered at times sufficiently close to provide the desired therapeutic effect in a synergistic manner. Thus, these terms are not limited to the exact simultaneous administration of the active agents.

[0153] In some embodiments, including cancer, the treatment regimen may include administering a compound of the invention in combination with one or more additional anti-cancer therapeutics. The dosage of the additional anti-cancer therapeutics can be the same as, or less than, the known or recommended dosages. See Hardman et al., eds., Goodman & Gilman’s The Pharmacological Basis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician’s Desk Reference 60th ed., 2006. Anti-cancer agents that can be used in combination with the compounds of the invention are known in the art. See, for example, U.S. Patent No. 9,101,622 (section 5.2 thereof). Representative examples of additional active agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, antibiotic insertions, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, microtubule inhibitors, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0154] In some embodiments, the compounds of the invention and additional anti-cancer therapeutic agents may be administered at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 to about 3 hours, about 3 to about 4 hours, about 4 to about 5 hours, about 5 to about 6 hours, about 6 to about 7 hours, about 7 to about 8 hours, about 8 to about 9 hours, about 9 to about 10 hours, about 10 to about 11 hours, about 11 to about 12 hours, about 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more anti-cancer therapeutic agents may be administered within the same patient visit.

[0155] In some embodiments, the compounds of formula (I, II, or III) and additional agents or therapeutic agents (e.g., anti-cancer therapeutic agents) are administered periodically. By way of example, in the context of cancer treatment, cycling therapy involves administering one or both anti-cancer therapeutic agents for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., the cycle, in order to reduce the development of resistance to one or both of the anti-cancer therapeutic agents, to avoid or reduce side effects of one or both of the anti-cancer therapeutic agents, and / or to improve the effectiveness of the therapy. In one example, cycling therapy involves administering a first anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, optionally followed by administering a third anti-cancer therapeutic agent for a period of time, etc., and repeating this sequential administration, i.e., the cycle, in order to reduce the development of resistance to one of the anti-cancer therapeutic agents, to avoid or reduce side effects of one of the anti-cancer therapeutic agents, and / or to improve the effectiveness of the anti-cancer therapeutic agent.

[0156] In some embodiments, the compounds of the invention may be used in combination with other anti-cancer agents, examples of which include 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., colorectal 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., colorectal cancer), altretamine (e.g., ovarian cancer), daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and Kaposi's sarcoma), trastuzumab (e.g., breast cancer, gastric cancer and esophageal cancer), rituximab (e.g., non-Hodgkin lymphoma), cetuximab (e.g., colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer), pertuzumab (e.g., metastatic HER2-positive breast cancer), alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T cell lymphoma (CTCL) and T cell lymphoma), panitumumab (e.g., colorectal cancer), tamoxifen (e.g., breast cancer), fulvestrant (e.g., breast cancer), letrozole (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 sarcoma, choriocarcinoma, testicular cancer and ovarian cancer), erlotinib (e.g., non-small cell lung cancer and pancreatic cancer), sorafenib (e.g., kidney cancer and liver cancer), temsirolimus (e.g., kidney cancer), bortezomib (e.g., multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., acute lymphoblastic leukemia), Cabometyx (e.g., hepatocellular carcinoma, medullary thyroid cancer and renal cell carcinoma), Keytruda (e.g., cervical cancer, gastric cancer, hepatocellular carcinoma, Hodgkin lymphoma, melanoma, Merkel cell carcinoma, non-small cell lung cancer, urothelial cancer 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 cancer) and regorafenib (e.g., colorectal cancer,Examples include gastrointestinal stromal tumors and hepatocellular carcinomas. Pharmaceutical kit

[0157] The present composition can be assembled into a kit or a pharmaceutical system. The kit or pharmaceutical system according to this aspect of the present invention comprises a carrier or package such as a box, carton, tube, etc., which tightly encloses one or more containers such as vials, tubes, ampoules or bottles containing the compound or pharmaceutical composition of formula (I, II or III) of the present invention. The kit or pharmaceutical system of the present invention may also include printed instructions for using the compound and composition.

[0158] These and other aspects of the present invention are intended to illustrate certain specific embodiments of the present invention, but are not intended to limit the scope defined by the claims, as will be further understood by considering the following examples.

Examples

[0159] These and other aspects of the present invention are intended to illustrate certain specific embodiments of the present invention, but are not intended to limit the scope defined by the claims, as will be further understood by considering the following examples.

[0160] Example 1: Synthesis of an important bromomaleimide intermediate

Chemical formula

[0161] In a 40 mL vial, 3-aminopiperidine-2,6-dione (1 g, 6.08 mmol, 1.0 eq) was dissolved in dioxane (14 mL, 0.45 M). Bromomaleic anhydride (621 μL, 6.68 mmol, 1.1 eq) was added, and the reaction mixture was stirred at 80 °C for 1 h. Sodium acetate (550 mg, 6.68 mmol, 1.1 eq) was added, and the reaction mixture was stirred at 80 °C for 5 h. Acetic anhydride (632 μL, 6.68 mmol, 1.1 eq) was added dropwise, and the reaction mixture was stirred at 100 °C for 15 h. After cooling to room temperature (rt), the reaction mixture was concentrated. The crude product was dissolved in CH2Cl2 and washed three times with saturated aqueous NaHCO3 and then with water. The organic layer was collected, dried over Na2SO4, and filtered. Concentration in vacuo gave a crude oil, which was dissolved in water and acetonitrile, frozen, and lyophilized. The title compound (1.25 g, 72% yield) was obtained as a light brown solid and used without further purification.

[0162] Example 2: General Synthetic Procedure for the Michael Addition of an Amine and Bromomaleimide Method A: Base-Promoted Michael Addition [Chemical formula]

[0163] In an 8 mL vial, the nucleophile NR2 (0.348 mmol, 1.0 eq), either commercially available or prepared beforehand as described below, was dissolved in dioxane (1 mL). A solution of 3-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (50 mg, 0.348 mmol, 1.0 eq) in dioxane (500 μL) was added to the reaction mixture, followed by triethylamine (60 μL, 0.418 mmol, 1.2 eq). Unless otherwise indicated, the reaction mixture was stirred at 65 °C overnight. After cooling to rt, the reaction mixture was concentrated in vacuo. Purification by silica flash chromatography and / or preparative TLC gave the Michael addition product.

[0164] In addition to amine nucleophiles, this synthetic procedure can be extended to the use of alcohol (ROH) nucleophiles and thiol (RSH) nucleophiles. Method B: Lewis acid-promoted Michael addition

Chem.

[0165] In an 8 mL vial, the commercially available nucleophile NR2 (0.383 mmol, 1.1 equiv) was dissolved in dioxane (1 mL). A solution of 3-(3-bromo-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (50 mg, 0.348 mmol, 1.0 equiv) in dioxane (1 mL) was added to the reaction mixture, followed by AlCl 3( 17 mg, 0.070 mmol, 0.20 equiv) was added. Unless otherwise indicated, the reaction mixture was stirred at rt for 1 h. After cooling to rt, the reaction mixture was diluted with water and extracted 3 times with CH2Cl2. The organic layer was collected, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography and / or preparative TLC gave the Lewis acid-promoted Michael addition product.

[0166] Example 3: General synthetic procedure for amine (NR2) coupling partners Method C: Synthesis of Int-2

Chem.

[0167] In an 8 mL vial, 3-nitrobenzylamine (250 mg, 1.33 mmol, 1.0 eq) was dissolved in dioxane (2 mL, 0.67 M). A solution of 3-chloro-4-methylphenyl isocyanate (244 mg, 1.46 mmol, 1.1 eq) in dioxane (1 mL) was added to the reaction mixture, followed by the addition of Et3N (203 μL, 1.46 mmol, 1.1 eq). The reaction mixture was stirred at 50 °C for 1 h. After cooling to rt, the reaction mixture was diluted with water and extracted three times with CH2Cl2. The organic layer was collected, dried over Na2SO4, filtered, and concentrated in vacuo to give crude Int-1 (72% yield), which was used without further purification.

[0168] In an 8 mL vial, Int-1 (307 mg, 0.96 mmol, 1.0 eq) was dissolved in THF (4.5 mL, 0.21 M). Saturated aqueous NH4Cl solution (2 mL) was added, followed by the addition of iron powder (1.1 g mg, 19 mmol, 20 eq). The reaction mixture was stirred at 55 °C for 3 h. After cooling to rt, the reaction mixture was diluted with water and extracted three times with EtOAc. The organic layer was collected, washed with brine, dried over Na2SO4, filtered through Celite®, and concentrated in vacuo to give crude Int-2 (quantitative yield) as a pale yellow solid, which was used without further purification. Method D: Synthesis of Int-3 [Chemical formula]

[0169] In an 8 mL vial, 1,3-phenylenediamine (150 mg, 1.39 mmol, 1.0 eq) was dissolved in dioxane (2 mL, 0.7 M). A solution of 3-chloro-4-methylphenyl isocyanate (256 mg, 1.53 mmol, 1.1 eq) in dioxane (1 mL) was added to the reaction mixture, followed by the addition of Et3N (213 μL, 1.53 mmol, 1.1 eq). The reaction mixture was stirred at 50 °C for 1 h. After cooling to rt, the reaction mixture was concentrated in vacuo to give crude Int-3 as a white solid, which was used without further purification. Method E: Synthesis of Int-5

Chem.

[0170] In an 8 mL vial, 3-nitrophenylacetic acid (200 mg, 1.1 mmol, 1.0 equiv) was dissolved in CH2Cl2 (2 mL, 0.55 M). Hexafluorophosphate azabenzotriazole tetramethyluronium (HATU) (460 mg, 1.21 mmol, 1.1 equiv), N,N-diisopropylethylamine (422 μL, 2.42 mmol, 2.2 equiv) and dimethylamine (84 μL, 1.21 mmol, 1.1 equiv) were added sequentially. The reaction mixture was stirred at reflux for 4 h. After cooling to rt, the reaction mixture was diluted with water and extracted three times with CH2Cl2. The organic layer was collected, dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica flash chromatography (0 - 100% EtOAc / hexane) afforded Int-4 (55% yield).

[0171] In an 8 mL vial, Int-4 (127 mg, 0.61 mmol, 1.0 equiv) was dissolved in THF (2 mL, 0.3 M). Saturated aqueous NH4Cl solution (1 mL) was added, followed by iron powder (681 mg, 12.2 mmol, 20 equiv). The reaction mixture was stirred at 55 °C for 15 h. After cooling to rt, the reaction mixture was diluted with water and extracted three times with CH2Cl2. The organic layer was collected, dried over Na2SO4, filtered through Celite® and concentrated in vacuo to give crude Int-5 (63% yield) as a yellow solid, which was used without further purification. Method F: Synthesis of Int-7

Chem.

[0172] In a 20 mL vial, (3-((tert-butoxycarbonyl)amino)phenyl)boronic acid (993 mg, 4.19 mmol) was dissolved in THF (5.6 mL). Palladium acetate (24 mg, 0.105 mmol), bipyridine (33 mg, 0.209 mmol) and (E)-but-2-enoic acid (180 mg, 2.09 mmol) were added sequentially. Water (1.7 mL) and AcOH (2.8 mL) were added and the reaction mixture was stirred at 80 °C for 14 h. After cooling to rt, the reaction mixture was extracted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered through Celite® and concentrated by rotary evaporation. Purification by silica flash chromatography (0 - 80% EtOAc / CH2Cl2) gave Int-6 (426.2 mg, 73% yield) as an orange oil.

[0173] In an 8 mL vial, Int-6 (100 mg, 0.358 mmol) was dissolved in DMF (2 mL). HATU (150 mg, 0.394), DIPEA (190 μL, 1.07 mmol) and 3-chloro-4-methylaniline (50 μL, 0.394 mmol) were added sequentially. The reaction mixture was stirred at rt for 3 h. The reaction mixture was extracted with EtOAc, washed twice with water and once with brine, dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude product was then dissolved in CH2Cl2 (3 mL) and cooled to 0 °C. Trifluoroacetic acid (1 mL) was added dropwise at 0 °C and then the mixture was slowly warmed to rt over 1 h. The reaction mixture was concentrated by rotary evaporation to give Int-7 (78.6 mg, 55% yield), which was carried forward without purification.

[0174] Example 4: General synthetic procedure for succinimide scaffolds. Method G: Hydrogenation of aminomaleimide [Chemical formula]

[0175] In an 8 mL vial, aminomaleimide was dissolved in 1:1 DMF / MeOH (3 mL). Palladium on carbon (Pd / C, 0.10 equivalent) was added, and H2 was bubbled through the reaction mixture with stirring overnight. The reaction mixture was filtered through Celite® to remove the Pd catalyst and washed with MeOH. The filtrate was collected and concentrated by rotary evaporation. Purification by preparative TLC (5% 1.75 N NH3 in MeOH / CH2Cl2) gave the succinimide product.

[0176] Example 5: Synthesis of 3-(3-(benzylamino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (1).

Chemical Structure

[0177] Compound 1 was prepared according to Method B. 1 1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.48 (t, J = 6.2, 1H), 7.35 (d, J = 4.3, 4H), 7.28 (h, J = 4.3, 1H), 4.97 (s, 1H), 4.84 (dd, J = 13.0, 5.4, 1H), 4.33 (d, J = 6.3, 2H), 2.81 (ddd, J = 17.0, 13.9, 5.4, 1H), 2.58 - 2.51 (m, 1H), 2.40 (qd, J = 13.2, 4.3, 1H), 1.94 - 1.88 (m, 1H). LC-MS m / z: (pos) 314.0 ([M + H] + )

[0178] Example 6: Synthesis of 3-(2,5-dioxo-3-(phenylamino)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (2).

Chemical Structure

[0179] Compound 2 was prepared according to Method B. 1H NMR(500 MHz,DMSO-d6)δ 11.05(s,1H), 9.81(s,1H), 7.46-7.35(m,4H), 7.13(t,J=7.2,1H), 5.74(s,1H), 4.96(dd,J=13 .0,5.4,1H), 2.85(ddd,1H), 2.61-2.52(m,1H), 2.45(qd,J=13.3,4.4,1H), 2.03-1.96(m,1H). LC-MS m / z:(pos)300.0([M+H] + ).

[0180] Example 7: Synthesis of 3-(3-((3-chloro-4-methylphenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (3). [ka]

[0181] Compound 3 was prepared according to Method A. 1 H NMR(500 MHz,DMSO-d6)δ 11.05(s,1H), 9.83(s,1H), 7.47(d,J=2.2,1H), 7.35(d,J=8.4,1H), 7.31(dd,J=8.2,2.2,1H), 5.76(s,1H), 4.96(dd,J= 13.0,5.4,1H), 2.86(ddd,J=17.3,13.9,5.5,1H), 2.60-2.54(m,1H), 2.48-2.41(m,1H), 2.30(s,3H), 2.02-1.96(m,1H). LC-MS m / z:(pos)348.0([M+H] + ).

[0182] Example 8: Synthesis of 3-(3-((4-chloro-3-methylphenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (4). [ka]

[0183] Compound 4 was prepared according to Method A.1 H NMR(500 MHz,DMSO-d6)δ 11.05(s,1H), 9.82(s,1H), 7.46-7.32(m,2H), 7.29(dd,J=8.7,2.5,1H), 5.84(s,1H), 4.96(dd,J=13.0,5.4, 1H), 2.86(ddd,J=17.1,13.9,5.5,1H), 2.60-2.54(m,1H), 2.49-2.42(m,1H), 2.34(s,3H), 2.02-1.97(m,1H). LC-MS m / z:(pos)348.1([M+H] + ).

[0184] Example 9: Synthesis of 5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)-2-methylbenzonitrile (5). [ka]

[0185] Compound 5 was prepared according to Method A. 1 H NMR(500 MHz,DMSO-d6)δ 11.06(s,1H), 9.93(s,1H), 7.74(d,J=2.3,1H), 7.65(dd,J=8.5,2.4,1H), 7.46(d,J=8.5,1H), 5.94(s,1H), 4.97(dd,J=13.0,5. 4,1H), 2.86(ddd,J=17.1,13.9,5.4,1H), 2.61-2.54(m,1H,duplication), 2.47-2.40(m,1H)2.45(s,3H), 2.00(dtd,J=12.8,5.5,2.3,1H). LC-MS m / z:(pos)339.1([M+H] + ).

[0186] Example 10: Synthesis of 3-(2,5-dioxo-3-((pyridin-3-ylmethyl)amino)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (6). [ka]

[0187] Compound 6 was prepared according to method B. LC-MS m / z: (pos) 314.0 ([M+H] + ).

[0188] Example 11: Synthesis of 3-(3-((3-(1H-imidazol-1-yl)propyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (7). [ka]

[0189] Compound 7 was prepared according to method B. LC-MS m / z: (pos) 331.3 ([M+H] + ).

[0190] Example 12: Synthesis of 3-(3-((1H-pyrazol-3-yl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (8). [ka]

[0191] Compound 8 was prepared according to method B. LC-MS m / z: (pos) 290.0 ([M+H] + ).

[0192] Example 13: Synthesis of 3-(3-((1H-imidazol-5-yl)methoxy)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (9). [ka]

[0193] Compound 9 was prepared according to method A at rt. LC-MS m / z: (pos) 305.0 ([M+H] + ).

[0194] Example 14: Synthesis of 3-(3-(2-(dimethylamino)ethoxy)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (10).

Chemical Structure

[0195] Compound 10 was prepared according to Method A at rt. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 5.99 (s, 1H), 4.93 (dd, J = 13.0, 5.3, 1H), 4.23 (t, J = 5.3, 2H), 2.82 (ddd, J = 17.2, 13.9, 5.5, 1H), 2.75 - 2.68 (m, 2H), 2.58 - 2.53 (m, 1H), 2.40 (qd, J = 13.2, 4.3, 1H), 2.25 (s, 6H), 1.99 - 1.94 (m, 1H). LC-MS m / z: (pos) 296.0 ([M+H] + )

[0196] Example 15: Synthesis of 3-(3-((2-(dimethylamino)ethyl)(methyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (11).

Chemical Structure

[0197] Compound 11 was prepared according to Method A at rt. LC-MS m / z: (pos) 309.1 ([M+H] + )

[0198] Example 16: Synthesis of 3-(3-((3-(dimethylamino)propyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (12).

Chemical Structure

[0199] Compound 12 was prepared according to method A at rt. 1 H NMR(500 MHz,DMSO-d6)δ 10.99(s,1H), 7.98(t,J=5.9,1H), 4.93(s,1H), 4.84(dd,J=13.0,5.4,1H), 3.14(q,J=6.6,2H), 2.82(ddd,J=17.0,13.9,5.4,1H), 2 .58-2.51(m,1H), 2.42(qd,J=13.2,4.4,1H), 2.24(t,J=6.8,2H), 2.12(s,6H), 1.92(dtd,J=13.1,5.4,2.3,1H), 1.67(p,J=6.9,2H). LC-MS m / z:(pos)309.1([M+H] + ).

[0200] Example 17: Synthesis of methyl (1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)glycinate (13). [ka]

[0201] Compound 13 was prepared according to method A at rt. 1 H NMR(500 MHz,DMSO-d6)δ 11.01(s,1H), 7.98(t,J=6.0,1H), 5.05(s,1H), 4.87(dd,J=13.0,5.3,1H), 4.03(d,J=6.0,2H), 3.68(s, 3H), 2.82(ddd,J=17.1,13.9,5.5,1H), 2.57-2.52(m,1H), 2.42(qd,J=13.2,4.4,1H), 1.97-1.91(m,1H). LC-MS m / z:(pos)296.0([M+H] + ).

[0202] Example 18: Synthesis of methyl 3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)propanoate (14). [ka]

[0203] Compound 14 was prepared according to method A at rt. 1 H NMR(500 MHz,DMSO-d6)δ 10.99(s,1H), 7.89(t,J=5.6,1H), 5.02(s,1H), 4.85(dd,J=13.0,5.3,1H), 3.61(s,3H), 3.36(q,J=6.5,2H), 2 .82(ddd,J=17.1,14.0,5.5,1H), 2.65(t,J=6.8,2H), 2.56-2.52(m,1H), 2.46-2.38(m,1H), 1.95-1.88(m,1H). LC-MS m / z:(pos)310.1([M+H] + ).

[0204] Example 19: Synthesis of methyl N-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-N-methylglycinate (15). [ka]

[0205] Compound 15 was prepared according to method A at rt. 1 H NMR(500 MHz,DMSO-d6)δ 10.99(s,1H), 5.19(s,1H), 4.84(dd,J=12.9,5.3,1H), 4.61(s,2H), 3.67(s,3H), 3.01(s, 3H), 2.85-2.77(m,1H), 2.59-2.51(m,1H), 2.39(qd,J=13.2,4.7,1H), 1.93-1.87(m,1H). LC-MS m / z:(pos)310.0([M+H] + ).

[0206] Example 20: Synthesis of ethyl (1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)glycinate (16). [ka]

[0207] Compound 16 was prepared at rt according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.97 (t, J = 6.3, 1H), 5.03 (s, 1H), 4.87 (dd, J = 13.0, 5.4, 1H), 4.14 (q, J = 7.1, 2H), 4.01 (d, J = 6.2, 2H), 2.83 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.58 - 2.52 (m, 1H), 2.42 (qd, J = 13.5, 4.7, 1H), 1.97 - 1.90 (m, 1H), 1.21 (t, J = 7.1, 3H). LC-MS m / z: (pos) 310.1 ([M+H] + )。

[0208] Example 21: Synthesis of ethyl N-(1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-N-methylglycinate (17).

Chemical Structure

[0209] Compound 17 was prepared at rt according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 5.19 (s, 1H), 4.84 (dd, J = 12.9, 5.3, 1H), 4.59 (s, 2H), 4.13 (q, J = 5.3, 2H), 3.01 (s, 3H), 2.80 (ddd, J = 13.9, 10.2, 6.9, 1H), 2.58 - 2.51 (m, 1H), 2.39 (qd, J = 13.1, 5.0, 1H), 1.92 - 1.86 (m, 1H), 1.20 (t, J = 7.1, 3H). LC-MS m / z: (pos) 324.1 ([M+H] + )。

[0210] Example 22: Synthesis of 3-(3-((1H-1,2,4-triazol-3-yl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (18). [Chemical formula]

[0211] Compound 18 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.48 (s, 1H), 6.41 (s, 1H), 5.10 - 5.01 (m, 1H), 2.86 (ddd, J = 17.3, 13.9, 5.5, 1H), 2.62 - 2.56 (m, 1H), 2.47 - 2.39 (m, 1H), 2.06 - 1.99 (m, 1H). LC-MS m / z: (pos) 291.0 ([M+H] + )

[0212] Example 23: Synthesis of 3-(2,5-dioxo-3-(thiazol-2-ylamino)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (19). [Chemical formula]

[0213] Compound 19 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.00 (s, 1H), 7.93 (d, J = 5.4, 1H), 7.29 (s, 1H), 6.54 (d, J = 5.4, 1H), 5.02 (dd, J = 13.0, 5.3, 1H), 2.85 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.60 - 2.55 (m, 1H), 2.47 - 2.40 (m, 1H), 2.02 - 1.97 (m, 1H). LC-MS m / z: (pos) 306.9 ([M+H] + )

[0214] Example 24: Synthesis of methyl 5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)-1H-1,2,4-triazole-3-carboxylate (20). [Chemical formula]

[0215] Compound 20 was prepared according to Method A. 1 H NMR(500 MHz,DMSO-d6)δ 11.13(s,1H), 7.57(s,2H), 7.03(s,1H), 5.08(dd,J=12.9,5.4,1H), 3.83(s,3H), 2.86 (ddd,J=17.2,13.9,5.5,1H), 2.62-2.57(m,1H), 2.46-2.39(m,1H), 2.05-2.01(m,1H). LC-MS m / z:(pos)349.0([M+H] + ).

[0216] Example 25: Synthesis of 4-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)butanoic acid (21). [ka]

[0217] Compound 21 was prepared according to method A at 75 °C. 1 H NMR(500 MHz,DMSO-d6)δ 8.03(s,1H), 4.96(s,1H), 4.85(dd,J=12.9,5.4,1H), 3.12(t,J=6.9,2H), 2.82(ddd,J=17.0,13.9,5.4,1H), 2 .56-2.54(m,1H), 2.42(qd,J=13.4,4.4,1H), 2.26(t,J=7.2,2H), 1.97-1.90(m,1H), 1.75(p,J=7.2,6.7,2H). LC-MS m / z:(pos)332.0([M+Na] + ).

[0218] Example 26: Synthesis of 5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)pentanoic acid (22). [ka]

[0219] Compound 22 was prepared according to method A at 75 °C. 1 H NMR(500 MHz,DMSO-d6)δ 8.00(s,1H), 4.95(s,1H), 4.84(dd,J=13.0,5.4,1H), 3.11(t,J=6.3,2H), 2.82(ddd,J=17.0,13.9,5.5,1H ), 2.58-2.51(m,1H), 2.42(qd,J=13.2,4.5,1H), 2.19(t,J=6.9,2H), 1.95-1.88(m,1H), 1.57-1.48(m,4H). LC-MS m / z:(pos)346.0([M+Na] + ).

[0220] Example 27: Synthesis of 3-(3-((3-(1H-tetrazol-5-yl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (23). [ka]

[0221] Compound 23 was prepared according to method A at 50 °C. 1 H NMR(500 MHz,DMSO-d6)δ 11.06(s,1H), 9.90(s,1H), 8.02(s,1H), 7.74(d,J=7.6,1H), 7.40(t,J=7.8,1H), 7.35-7.30(m,1H), 5.64(s, 1H), 4.98(dd,J=13.0,5.4,1H), 2.87(ddd,J=5.3,1H), 2.60(m,1H), 2.54-2.43(m,1H,duplication), 2.06-1.97(m,1H). LC-MS m / z:(pos)368.0([M+Na] + ).

[0222] Example 28: Synthesis of 3-(3-((3,4-dimethylphenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (24). [ka]

[0223] Compound 24 was prepared at 50 °C according to Method A. LC-MS m / z: (pos) 328.0 ([M+H] + )

[0224] Example 29: Synthesis of 3-(3-((4-chlorophenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (25).

Chemical Structure

[0225] Compound 25 was prepared at 50 °C according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.91 (s, 1H), 7.55 - 7.39 (m, 4H), 5.79 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 2.86 (ddd, J = 17.2, 13.9, 5.5, 1H), 2.60 - 2.55 (m, 1H), 2.48 - 2.42 (m, 1H), 2.02 - 1.97 (m, 1H). LC-MS m / z: (pos) 334.0 ([M+H] + )

[0226] Example 30: Synthesis of 3-(3-((3-chlorophenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (26).

Chemical Structure

[0227] Compound 26 was prepared at 55 °C according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.82 (s, 1H), 7.48 (s, 1H), 7.46 - 7.36 (m, 2H), 7.18 - 7.16 (m, 1H), 5.85 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 2.86 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.58 (ddd, J = 17.1, 4.4, 2.4, 1H), 2.49 - 2.41 (m, 1H), 2.00 (dtd, J = 12.9, 5.4, 2.4, 1H). LC-MS m / z: (pos) 334.0 ([M+H] + )。

[0228] Example 31: Synthesis of 3-(2,5-dioxo-3-(quinolin-3-ylamino)-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (27).

Chemical Structure

[0229] Compound 27 was prepared according to Method A. LC-MS m / z: (pos) 351.0 ([M+H] + )。

[0230] Example 32: Synthesis of 3-(3-(methyl(phenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (28).

Chemical Structure

[0231] Compound 28 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.41 (t, J = 7.7, 2H), 7.34 - 7.28 (m, 3H), 5.26 (s, 1H), 4.82 (dd, J = 12.9, 5.4, 1H), 3.42 (s, 3H), 2.80 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.57 - 2.51 (m, 1H), 2.37 (qd, J = 13.2, 4.4, 1H), 1.91 (dtd, J = 13.0, 5.4, 2.3, 1H). LC-MS m / z: (pos) 314.0 ([M + H] + )。

[0232] Example 33: Synthesis of 3-(3-((4-(1H-imidazol-1-yl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (29).

Chemical Structure

[0233] Compound 29 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.97 (s, 1H), 8.22 (s, 1H), 7.74 - 7.70 (m, 1H), 7.68 - 7.62 (m, 2H), 7.58 - 7.52 (m, 2H), 7.09 (d, J = 10.2, 1H), 5.78 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 2.86 (ddd, J = 17.0, 13.9, 5.5, 1H), 2.58 (ddd, J = 17.2, 4.5, 2.5, 1H), 2.49 - 2.43 (m, 1H), 2.00 (dtd, J = 12.9, 5.4, 2.4, 1H). LC-MS m / z: (pos) 366.1 ([M + H] + )。

[0234] Example 34: Synthesis of ethyl 3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzoate (30).

Chemical Structure

[0235] Compound 30 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.03 (s, 1H), 8.03 (s, 1H), 7.77 - 7.62 (m, 2H), 7.54 (t, J = 7.9, 1H), 5.76 (s, 1H), 4.98 (dd, J = 13.0, 5.4, 1H), 4.33 (q, J = 7.1, 2H), 2.86 (ddd, J = 17.0, 13.9, 5.5, 1H), 2.66 - 2.55 (m, 1H), 2.48 - 2.41 (m, 1H), 2.04 - 1.97 (m, 1H), 1.33 (t, J = 7.1, 3H). LC-MS m / z: (pos) 372.1 ([M + H] + )

[0236] Example 35: Synthesis of 3-(3 - ((3-(1H - pyrazol - 3 - yl)phenyl)amino)-2,5 - dioxo - 2,5 - dihydro - 1H - pyrrol - 1 - yl)piperidine - 2,6 - dione (31).

Chemical formula

[0237] Compound 31 was prepared at 50 °C according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.85 (s, 1H), 7.88 - 7.64 (m, 2H), 7.55 (d, J = 7.6, 1H), 7.42 (t, J = 7.9, 1H), 7.35 (d, J = 8.2, 1H), 6.71 (d, J = 2.2, 1H), 5.75 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 2.86 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.64 - 2.55 (m, 1H), 2.49 - 2.43 (m, 1H), 2.00 (dtd, J = 12.9, 5.4, 2.3, 1H). LC-MS m / z: (pos) 366.1 ([M + H] + )

[0238] Example 36: Synthesis of 3-(3-((1H-indazol-6-yl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (32). [Chemical formula]

[0239] Compound 32 was prepared according to Method A at 50 °C. 1 H NMR (500 MHz, DMSO-d6) δ 12.91 (s, 1H), 11.06 (s, 1H), 9.96 (s, 1H), 8.03 (s, 1H), 7.75 (d, J = 8.7, 1H), 7.49 (s, 1H), 7.26 (dd, J = 8.7, 1.9, 1H), 5.76 (s, 1H), 4.98 (dd, J = 12.9, 5.4, 1H), 2.87 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.64 - 2.56 (m, 1H), 2.48 - 2.44 (m, 1H), 2.04 - 1.98 (m, 1H). LC-MS m / z: (pos) 340.1 ([M+H] + )

[0240] Example 37: Synthesis of 3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)-N,N-dimethylbenzamide (33). [Chemical formula]

[0241] Compound 33 was prepared according to Method A. The aniline coupling partner was prepared according to Method E. 11H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.89 (s, 1H), 7.48 (d, J = 8.2, 1H), 7.44 (t, J = 7.8, 1H), 7.41 (s, 1H), 7.13 (d, J = 7.3, 1H), 5.78 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 2.98 (s, 3H), 2.91 (s, 3H), 2.89 - 2.81 (m, 1H), 2.64 - 2.54 (m, 1H), 2.49 - 2.42 (m, 1H), 2.03 - 1.97 (m, 1H). LC-MS m / z: (pos) 371.1 ([M+H] + )。

[0242] Example 38: Synthesis of 4 - ((1-(2,6 - dioxopiperidin - 3 - yl)-2,5 - dioxo - 2,5 - dihydro - 1H - pyrrol - 3 - yl)amino)-N,N - dimethylbenzamide (34).

Chem.

[0243] Compound 34 was prepared according to Method A. The aniline coupling partner was prepared according to Method E. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.90 (s, 1H), 7.47 (d, J = 8.7, 2H), 7.43 (d, J = 8.7, 2H), 5.86 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 2.95 (s, 6H), 2.86 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.58 (ddd, J = 17.2, 4.6, 2.5, 1H), 2.49 - 2.42 (m, 1H), 2.04 - 1.99 (m, 1H). LC-MS m / z: (pos) 371.1 ([M+H] + )。

[0244] Example 39: Synthesis of 2 - (3 - ((1-(2,6 - dioxopiperidin - 3 - yl)-2,5 - dioxo - 2,5 - dihydro - 1H - pyrrol - 3 - yl)amino)phenyl)-N,N - dimethylacetamide (35).

Chem.

[0245] Compound 35 was prepared according to Method A. The aniline coupling partner was prepared according to Method E. 1 H NMR(500 MHz,DMSO-d6)δ 11.05(s,1H), 9.81(s,1H), 7.34-7.25(m,3H), 6.97(d,J=7.0,1H), 5.72(s,1H), 4.96(dd,J=13.0,5.4,1H), 3.7 2(s,2H), 3.01(s,3H), 2.91-2.80(m,1H), 2.85(s,3H), 2.62-2.54(m,1H), 2.49-2.43(m,1H), 2.03-1.97(m,1H). LC-MS m / z:(pos)385.2([M+H] + ).

[0246] Example 40: Synthesis of 2-(4-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N,N-dimethylacetamide (36). [ka]

[0247] Compound 36 was prepared according to Method A. The aniline coupling partner was prepared according to Method E. 1 H NMR(500 MHz,DMSO-d6)δ 11.05(s,1H), 9.79(s,1H), 7.35(d,J=8.2,2H), 7.22(d,J=8.2,2H), 5.70(s,1H), 4.96(dd,J=12.9,5.4,1H), 3.6 6(s,2H), 3.00(s,3H), 2.91-2.83(m,1H), 2.83(s,3H), 2.61-2.54(m,1H), 2.49-2.42(m,1H), 2.03-1.96(m,1H). LC-MS m / z:(pos)385.2([M+H] + ).

[0248] Example 41: Synthesis of 3-(3-((1H-Indol-6-yl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (37). [Chemical formula]

[0249] Compound 37 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 11.02 (s, 1H), 9.84 (s, 1H), 7.53 (d, J = 8.5, 1H), 7.43 (s, 1H), 7.34 (t, J = 2.6, 1H), 7.12 (dd, J = 8.5, 1.6, 1H), 6.41 (t, J = 2.5, 1H), 5.56 (s, 1H), 4.96 (dd, J = 12.9, 5.4, 1H), 2.87 (ddd, J = 17.2, 13.9, 5.4 Hz, 1H), 2.61 - 2.55 (m, 1H), 2.49 - 2.43 (m, 1H), 2.02 - 1.98 (m, 1H). LC-MS m / z: (pos) 339.0 ([M+H] + )

[0250] Example 42: Synthesis of 3-(3-([1,1'-Biphenyl]-4-ylamino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (38). [Chemical formula]

[0251] Compound 38 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.94 (s, 1H), 7.69 (d, J = 8.6, 2H), 7.67 (d, J = 7.8, 3H), 7.53 (d, J = 8, 2H), 7.46 (t, J = 7.6, 2H), 7.35 (t, J = 7.3, 1H), 5.82 (s, 1H), 4.98 (dd, J = 13.0, 5.4, 1H), 2.87 (ddd, J = 17.1, 13.8, 5.4, 1H), 2.61 - 2.56 (m, 1H), 2.49 - 2.44 (m, 1H), 2.04 - 1.99 (m, 1H). LC-MS m / z: (pos) 376.2 ([M + H] + ).

[0252] Example 43: Synthesis of 3-(3-((4-Benzylphenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (39).

Chem.

[0253] Compound 39 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.77 (s, 1H), 7.34 (d, J = 8.4, 2H), 7.29 (t, J = 7.5, 2H), 7.23 (d, J = 8.1, 4H), 7.19 (t, J = 7.2, 1H), 5.67 (s, 1H), 4.95 (dd, J = 13.0, 5.4, 1H), 3.92 (s, 2H), 2.85 (ddd, J = 17.3, 13.9, 5.5, 1H), 2.57 (dt, J = 17.2, 3.3, 1H), 2.49 - 2.42 (m, 1H), 2.01 - 1.96 (m, 1H). LC-MS m / z: (pos) 390.2 ([M + H] + ).

[0254] Example 44: Synthesis of 1-(3-Chloro-4-methylphenyl)-3-(2-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)ethyl)urea (41).

Chem.

[0255] Compound 41 was prepared according to Method A. The amine coupling partner was prepared according to Method D. 1 H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.70 (s, 1H), 7.93 (t, J = 5.5, 1H), 7.63 (d, J = 1.9, 1H), 7.17 (d, J = 8.3, 1H), 7.12 (dd, J = 8.3, 1.9, 1H), 6.31 (t, J = 5.7, 1H), 5.04 (s, 1H), 4.85 (dd, J = 13.0, 5.4, 1H), 3.29 (q, J = 6.1, 2H), 3.21 (q, J = 6.0, 2H), 2.82 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.58 - 2.52 (m, 1H), 2.41 (qd, J = 13.3, 4.4, 1H), 2.23 (s, 3H), 1.93 - 1.88 (m, 1H). LC-MS m / z: (pos) 434.2 ([M+H] + )。

[0256] Example 45: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(4-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)urea (42).

Chem.

[0257] Compound 42 was prepared according to Method A. The aniline coupling partner was prepared according to Method D. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.77 (s, 1H), 8.76 (s, 2H), 7.68 (s, 1H), 7.46 (d, J = 8.9, 2H), 7.35 (d, J = 8.8, 2H), 7.24 (d, J = 8.3, 1H), 7.18 (dd, J = 8.2, 1.4, 1H), 5.64 (s, 1H), 4.95 (dd, J = 12.9, 5.3, 1H), 2.90 - 2.82 (m, 1H), 2.60 - 2.55 (m, 1H), 2.48 - 2.41 (m, 1H), 2.26 (s, 3H), 2.01 - 1.97 (m, 1H). LC-MS m / z: (pos) 482.2 ([M+H] + )。

[0258] Example 46: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)urea (43).

Chemical Structure

[0259] Compound 43 was prepared according to Method A. The aniline coupling partner was prepared according to Method D. 1 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.86 (s, 1H), 8.84 (s, 1H), 8.81 (s, 1H), 7.69 (d, J = 2.3, 1H), 7.65 (t, J = 2.1, 1H), 7.33 - 7.19 (m, 3H), 7.15 (dd, J = 8.1, 2.0, 1H), 7.06 (dd, J = 8.0, 2.2, 1H), 5.71 (s, 1H), 4.98 (dd, J = 13.0, 5.4, 1H), 2.87 (ddd, J = 17.0, 13.9, 5.4, 1H), 2.62 - 2.56 (m, 1H), 2.47 (qd, J = 13.4, 4.5, 1H), 2.27 (s, 3H), 2.05 - 1.99 (m, 1H). LC-MS m / z: (pos) 482.2 ([M+H] + )。

[0260] Example 47: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (44).

Chem.

[0261] Compound 44 was prepared according to Method A. The aniline coupling partner was prepared according to Method C. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.84 (s, 1H), 8.70 (s, 1H), 7.69 - 7.61 (m, 1H), 7.36 (s, 1H), 7.33 (d, J = 7.5, 1H), 7.30 (d, J = 8.0, 1H), 7.17 (d, J = 8.3, 1H), 7.13 (dd, J = 8.4, 1.6, 1H), 7.05 (d, J = 7.2, 1H), 6.70 (t, J = 6.0, 1H), 5.77 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 4.30 (d, J = 6.0, 2H), 2.86 (ddd, J = 17.0, 13.9, 5.4, 1H), 2.60 - 2.55 (m, 1H), 2.45 (dd, J = 13.4, 4.1, 1H), 2.23 (s, 3H), 2.01 - 1.97 (m, 1H). LC-MS m / z: (pos) 496.3 ([M + H] + )

[0262] Example 48: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(2-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (45).

Chem.

[0263] Compound 45 was prepared according to Method A. The aniline coupling partner was prepared according to Method C. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.76 (s, 1H), 8.77 (s, 1H), 7.62 (d, J = 2.1, 1H), 7.44 (dd, J = 7.7, 1.5, 1H), 7.41 - 7.30 (m, 2H), 7.25 (td, J = 7.4, 1.6, 1H), 7.18 (d, J = 8.3, 1H), 7.12 (dd, J = 8.3, 2.2, 1H), 6.80 (t, J = 6.0, 1H), 5.21 (s, 1H), 4.95 (dd, J = 13.0, 5.4, 1H), 4.28 (d, J = 6.1, 2H), 2.86 (ddd, J = 17.0, 13.8, 5.4, 1H), 2.61 - 2.54 (m, 1H), 2.45 (qd, J = 4.3, 1H), 2.23 (s, 3H), 2.00 - 1.93 (m, 1H). LC-MS m / z: (pos) 496.3 ([M + H] + )。

[0264] Example 49: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(4-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (46).

Chemical Structure

[0265] Compound 46 was prepared according to Method A. The aniline coupling partner was prepared according to Method C. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.81 (s, 1H), 8.66 (s, 1H), 7.66 (s, 1H), 7.39 (d, J = 8.1, 2H), 7.31 (d, J = 8.1, 2H), 7.17 (d, J = 8.3, 1H), 7.12 (d, J = 7.7, 1H), 6.66 (t, J = 5.6, 1H), 5.71 (s, 1H), 4.95 (dd, J = 12.9, 5.4, 1H), 4.26 (d, J = 5.5, 2H), 2.86 (ddd, J = 17.8, 14.0, 5.4, 1H), 2.61 - 2.53 (m, 1H), 2.45 (qd, J = 13.7, 4.3, 1H), 2.23 (s, 3H), 2.02 - 1.96 (m, 1H), 1.23 (s, 2H). LC-MS m / z: (pos) 496.2 ([M + H] + )。

[0266] Example 50: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)propyl)urea (47).

Chemical Structure

[0267] Compound 47 was prepared according to Method A. The alkylamine coupling partner was prepared according to Method D. 1 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.56 (s, 1H), 7.95 (t, J = 5.8, 1H), 7.63 (d, J = 1.6, 1H), 7.16 (d, J = 8.3, 1H), 7.10 (dd, J = 8.3, 1.7, 1H), 6.22 (t, J = 5.6, 1H), 4.97 (s, 1H), 4.85 (dd, J = 12.9, 5.4, 1H), 3.13 (dq, J = 18.7, 6.4, 4H), 2.82 (ddd, J = 17.4, 14.2, 5.4, 1H), 2.57 - 2.52 (m, 1H), 2.42 (ddd, J = 13.2, 4.3, 1H), 2.22 (s, 3H), 1.95 - 1.88 (m, 1H), 1.71 (m, J = 6.8, 2H). LC-MS m / z: (pos) 448.2 ([M + H]+ )。

[0268] Example 51: Synthesis of 3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl (3-chloro-4-methylphenyl)carbamate (48).

Chem.

[0269] Compound 48 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.87 (s, 1H), 8.83 (s, 1H), 7.69 (d, 1H), 7.61 (s, 1H), 7.44 (d, J = 8.2, 1H), 7.34 (t, J = 7.8, 1H), 7.24 (d, J = 8.3, 1H), 7.19 (dd, 1H), 7.09 (d, J = 7.5, 1H), 6.07 (s, 1H), 5.20 (s, 2H), 4.94 (dd, J = 13.0, 5.3, 1H), 2.86 - 2.78 (m, 1H), 2.57 - 2.52 (m, 1H), 2.40 (qd, J = 13.0, 4.2, 1H), 2.32 - 2.27 (m, 1H), 2.26 (s, 3H). LC-MS m / z: (pos) 497.2 ([M+H] + )。

[0270] Example 52: Synthesis of N-(3-chloro-4-methylphenyl)-3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzamide (49).

Chem.

[0271] Compound 49 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.36 (s, 1H), 9.98 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.68 (d, J = 7.7, 1H), 7.66 - 7.57 (m, 2H), 7.54 (t, J = 7.8, 1H), 7.33 (d, J = 8.2, 1H), 5.87 (s, 1H), 4.98 (dd, J = 13.0, 5.4, 1H), 2.87 (ddd, J = 16.9, 13.9, 5.5, 1H), 2.61 - 2.55 (m, 1H), 2.49 - 2.43 (m, 1H), 2.30 (s, 3H), 2.03 - 1.98 (m, 1H). LC-MS m / z: (pos) 467.3 ([M + H] + )。

[0272] Example 53: Synthesis of N-(3-chloro-4-methylphenyl)-2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acetamide (50).

Chemical Structure

[0273] Compound 50 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.31 (s, 1H), 9.83 (s, 1H), 7.80 (d, J = 2.2, 1H), 7.39 (s, 1H), 7.37 (dd, J = 8.3, 2.2, 1H), 7.35 - 7.29 (m, 2H), 7.26 (d, J = 8.3, 1H), 7.08 (d, J = 6.7, 1H), 5.77 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 3.66 (s, 2H), 2.89 - 2.82 (m, 1H), 2.57 (ddd, J = 17.2, 4.4, 2.4 1H), 2.48 - 2.41 (m, 1H), 2.26 (s, 3H), 2.03 - 1.97 (m, 1H). LC-MS m / z: (pos) 481.2 ([M + H] + )。

[0274] Example 54: Synthesis of 3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl(3-chloro-4-methylphenyl)carbamate (51).

Chemical formula

[0275] Compound 51 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.41 (t, J = 8.1, 1H), 7.29 (d, J = 8.0, 1H), 7.24 (d, J = 8.2, 1H), 7.20 (dd, J = 8.4, 2.1, 1H), 6.97 (dd, J = 8.2, 2.4, 1H), 5.73 (s, 1H), 5.01 (dd, J = 13.1, 5.3, 1H), 2.89 - 2.81 (m, 1H), 2.61 - 2.55 (m, 1H), 2.46 - 2.39 (m, 1H), 2.26 (s, 3H), 2.05 - 2.01 (m, 1H). LC-MS m / z: (pos) 483.2 ([M+H] + )

[0276] Example 55: Synthesis of 3-(3-chloro-4-methylphenyl)-1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)-1-methylurea (52).

Chemical formula

[0277] Compound 52 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.86 (s, 1H), 8.50 (s, 1H), 7.67 (d, 1H), 7.45 - 7.25 (m, 4H), 7.19 (d, J = 8.3, 1H), 7.02 (d, J = 7.2, 1H), 5.72 (s, 1H), 4.96 (dd, J = 13.0, 5.3, 1H), 4.56 (s, 2H), 2.94 (s, 3H), 2.90 - 2.82 (m, 1H), 2.60 - 2.54 (m, 1H), 2.49 - 2.42 (m, 1H), 2.24 (s, 3H), 2.01 - 1.96 (m, 1H). LC-MS m / z: (pos) 510.3 ([M + H] + )。

[0278] Example 56: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propanamide (53).

Chemical Structure

[0279] Compound 53 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.99 (s, 1H), 9.76 (s, 1H), 7.77 (d, 1H), 7.33 (dd, 1H), 7.32 - 7.19 (m, 4H), 7.01 (d, J = 7.3, 1H), 5.76 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 2.92 (t, J = 7.6, 2H), 2.86 (ddd, J = 17.1, 14.0, 5.6, 1H), 2.63 (t, J = 7.6, 2H), 2.60 - 2.55 (m, 1H), 2.49 - 2.41 (m, 1H), 2.25 (s, 3H), 1.99 (dtd, J = 13.3, 5.6, 2.3, 1H). LC-MS m / z: (pos) 495.2 ([M + H] + )。

[0280] Example 57: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)urea (54).

Chemical Structure

[0281] Compound 54 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.82 (s, 1H), 8.48 (s, 1H), 7.62 (d, J = 1.9, 1H), 7.37 (s, 1H), 7.35 (t, J = 7.8, 1H), 7.31 - 7.26 (m, 1H), 7.16 (d, J = 8.3, 1H), 7.12 - 7.06 (m, 2H), 6.72 (d, J = 7.8, 1H), 5.75 (s, 1H), 4.96 (dd, J = 12.9, 5.4, 1H), 4.82 (p, J = 6.9, 1H), 2.86 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.57 (dt, J = 17.2, 3.3, 1H), 2.49 - 2.43 (m, 1H), 2.22 (s, 3H), 2.02 - 1.96 (m, 1H), 1.39 (d, J = 6.9, 3H). LC-MS m / z: (pos) 510.3 ([M + H] + )

[0282] Example 58: Synthesis of 1-(3,4-dimethylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)urea (55).

Chemical Structure

[0283] Compound 55 was prepared according to Method A. LC-MS m / z: (pos) 462.3 ([M + H] + )

[0284] Example 59: Synthesis of 1-(3,4-dichlorophenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)urea (56).

Chem.

[0285] Compound 56 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.86 (s, 1H), 9.07 (s, 1H), 8.97 (s, 1H), 7.86 (d, J = 2.5, 1H), 7.64 (t, J = 2.1, 1H), 7.53 (d, J = 8.8, 1H), 7.36 (dd, J = 8.8, 2.5, 1H), 7.28 (t, J = 8.2, 1H), 7.17 - 7.14 (m, 1H), 7.06 (dd, J = 8.0, 1.5, 1H), 5.70 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 2.86 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.58 (dt, J = 17.3, 3.4, 1H), 2.49 - 2.43 (m, 1H), 2.03 - 1.97 (m, 1H). LC-MS m / z: (pos) 502.2 ([M+H] + )

[0286] Example 60: Synthesis of (E)-N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acrylamide (57).

Chem.

[0287] Compound 57 was prepared according to Method A. LC-MS m / z: (pos) 493.2 ([M+H] + )

[0288] Example 61: Synthesis of 1-(3,4-dimethylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (58).

Chemical formula

[0289] Compound 58 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.84 (s, 1H), 8.37 (s, 1H), 7.36 (s, 1H), 7.35 - 7.31 (m, 1H), 7.29 (d, J = 8.1, 1H), 7.18 (s, 1H), 7.10 (d, 1H), 7.05 (d, J = 7.2, 1H), 6.96 (d, J = 8.1, 1H), 6.57 (t, J = 5.9, 1H), 5.77 (s, 1H), 4.96 (dd, J = 13.0, 5.3, 1H), 4.29 (d, J = 5.8, 2H), 2.86 (ddd, J = 17.0, 13.9, 5.4, 1H), 2.57 (dt, J = 17.0, 3.2, 1H), 2.49 - 2.42 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.02 - 1.96 (m, 1H). LC-MS m / z: (pos) 476.3 ([M + H] + )

[0290] Example 62: Synthesis of 1-(3,4-dichlorophenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (59).

Chemical formula

[0291] Compound 59 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.84 (s, 1H), 8.96 (s, 1H), 7.85 (d, J = 2.3, 1H), 7.45 (d, J = 8.8, 1H), 7.37 - 7.26 (m, 4H), 7.05 (d, J = 7.2, 1H), 6.84 (t, J = 5.9, 1H), 5.76 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 4.31 (d, J = 5.9, 2H), 2.86 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.57 (dt, J = 17.3, 3.3, 1H), 2.49 - 2.42 (m, 1H), 1.99 (dtd, J = 11.2, 5.7, 2.4, 1H). LC-MS m / z: (pos) 516.1 ([M + H] + )。

[0292] Example 63: Synthesis of 2-(3,4-dimethylphenyl)-N-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)acetamide (60).

Chemical Structure

[0293] Compound 60 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.81 (s, 1H), 8.51 (s, 1H), 7.38 - 7.21 (m, 3H), 7.06 - 7.00 (m, 2H), 7.00 - 6.94 (m, 2H), 5.73 (s, 1H), 4.97 (dd, J = 12.9, 5.0, 1H), 4.27 (d, J = 5.5, 2H), 3.39 (s, 2H), 2.87 (ddd, J = 17.9, 13.9, 5.4, 1H), 2.61 - 2.55 (m, 1H), 2.48 - 2.43 (m, 1H), 2.16 (s, 6H), 2.03 - 1.99 (m, 1H). LC-MS m / z: (pos) 475.3 ([M + H] + )。

[0294] Example 64: Synthesis of 2-(3,4-dichlorophenyl)-N-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)acetamide (61).

Chem.

[0295] Compound 61 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.82 (s, 1H), 8.63 (t, J = 5.9, 1H), 7.55 (d, J = 8.2, 1H), 7.53 (d, J = 1.6, 1H), 7.36 - 7.22 (m, 4H), 6.99 (d, J = 6.8, 1H), 5.73 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 4.28 (d, J = 5.9, 2H), 3.52 (s, 2H), 2.87 (ddd, J = 17.2, 13.8, 5.4, 1H), 2.58 (dt, J = 17.2, 3.3, 1H), 2.49 - 2.43 (m, 1H), 2.00 (ddd, J = 12.7, 6.1, 3.7, 1H). LC-MS m / z: (pos) 515.1 ([M+H] + )

[0296] Example 65: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenethyl)urea (62).

Chem.

[0297] Compound 62 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.77 (s, 1H), 8.56 (s, 1H), 7.64 (s, 1H), 7.41 - 7.19 (m, 3H), 7.15 (d, J = 8.3, 1H), 7.08 (d, J = 8.3, 1H), 7.00 (d, J = 7.3, 1H), 6.15 (tz, J = 5.3, 1H), 5.77 (s, 1H), 4.96 (dd, J = 12.9, 5.2, 1H), 3.41 - 3.32 (m, 2H), 2.90 - 2.82 (m, 1H), 2.77 (t, J = 6.8, 2H), 2.60 - 2.55 (m, 1H), 2.48 - 2.43 (m, 1H), 2.22 (s, 3H), 2.02 - 1.96 (m, 1H). LC-MS m / z: (pos) 510.2 ([M + H] + ).

[0298] Example 66: Synthesis of 3-(3-((3-(((3-chloro-4-methylphenyl)amino)methyl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (63). [Chemical formula]

[0299] Compound 63 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.80 (s, 1H), 7.35 (s, 1H), 7.32 (t, J = 7.7, 1H), 7.27 (d, J = 8.4, 1.4, 1H), 7.10 (d, J = 7.4, 1H), 6.98 (d, J = 8.3, 1H), 6.59 (d, J = 2.3, 1H), 6.47 (dd, J = 8.3, 2.3, 1H), 6.41 (t, J = 6.3, 1H), 5.66 (s, 1H), 4.95 (dd, J = 13.0, 5.4, 1H), 4.28 (d, J = 6.2, 2H), 2.85 (ddd, J = 17.1, 13.8, 5.4, 1H), 2.57 (dt, J = 16.9, 3.3, 1H), 2.48 - 2.42 (m, 1H), 2.13 (s, 3H), 1.99 (ddd, J = 7.1, 5.6, 2.9, 1H). LC-MS m / z: (pos) 453.2 ([M + H] +)。

[0300] Example 67: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)oxy)benzyl)urea (64).

Chem.

[0301] Compound 64 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.72 (s, 1H), 7.64 (d, J = 2.1, 1H), 7.47 (t, J = 8.1, 1H), 7.30 - 7.24 (m, 3H), 7.17 (d, J = 8.4, 1H), 7.13 (dd, J = 8.3, 2.1, 1H), 6.74 (t, J = 6.0, 1H), 5.70 (s, 1H), 5.00 (dd, J = 13.0, 5.4, 1H), 4.34 (d, J = 5.9, 2H), 2.85 (ddd, J = 17.2, 13.9, 5.5, 1H), 2.57 (ddd, J = 17.3, 4.6, 2.6, 1H), 2.47 - 2.38 (m, 2H), 2.23 (s, 3H), 2.01 (dtd, J = 12.9, 5.4, 2.5, 1H). LC-MS m / z: (pos) 497.15 ([M+H] + )。

[0302] Example 68: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propan-2-yl)urea (69).

Chem.

[0303] Compound 69 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.82 (s, 1H), 8.58 (s, 1H), 7.57 (d, J = 2.1, 1H), 7.45 (s, 1H), 7.32 (t, J = 7.9, 1H), 7.23 (dd, 1H), 7.15 (t, 2H), 7.01 (dd, J = 8.3, 2.2, 1H), 6.73 (s, 1H), 5.62 (s, 1H), 4.95 (dd, J = 13.0, 5.4, 1H), 2.89 - 2.81 (m, 1H), 2.57 (ddd, J = 17.1, 4.5, 2.5, 1H), 2.49 - 2.42 (m, 1H), 2.21 (s, 3H), 1.98 (dtt, J = 12.9, 5.5, 2.8, 1H), 1.59 (s, 6H). LC-MS m / z: (pos) 524.17 ([M+H] + )。

[0304] Example 69: Synthesis of 1-(3-chloro-4-methylphenyl)-3-((1R)-1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)urea (70).

Chemical formula

[0305] Compound 70 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.82 (s, 1H), 8.48 (s, 1H), 7.62 (d, J = 2.1, 1H), 7.37 (t, J = 1.9, 1H), 7.34 (t, J = 7.8, 1H), 7.31 - 7.26 (m, 1H), 7.16 (d, J = 8.4, 1H), 7.12 - 7.05 (m, 2H), 6.72 (d, J = 7.8, 1H), 5.75 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 4.82 (p, J = 7.0, 1H), 2.86 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.57 (ddd, J = 17.1, 4.5, 2.6, 1H), 2.49 - 2.42 (m, 1H), 2.22 (s, 3H), 2.02 - 1.97 (m, J = 10.5, 5.4, 3.1, 1H), 1.39 (d, J = 7.0, 3H). LC-MS m / z: (pos) 510.13 ([M+H] + ).

[0306] Example 70: Synthesis of 1-(3-chloro-4-methylphenyl)-3-((1S)-1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)urea (71).

Chemical Structure

[0307] Compound 71 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.82 (s, 1H), 8.47 (s, 1H), 7.62 (d, J = 2.1, 1H), 7.37 (t, J = 1.9, 1H), 7.34 (t, J = 7.8, 1H), 7.30 - 7.27 (m, 1H), 7.16 (d, J = 8.4, 1H), 7.11 - 7.06 (m, 2H), 6.72 (d, J = 7.8, 1H), 5.75 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 4.82 (p, J = 7.0, 1H), 2.86 (ddd, J = 17.1, 14.0, 5.4, 1H), 2.57 (dt, J = 17.1, 3.4, 1H), 2.49 - 2.42 (m, 1H), 2.22 (s, 3H), 2.02 - 1.97 (m, J = 10.5, 5.4, 3.1, 1H), 1.39 (d, J = 7.0, 3H). LC-MS m / z: (pos) 510.07 ([M+H] + ).

[0308] Example 71: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propyl)urea (74).

Chemical Structure

[0309] Compound 74 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.82 (s, 1H), 8.46 (s, 1H), 7.62 (d, J = 2.1, 1H), 7.37 - 7.31 (m, 2H), 7.31 - 7.26 (m, 1H), 7.16 (d, J = 8.4, 1H), 7.07 (dd, J = 8.4, 2.1, 2H), 6.74 (d, J = 8.1, 1H), 5.74 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 4.61 (q, J = 7.3, 1H), 2.86 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.57 (dt, J = 17.0, 3.5, 1H), 2.49 - 2.41 (m, 1H), 2.21 (s, 3H), 2.00 (ddt, J = 13.0, 5.5, 2.7, 1H), 1.73 (p, J = 7.2, 2H), 0.87 (t, J = 7.3, 3H). LC-MS m / z: (pos) 524.17 ([M+H] + )。

[0310] Example 72: Synthesis of 3-(3-(3-chloro-4-methylphenyl)ureido)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N,N-dimethylpropanamide (76).

Chemical Structure

[0311] Compound 76 was prepared according to Method A. LC-MS m / z: (pos) 581.15 ([M+H] + )。

[0312] Example 73: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(2-chloro-5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (77).

Chemical Structure

[0313] Compound 77 was prepared according to Method A. LC-MS m / z: (pos) 530.12 ([M+H] + )。

[0314] Example 74: Synthesis of N-(3-chloro-4-methylphenyl)-2-((3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)amino)acetamide (78).

Chemical Structure

[0315] Compound 78 was prepared according to Method A. LC-MS m / z: (pos) 496.15 ([M+H] + )。

[0316] Example 75: Synthesis of 1-benzyl-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (81).

Chemical Structure

[0317] Compound 81 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.83 (s, 1H), 7.38 - 7.16 (m, 11H), 5.74 (s, 1H), 4.97 (dd, J = 12.5, 4.5, 1H), 4.26 - 4.21 (m, 4H), 2.92 - 2.80 (m, 1H), 2.62 - 2.55 (m, 1H), 2.48 - 2.39 (m, 1H, overlapping with DMSO solvent peak), 2.02 - 1.96 (m, 1H). LC-MS m / z: (pos) 462.18 ([M+H] + )。

[0318] Example 76: Synthesis of 1-(4-chloro-3-methylbenzyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)urea (82).

Chem.

[0319] Compound 82 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.82 (s, 1H), 7.33 - 7.24 (m, 5H), 7.11 (dd, 1H), 7.01 (d, J = 7.1, 1H), 6.54 (q, J = 5.8, 2H), 5.74 (s, 1H), 4.97 (dd, J = 12.9, 5.4, 1H), 4.24 (d, J = 6.0, 2H), 4.19 (d, J = 5.9, 2H), 2.91 - 2.82 (m, 1H), 2.61 - 2.55 (m, 1H), 2.49 - 2.43 (m, 1H), 2.28 (s, 3H), 2.03 - 1.98 (m, 1H). LC-MS m / z: (pos) 510.13 ([M+H] + )

[0320] Example 77: Synthesis of 2-((3-(3-chloro-4-methylphenyl)ureido)methyl)-4-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl dimethylcarbamate (95).

Chem.

[0321] Compound 95 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.90 (s, 1H), 8.75 (s, 1H), 7.65 (d, J = 2.1, 1H), 7.39 (d, J = 2.7, 1H), 7.32 (dd, J = 8.7, 2.7, 1H), 7.17 (d, J = 8.4, 1H), 7.15 - 7.07 (m, 2H), 6.52 (t, J = 5.9, 1H), 5.72 (s, 1H), 4.95 (dd, J = 13.0, 5.4, 1H), 4.24 (d, J = 5.8, 2H), 3.07 (s, 3H), 2.90 (s, 3H), 2.86 - 2.81 (m, 1H), 2.57 (m, 1H), 2.48 - 2.42 (m, 1H), 2.23 (s, 3H), 1.99 (dtd, J = 8.4, 5.4, 2.9, 1H). LC-MS m / z: (pos) 583.21 ([M + H] + )。

[0322] Example 78: Synthesis of N-(3-chloro-4-methylphenyl)-5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)isoindoline-2-carboxamide (107).

Chemical Structure

[0323] Compound 107 was prepared according to Method A. LC-MS m / z: (pos) 508.18 ([M + H] + )。

[0324] Example 79: Synthesis of N-(3-chloro-4-methylphenyl)-7-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxamide (109).

Chemical Structure

[0325] Compound 109 was prepared according to Method A. LC-MS m / z: (pos) 522.10 ([M + H]+ )。

[0326] Example 80: Synthesis of 3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenethyl (3-chloro-4-methylphenyl)carbamate (110).

Chem.

[0327] Compound 110 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.76 (s, 1H), 9.71 (s, 1H), 7.57 (s, 1H), 7.37 - 7.33 (m, 1H), 7.34 - 7.23 (m, 3H), 7.22 (d, J = 8.3, 1H), 7.06 (dt, J = 7.2, 1.5, 1H), 5.80 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 4.33 (t, J = 6.7, 2H), 2.98 (t, J = 6.7, 2H), 2.86 (ddd, J = 17.1, 13.8, 5.3, 1H), 2.58 (dt, J = 17.3, 3.4, 1H), 2.47 - 2.42 (m, 1H), 2.02 - 1.98 (m, 1H). LC-MS m / z: (pos) 511.07 ([M+H] + )。

[0328] Example 81: Synthesis of 3-(3-((3-(3-chloro-4-methylphenyl)ureido)methyl)-5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-1,1-dimethylurea (112).

Chem.

[0329] Compound 112 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.82 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.68 (d, J = 2.0, 1H), 7.49 (s, 1H), 7.21 (s, 1H), 7.18 (d, J = 8.4, 1H), 7.12 (dd, J = 8.3, 2.1, 1H), 6.95 (s, 1H), 6.62 (t, J = 5.9, 1H), 5.74 (s, 1H), 4.95 (dd, J = 13.0, 5.4, 1H), 4.22 (d, J = 5.9, 2H), 2.93 (s, 6H), 2.85 (ddd, 1H), 2.57 (dt, J = 17.3, 3.4, 1H), 2.49 - 2.42 (m, 1H), 2.23 (s, 3H), 1.99 (dtt, J = 10.7, 5.3, 2.2, 1H). LC-MS m / z: (pos) 582.15 ([M + H] + )。

[0330] Example 82: Synthesis of 1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)-3-phenylurea (119).

Chemical Structure

[0331] Compound 119 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.84 (s, 1H), 8.58 (s, 1H), 7.49 - 7.25 (m, 5H), 7.21 (t, J = 7.8, 2H), 7.06 (d, J = 7.2, 1H), 6.89 (t, J = 7.3, 1H), 6.65 (t, J = 5.9, 1H), 5.77 (s, 1H), 4.96 (dd, J = 13.0, 5.3, 1H), 4.31 (d, J = 5.9, 2H), 2.89 - 2.81 (m, 1H), 2.60 - 2.55 (m, 1H), 2.47 - 2.43 (m, 1H), 2.02 - 1.96 (m, 1H), 1.23 (s, 3H). LC-MS m / z: (pos) 448.20 ([M + H] + )。

[0332] Example 83: Synthesis of 1-(4-chloro-3-methylbenzyl)-3-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)urea (120).

Chem.

[0333] Compound 120 was prepared according to Method A. LC-MS m / z: (pos) 524.17 ([M+H] + )。

[0334] Example 84: Synthesis of N-(3-chloro-4-methylbenzyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propanamide (121).

Chem.

[0335] Compound 121 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.81 (s, 1H), 7.37 - 7.15 (m, 5H), 7.06 (t, J = 6.8, 2H), 6.55 (d, J = 8.1, 1H), 6.35 (t, J = 6.1, 1H), 5.74 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 4.76 (p, J = 7.2, 1H), 4.20 - 4.10 (m, 2H), 2.86 (ddd, J = 17.2, 13.9, 5.5, 1H), 2.61 - 2.55 (m, 1H), 2.48 - 2.43 (m, 1H), 2.27 (s, 3H), 2.02 - 1.97 (m, 1H), 1.34 (d, J = 7.0, 2H). LC-MS m / z: (pos) 509.13 ([M+H] + )。

[0336] Example 85: Synthesis of N-(3-chloro-4-methylbenzyl)-3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzamide (122).

Chemical Structure

[0337] Compound 122 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.94 (s, 1H), 9.10 (t, J = 6.0, 1H), 7.82 (t, J = 2.0, 1H), 7.62 (dt, J = 7.7, 1H), 7.58 (ddd, J = 8.2, 2.5, 1.1, 1H), 7.49 (t, J = 7.9, 1H), 7.35 (d, J = 1.7, 1H), 7.31 (d, J = 7.8, 1H), 7.20 (dd, J = 7.8, 1.8, 1H), 5.85 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 4.45 (d, J = 5.9, 2H), 2.86 (ddd, J = 17.2, 13.9, 5.4, 1H), 2.58 (dt, J = 17.3, 3.3, 1H), 2.48 - 2.43 (m, 1H), 2.30 (s, 3H), 2.00 (dtd, J = 12.9, 5.4, 2.2, 1H). LC-MS m / z: (pos) 481.17 ([M+H] + )

[0338] Example 86: Synthesis of N-(3-chloro-4-methylbenzyl)-2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)acetamide (123).

Chemical Structure

[0339] Compound 123 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.81 (s, 1H), 8.59 (t, J = 5.9, 1H), 7.36 - 7.21 (m, 5H), 7.09 (dd, 1H), 7.05 - 6.99 (m, 1H), 5.74 (s, 1H), 4.97 (dd, J = 13.0, 5.4, 1H), 4.23 (d, J = 5.8, 2H), 3.50 (s, 2H), 2.86 (ddd, J = 17.2, 13.9, 5.4, 1H), 2.61 - 2.55 (m, 1H), 2.48 - 2.43 (m, 1H), 2.27 (s, 3H), 1.99 (dtd, J = 10.9, 5.3, 2.6, 1H). LC-MS m / z: (pos) 495.09 ([M+H] + ).

[0340] Example 87: Synthesis of 1-(3-chloro-4-methylphenyl)-3-(5-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)naphthalen-1-yl)urea (124).

Chemical Structure

[0341] Compound 124 was prepared according to Method A. LC-MS m / z: (pos) 532.07 ([M+H] + ).

[0342] Example 88: Synthesis of N-(3-chloro-4-methylphenyl)-2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenoxy)acetamide (125).

Chemical Structure

[0343] Compound 125 was prepared according to Method A. LC-MS m / z: (pos) 497.23 ([M+H] + ).

[0344] Example 89: Synthesis of 1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea (126). [Chemical formula]

[0345] Compound 126 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.77 (s, 1H), 8.72 (s, 1H), 7.87 (d, J = 2.0, 1H), 7.41 (dd, 1H), 7.36 - 7.15 (m, 4H), 7.00 (d, J = 7.4, 1H), 6.18 (t, J = 5.6, 1H), 5.77 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 3.35 (q, J = 6.8, 2H), 2.86 (ddd, 1H), 2.77 (t, J = 7.0, 2H), 2.58 (ddd, J = 17.1, 4.4, 2.4, 1H), 2.47 - 2.43 (m, 1H), 2.33 (s, 3H), 1.99 (dtd, J = 13.0, 5.5, 5.1, 2.1, 1H). LC-MS m / z: (pos) 544.16 ([M+H] + )

[0346] Example 90: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N-methylpropanamide (127). [Chemical formula]

[0347] Compound 127 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.73 (s, 1H), 7.36 (d, J = 8.1, 1H), 7.27 (d, J = 1.9, 1H), 7.26 - 7.20 (m, 2H), 7.18 - 7.04 (m, 2H), 6.85 (s, 1H), 5.66 (s, 1H), 4.97 (dd, 1H), 3.12 (s, 3H), 2.86 (ddd, J = 17.4, 14.1, 5.5, 1H), 2.79 (t, J = 7.5, 2H), 2.69 (s, 2H), 2.60 - 2.55 (m, 1H), 2.49 - 2.42 (m, 1H), 2.30 (s, 3H), 1.99 (dtt, J = 11.1, 5.5, 2.3, 1H). LC-MS m / z: (pos) 509.13 ([M+H] + )。

[0348] Example 91: Synthesis of 1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)benzyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea (128).

Chemical Structure

[0349] Compound 128 was prepared according to Method A. 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.84 (s, 1H), 8.86 (s, 1H), 7.88 (s, 1H), 7.46 (d, J = 8.1, 1H), 7.41 - 7.21 (m, 4H), 7.06 (d, J = 7.2, 1H), 6.75 (t, J = 5.8, 1H), 5.77 (s, 1H), 4.96 (dd, J = 12.9, 5.3, 1H), 4.31 (d, J = 5.8, 2H), 2.86 (ddd, J = 17.1, 13.9, 5.5, 1H), 2.60 - 2.54 (m, 1H), 2.47 - 2.42 (m, 1H), 2.34 (s, 3H), 2.02 - 1.96 (m, 1H). LC-MS m / z: (pos) 530.12 ([M+H] + )。

[0350] Example 92: Synthesis of N-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propanamide (129).

Chemical formula

[0351] Compound 129 was prepared according to Method A. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.44 (s, 1H), 9.77 (s, 1H), 8.01 (d, J = 1.7, 1H), 7.78 (d, J = 8.8, 1H), 7.63 (dd, 1H), 7.32 - 7.27 (m, 2H), 7.25 (dt, J = 6.9, 1.2, 1H), 7.01 (d, J = 7.5, 1H), 5.76 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 2.94 (t, J = 7.5, 2H), 2.90 - 2.82 (m, 1H), 2.71 (t, J = 7.6, 2H), 2.58 (ddd, J = 17.1, 4.5, 2.5, 1H), 2.49 - 2.41 (m, 1H), 1.99 (dtd, J = 12.8, 5.4, 2.4, 1H). LC-MS m / z: (pos) 549.07 ([M+H] + )

[0352] Example 93: Synthesis of 3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)propanamide (130).

Chemical formula

[0353] Compound 130 was prepared according to Method A. 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.13 (s, 1H), 9.76 (s, 1H), 7.98 (d, J = 2.0, 1H), 7.68 (dd, J = 8.3, 1.8, 1H), 7.34 (d, J = 8.4, 1H), 7.31 - 7.27 (m, 2H), 7.25 (dt, J = 7.1, 1.2, 1H), 7.01 (d, J = 7.3, 1H), 5.76 (s, 1H), 4.96 (dd, J = 13.0, 5.4, 1H), 2.93 (t, J = 7.6, 2H), 2.86 (ddd, J = 17.1, 13.9, 5.4, 1H), 2.65 (t, J = 7.6, 2H), 2.60 - 2.55 (m, 1H), 2.49 - 2.42 (m, 1H), 2.36 (d, 3H), 1.99 (dtd, J = 12.7, 5.3, 2.3, 1H). LC-MS m / z: (pos) 529.12 ([M + H] + ).

[0354] Example 94: Synthesis of 1-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea (131).

Chemical formula

[0355] Compound 131 was prepared according to Method A. LC-MS m / z: (pos) 544.16 ([M + H] + ).

[0356] Example 95: Synthesis of 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)urea (132).

Chemical formula

[0357] Compound 132 was prepared according to Method A. LC-MS m / z: (pos) 564.10 ([M+H] + ).

[0358] Example 96: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)pentanamide (134).

Chem.

[0359] Compound 134 was prepared according to Method A. The aniline coupling partner was prepared according to Method F. LC-MS m / z: (pos) 523.16 ([M+H] + ).

[0360] Example 97: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-3-methylbutanamide (136).

Chem.

[0361] Compound 136 was prepared according to Method A. The aniline coupling partner was prepared according to Method F. LC-MS m / z: (pos) 523.16 ([M+H] + ).

[0362] Example 98: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-3-methylbutanamide (137).

Chem.

[0363] Compound 137 was prepared according to Method A. LC-MS m / z: (pos) 509.18 ([M+H] + )。

[0364] Example 99: Synthesis of N-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)pentanamide (138).

Chemical Structure

[0365] Compound 138 was prepared according to Method A. The aniline coupling partner was prepared according to Method F. LC-MS m / z: (pos) 577.19 ([M+H] + )。

[0366] Example 100: Synthesis of N-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propan-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide (139).

Chemical Structure

[0367] Compound 139 was prepared according to Method A. LC-MS m / z: (pos) 543.22 ([M+H] + )。

[0368] Example 101: Synthesis of 3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N-(3-(trifluoromethyl)phenyl)butanamide (140).

Chemical Structure

[0369] Compound 140 was prepared according to Method A. The aniline coupling partner was prepared according to Method F. LC-MS m / z: (pos) 529.42 ([M+H] + )。

[0370] Example 102: Synthesis of N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)-3-(trifluoromethyl)benzamide (141).

Chemical Structure

[0371] Compound 141 was prepared according to Method A. LC-MS m / z: (pos) 515.44 ([M+H] + )。

[0372] Example 103: Synthesis of N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)-2-(3-(trifluoromethyl)phenyl)acetamide (142).

Chemical Structure

[0373] Compound 142 was prepared according to Method A. LC-MS m / z: (pos) 529.42 ([M+H] + )。

[0374] Example 104: Synthesis of 3-chloro-N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)-4-(trifluoromethyl)benzamide (143).

Chemical Structure

[0375] Compound 143 was prepared according to Method A. LC-MS m / z: (pos) 549.41 ([M+H] + )。

[0376] Example 105: Synthesis of 1-(3-chloro-4-methylphenyl)-3-((1S)-1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxopyrrolidin-3-yl)amino)phenyl)ethyl)urea (144).

Chem.

[0377] Compound 144 was prepared according to Method G. LC-MS m / z: (pos) 512.49 ([M+H] + )。

[0378] Example 106: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxopyrrolidin-3-yl)-amino)phenyl)-3-methylbutanamide (145).

Chem.

[0379] Compound 145 was prepared according to Method G. LC-MS m / z: (pos) 525.46 ([M+H] + )。

[0380] Example 107: Synthesis of N-(3-chloro-4-methylphenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxopyrrolidin-3-yl)amino)phenyl)butanamide (146).

Chem.

[0381] Compound 146 was prepared according to Method G. LC-MS m / z: (pos) 511.49 ([M+H] + )。

[0382] Example 108: Synthesis of 2-(3,4-difluorophenyl)-N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)acetamide (147).

Chemical Structure

[0383] Compound 147 was prepared according to Method A. LC-MS m / z: (pos) 497.51 ([M+H] + )。

[0384] Example 109: Synthesis of 3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N-(3-(trifluoromethyl)phenyl)propanamide (148).

Chemical Structure

[0385] Compound 148 was prepared according to Method A. LC-MS m / z: (pos) 515.44 ([M+H] + )。

[0386] Example 110: Synthesis of 3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)-N-(4-(trifluoromethyl)phenyl)propanamide (149).

Chemical Structure

[0387] Compound 149 was prepared according to Method A. LC-MS m / z: (pos) 515.44 ([M+H] + )。

[0388] Example 111: Synthesis of N-(3,4-difluorophenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propanamide (150).

Chemical formula

[0389] Compound 150 was prepared according to Method A. LC-MS m / z: (pos) 483.47 ([M+H] + )。

[0390] Example 112: Synthesis of N-(2,4-difluorophenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propanamide (151).

Chemical formula

[0391] Compound 151 was prepared according to Method A. LC-MS m / z: (pos) 483.47 ([M+H] + )。

[0392] Example 113: Synthesis of N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)-2-(4-(trifluoromethyl)phenyl)acetamide (152).

Chemical formula

[0393] Compound 152 was prepared according to Method A. LC-MS m / z: (pos) 529.08 ([M+H] + ).

[0394] Example 114: Synthesis of N-(3-chlorophenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-amino)phenyl)propanamide (153).

Chemical Structure

[0395] Compound 153 was prepared according to Method A. LC-MS m / z: (pos) 481.15 ([M+H] + ).

[0396] Example 115: Synthesis of N-(4-chlorophenyl)-3-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-amino)phenyl)propanamide (154).

Chemical Structure

[0397] Compound 154 was prepared according to Method A. LC-MS m / z: (pos) 481.15 ([M+H] + ).

[0398] Example 116: Synthesis of 2-(3-chlorophenyl)-N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)acetamide (155).

Chemical Structure

[0399] Compound 155 was prepared according to Method A. LC-MS m / z: (pos) 495.07 ([M+H]+ )。

[0400] Example 117: Synthesis of 2-(4-chlorophenyl)-N-(1-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)ethyl)acetamide (156).

Chem.

[0401] Compound 156 was prepared according to Method A. LC-MS m / z: (pos) 495.12 ([M+H] + )。

[0402] Example 118: Synthesis of 2-(3-chloro-4-(trifluoromethyl)phenyl)-N-(2-(3-((1-(2,6-dioxopiperidin-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)amino)phenyl)propan-2-yl)acetamide (159).

Chem.

[0403] Compound 159 was prepared according to Method A. LC-MS m / z: (pos) 577.15 ([M+H] + )。

[0404] Example 119: Optimization of imide analogs that induce potent and selective Helios degradation

[0405] A focused library of imide analogs was synthesized and evaluated for their ability to induce dimerization of CRBN and Helios in a time-resolved fluorescence energy transfer (TR-FRET) assay (Figure 1A). Briefly, compounds were incubated with biotinylated Helios, streptavidin-labeled terbium, and GFP-tagged CRBN; compounds that were more potent dimerizers induced higher FRET signals (520 / 490 signal ratio). Consistent with previous reports, lenalidomide had minimal activity, while CC-885 had some activity (Figure 1B). Importantly, Compound 44 of the present invention showed higher activity than CC-885 at all test concentrations, and treatment of Jurkat cells with Compound 44 induced loss of both Ikaros and Helios after 24 hours of treatment without affecting the level of GSPT1.

[0406] Compound 54 of the present invention showed an even higher score than Compound 44 in the TR-FRET assay at all concentrations tested (Figure 2A). In contrast to Compound 44, which required 24 hours of treatment, Compound 54 induced CRBN-dependent Helios degradation after only 4 hours of treatment (Figures 2B and 2C). Furthermore, Compound 54 lost some of its degradation activity against Ikaros compared to Compound 44 (Figures 2B and 2C). Importantly, co-treatment with the proteasome inhibitor bortezomib or MLN 4924, an inhibitor of NEDD8-activating enzyme (NAE) essential for the activation of Cullin-RING ubiquitin ligases such as CRL4, prevented Helios degradation together, demonstrating that Compound 54 induces proteasome-dependent degradation (Figure 2D). Finally, treatment with Compound 54 did not affect the mRNA level of IKZF2 (Figure 2E). These results demonstrate that Helios is a degradable target. CRBN Example 120: Helios degradation attenuates the Treg-suppressive phenotype

[0407]

[0408] ​IKZF1 / 3 is resistant to IMiD-mediated degradation in mouse cells, which can be rescued by mutating a single amino acid (Ile 391) on the surface of mouse CRBN to a similar human residue (Val). To determine whether Helios follows a similar pattern, wild-type or Crbn I391V / I391V Mouse-derived Hoxb8 immortalized myeloid progenitor cells were treated with compound 54. The results showed that Helios is only degraded in Crbn I391V / I391V cells (Figure 3). Thus, Helios is degradable in mouse cells only when mouse cells express "humanized" CRBN.

[0409] Example 121: Mass spectrometry

[0410] Mass spectrometry profiling of IMiDs (e.g., thalidomide, lenalidomide, and pomalidomide) is shown in Donovan et al., eLife 7:e38430 (2018) and Sievers et al., Science 362:eaat0572 (2018).

[0411] Sample preparation TMT LC-MS3 mass spectrometry

[0412] H9 hESCs, Kelly, SK-N-DZ, and MM1s cells were treated with DMSO, 1 μM pomalidomide, 5 μM lenalidomide, or 10 μM thalidomide in biological triplicates (DMSO) or biological duplicates (pomalidomide, lenalidomide, thalidomide) for 5 hours, and the cells were harvested by centrifugation. Lysis buffer (8 M urea, 50 mM NaCl, 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (EPPS) pH 8.5, 1× Roche protease inhibitor, and 1× Roche PhosSTOP™) was added to the cell pellet, and the cells were homogenized by passing them 20 times through a 21-gauge (1.25-inch long) needle to obtain 0.5 - 4 mg mL -1A cell lysate with the protein concentration of was obtained. The homogenized sample was clarified by centrifugation at 20,000×g for 10 minutes at 4°C. The final protein concentration in the cell lysate was determined using a Micro - BCA assay (Pierce™). 200 μg of protein for each sample was reduced and alkylated as previously described (An et al., Nat. Commun. 8:15398 (2017)) (Figure 4).

[0413] Proteins were precipitated using methanol / chloroform. Briefly, 4 volumes of methanol were added to the cell lysate, followed by 1 volume of chloroform, and finally 3 volumes of water were added. The mixture was vortexed and centrifuged at 14,000×g for 5 minutes to separate the chloroform phase from the aqueous phase. The precipitated protein was washed with 3 volumes of methanol, centrifuged at 14,000×g for 5 minutes, and the resulting washed precipitated protein was air - dried.

[0414] The precipitated protein was resuspended in 4M urea, 50 mM HEPES pH 7.4, and then 200 mM EPPS pH 8 was added for digestion with LysC (1:50; enzyme: protein) and diluted to 1M urea at room temperature for 12 hours. The LysC digest was diluted in 0.5M urea, 200 mM EPPS pH 8, and then digested with trypsin (1:50; enzyme: protein) at 37°C for 6 hours. The tandem mass tag (TMT) reagent (Thermo Fisher Scientific) was dissolved in anhydrous acetonitrile (ACN) according to the manufacturer's instructions.

[0415] Anhydrous ACN was added to each peptide sample to a final concentration of 30 v / v%, and the TMT reagent was added to each sample at a peptide:TMT labeling ratio of 1:4 to induce labeling. The 10 - plex labeling reaction was carried out at room temperature for 1.5 hours, and the reaction was quenched by adding 0.3% hydroxylamine at room temperature for 15 minutes. The sample channels were combined at a ratio of 1:1:1:1:1:1:1:1:1:1, C 18Desalted using a solid-phase extraction cartridge (Waters) and analyzed by liquid chromatography-mass spectrometry (LC-MS) for channel ratio comparison. Then, samples were combined using the adjusted volumes determined by channel ratio analysis and dried in a speed vacuum. The combined samples were then resuspended in 1% formic acid, acidified (pH 2 - 3), and subjected to desalting by C18 SPE (Sep-Pak®, Waters).

[0416] Samples were then fractionated offline into 96 fractions by high-pH reversed-phase high-performance liquid chromatography (HPLC) (Agilent LC 1260) through an aeris peptide xb-c18 column (phenomenex®) using mobile phase A containing 5% acetonitrile and 10 mM NH4HCO3 in LC-MS grade H2O and mobile phase B containing 90% acetonitrile and 10 mM NH4HCO3 in LC-MS grade H2O (both pH 8.0). The 96 fractions obtained were then pooled discontinuously into 24 or 48 fractions, and all fractions were used for subsequent mass spectrometry.

[0417] Data were collected using an Orbitrap Fusion™ Lumos™ mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) coupled to a Proxeon EASY-nLC™ 1200 LC pump (Thermo Fisher Scientific). Peptides were separated on a 50 cm and 75 μm inner diameter EASY-Spray™ column (ES 803, Thermo Fisher Scientific). Peptides were separated using a 3-hour gradient of 6 - 27% acetonitrile in 1.0% formic acid at a flow rate of 300 nL / min. Each analysis used an MS3-based TMT method as previously described (McAlister et al., Anal. Chem. 86:7150 - 7158 (2014)). For peptide measurements in the Orbitrap, a mass range of m / z 350 - 1350, resolution 120,000, AGC target 1×10 6, data was acquired using a maximum injection time of 100 ms and dynamic exclusion of 90 seconds. The normalized collision energy (NCE) was set to 35%, the AGC target was set to 1.8×10 4 and the maximum injection time was set to 120 ms to acquire data-dependent MS2 spectra on the ion trap. The HCD collision energy was set to 55%, the AGC target was set to 1.5×10 5 and the maximum injection time was set to 150 ms, the resolution was set to 50,000, and the maximum synchronous precursor selection (SPS) precursor was set to 10 to acquire MS3 scans on the Orbitrap.

[0418] LC-MS data analysis

[0419] Proteome Discoverer 2.2 (Thermo Fisher) was used for RAW file processing and controlling false discovery rates at the peptide and protein levels, protein assembly from peptides, and protein quantification from peptides. MS / MS spectra were searched against the Uniprot human database (September 2016) in both forward and reverse sequences. The database search criteria were as follows: trypsin with two missed cleavages, a precursor mass tolerance of 20 ppm, a fragment ion mass tolerance of 0.6 Da, static alkylation of cysteine (57.02146 Da), static TMT labeling of lysine residues and the N-terminus of peptides (229.16293 Da), and variable oxidation of methionine (15.99491 Da). TMT reporter ion intensities were measured using a 0.003 Da window around the theoretical m / z for each reporter ion in the MS3 scan. Peptide spectrum matches with low-quality MS3 spectra were excluded from quantification (total signal-to-noise > 200 over 10 channels and precursor isolation specificity < 0.5). Reporter ion intensities were normalized and scaled using in-house scripts and the R framework (R Core Team, R Foundation for Statistical Computing, Vienna, Austria (2013)). Statistical analysis was performed using the limma package within the R framework (Ritchie et al., Nucleic Acids Res. 43: e47 (2015)).

[0420] Example 122: Biochemical TR-FRET and Dissection of IKZF 2, GSPT1 and SALL4 ZNF 1-2.

[0421] A focused library of imide analogs was synthesized and evaluated for their ability to induce dimerization of CRBN and Helios in the time-resolved fluorescence energy transfer (TR-FRET) assay (Table 1) and the fluorescence mCherry reporter, GFP-tagged IKZF 1, IKZF 2, SALL4 and GSPT 1 dissection assays (both described below).

[0422] TR-FRET dimerization assay

[0423] Compounds in the binding assay were dispensed into a 384-well microplate (Corning, 4514) containing 100 nM biotinylated strep-avi-IKZF1 or strep-avi-IKZF2, 200 nM His6-spy-DDB 1ΔB-His-spy-CRBN, and 2 nM terbium-binding streptavidin (Invitrogen™) in a buffer containing 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM TCEP, and 0.1% Pluronic F-68 solution (Sigma-Aldrich®) using pin transfer into 1% DMSO. Prior to performing the TR-FRET measurement, the reactants were incubated at rt for 15 minutes. After exciting terbium fluorescence at 337 nm, the emissions at 490 nm (terbium) and 520 nm (Bodipy) were recorded over 600 μs with a 70 μs delay to reduce background fluorescence, and the reaction was followed over a 30×200 second cycle for each data point using a PHERAstar® FS microplate reader (BMG Labtech). The TR-FRET signal for each data point was extracted by calculating the 520 / 490 nm ratio. Data from single measurements (n = 1), calculated as the average of at least 3 technical replicates per well per experiment, are shown in Table 1. Bodipy-Spycatcher

[0424] Cell lysis assay ​IKZF1Δ, IKZF2Δ, GSPT1, and SALL4 ZnF1-2 were subcloned into a mammalian pcDNA5 / FRT vector (ampicillin and hygromycin B resistant) modified to contain MCS-eGFP-P2A-mCherry. A stable cell line expressing the eGFP-protein fusion and the mCherry reporter was generated using the Flp-In™ 293 system. Plasmid (0.3 μg) and pOG44 (4.7 μg) DNA were preincubated for 20 min in 100 μl of Opti-MEM® I (Gibco®, Life Technologies®) medium containing 0.05 mg / ml Lipofectamine® 2000 (Invitrogen®) and added to Flp-In™ 293 cells containing 1.9 ml of DMEM medium (Gibco®, Life Technologies®) per well in a 6-well plate format (Falcon, 353046). Cells were grown for 48 h and then selected in DMEM medium containing 50 μg / mL hygromycin B (REF 10687010, Invitrogen®) as a selection marker in a 10 cm 2Transferred to plates (Corning, 430165). After 2 - 3 passage cycles, cells expressing eGFP and mCherry were enriched using FACS (FACSAria™ II, BD). Cells stably expressing IKZF1Δ, IKZF2Δ, GSPT1 or SALL4 Znf1 - 2 GFP fusions containing the mCherry reporter were seeded at 30 - 50% confluence into 384 - well plates containing FluoroBrite™ DMEM medium (Thermo Fisher Scientific, A18967) containing 50 μL of 10% FBS per well the day before compound treatment. Compound titrations were dispensed using a D300e digital dispenser (HP) normalized to 0.5% DMSO and incubated with the cells for 5 hours. The assay plates were immediately imaged with 488 nm and 561 nm lasers in a 2 μm x 1 μm grid per well format using an Acumen® High Content Imager (TTP Labtech). The resulting images were analyzed using CellProfiler™. A series of image analysis steps (the “image analysis pipeline”) were constructed. First, the red and green channels were aligned, trimmed to target the center of each well (to avoid analyzing cells that aggregated at the edges), and the background illumination function was calculated separately for both the red and green channels of each well and subtracted to correct for illumination variations across the 384-well plate due to various sources of error. Next, additional steps were applied to the green channel to suppress the analysis of large autofluorescence artifacts and enhance the analysis of cell-specific fluorescence by selecting objects with a given size, 30 A.U. and a given shape, speckle. Next, mCherry-positive cells were identified by red channel filtering using intensity to distinguish aggregated objects for objects between 8 and 60 pixels in diameter. Next, the green channel was split into GFP-positive and negative regions, and an object was classified as GFP-positive if at least 40% of it overlapped with the GFP-positive region. Next, the ratio of GFP-positive cells / mCherry-positive cells in each well was calculated, and the green and red images were rescaled for visualization. Representative data from n = 1 measurements at three concentrations of ligand after 5 hours of incubation are shown in Tables 1 and 2. Table 1. Biochemical TR-FRET and degradation of IKZF2.

Table 1-1

Table 1-2

Table 2-1

Table 2-2

Table 3

[0425] The compounds of the present invention in Table 3 are potent degraders of IKZF1 and IKZF2. Compounds 71 and 74 are the most potent against IKZF2. Compound 139 achieved a 10-fold degradation selectivity of IKZF2 / IKZF1, compound 74 achieved an approximately 4-fold selectivity of IKZF2 / IKZF1, and compounds 49, 78, and 125 were the most potent against IKZF1. None of the tested compounds showed degradation of GSPT1. The degradation assay was performed as described above. Specifically, the compounds were used in triplicate with a 11-point dose response range of 1 μM to 2.5 pM using D300(HP), and the DMSO across the plate was normalized to 0.5%. Degradation was measured after 5 hours of compound treatment, and the concentration (DC 50、5時間 ) that resulted in half degradation at 5 hours was calculated using a non-linear fitting variable slope model (GraphPad Software).

[0426] Example 123: Time-resolved fluorescence energy transfer ratio in the IKFZ2-CRBN dimerization assay (TR-FRET)

[0427] BODIPY-labeled CRBN (DDB1ΔB-CRBN) complexed with damage-specific DNA-binding protein 1 (DDB1) having an internal deletion of a flexible BPB propeller and in vitro biotinylated IKZF2 were treated in the presence of tracer amounts of terbium-streptavidin (Tb-SA) while increasing the concentration of the test compound. Using a PHERAstar® plate reader (BMG) that utilizes two synchronized PMTs to reduce background, the compound-induced recruitment of IKZF2 to CRBN was quantified according to the 520 / 490 TR-FRET ratio. The results showed that compound 69 induced a higher TR-FRET signal than CC-885 (positive control) or lenalidomide (negative control) (Figure 5).

[0428] Example 124: Degradation in Crbn− / − Jurkat Cells

[0429] Cells were lysed in M-PER buffer (Thermo Scientific) containing a protease / phosphatase inhibitor cocktail (Roche). Protein concentration was measured using a BCA assay (Pierce™). Equal amounts of each sample were loaded onto a 4–12% Bis-Tris gel (Invitrogen™), transferred to a nitrocellulose membrane, and immunoblotted with the indicated antibodies. IRDye® 800-labeled goat anti-rabbit IgG and IRDye® 680-labeled goat anti-mouse IgG (LI-COR®) secondary antibodies were purchased from LI-COR®, and the membrane was detected with an Odyssey® detection system (LI-COR® Biosciences). Immunoblots of GSPT1, Ikaros, Helios, and actin from wild-type or Crbn− / − Jurkat cells treated with compound 69 at the indicated concentrations for 4 hours showed that compound 69 induced CRBN-dependent Helios degradation but did not affect the stability of GSPT1 or Ikaros (Figure 6).

[0430] Example 125: Degradation in Jurkat cells

[0431] Cells were lysed in M-PER buffer (Thermo Scientific) containing protease / phosphatase inhibitor cocktail (Roche). Protein concentration was measured using the BCA assay (Pierce™). Equal amounts of each sample were loaded onto a 4-12% Bis-Tris gel (Invitrogen™), transferred to a nitrocellulose membrane, and immunoblotted with the indicated antibodies. IRDye® 800 labeled goat anti-rabbit IgG and IRDye® 680 labeled goat anti-mouse IgG (LI-COR®) secondary antibodies were purchased from LI-COR®, and the membrane was detected with an Odyssey detection system (LI-COR® Biosciences). Immunoblots of Ikaros and Helios from Jurkat cells treated with 1 μM compound 69 with or without 1 μM carfilzomib (a proteasome inhibitor) for 4 hours showed that Helios degradation induced by compound 69 is proteasome-dependent (Figure 7).

[0432] Example 126: Flow cytometry of Ikaros and Helios

[0433] Spleen cells were fixed / permeabilized and stained with fluorescently conjugated antibodies. FACS plots of mouse spleen cells were stained for TCRβ, CD4, CD8, and FoxP3 (Figure 8A). Crbn I391V / I 391V Treatment of Ikaros and Helios in mouse-derived spleen T cell subsets with 1 μM of the indicated compounds for 16 hours demonstrated that compound 69 can induce Helios degradation but not Ikaros degradation in regulatory T cells (Figure 8B).

[0434] Example 127: Increased IFNγ production

[0435] Foxp3+ regulatory T cells, Crbn I391V / I391VSpleen-derived CD4+CD25+ T cells were isolated by sorting, treated with 2 μM of compound 69, 5 ng / mL of IL-2 and 20 ng / mL of IL4 for 4 days, and then restimulated with PMA / ionomycin for 5 hours. The cells were then fixed / permeabilized and stained with fluorescent dye-conjugated antibodies. Figure 9A shows a FACS plot for IFNγ. Figure 9B is a bar graph showing the percent increase in IFNγ by treatment with compound 69. Figure 9C shows the level of Helios in Tregs treated with DMSO or compound 69. These results demonstrate that compound 69 can induce the degradation of Helios in Tregs, resulting in an increased production of IFNγ upon restimulation.

[0436] All patent publications and non-patent publications indicate the level of skill of those skilled in the art to which the present invention pertains. All of these publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0437] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the present invention. Accordingly, it should be understood that numerous modifications can be made to the exemplary embodiments without departing from the spirit and scope of the present invention as defined by the appended claims, and other arrangements can be devised. The present invention also includes the following embodiments. [1] A compound represented by the structure of formula I:

Chemical formula

Chemical formula

[10] The compound according to [9], wherein the N-aryl group is optionally substituted pyridinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, optionally substituted tetrazolyl, optionally substituted thiazolyl, optionally substituted quinolinyl, optionally substituted indolyl, or optionally substituted indazolyl.

[11] The compound according to [8], wherein Y represents optionally substituted C1-C5 alkyl.

[12] The compound according to [8], which represents phenyl optionally substituted by Y or benzyl optionally substituted by Y.

[13] Y is phenyl, benzyl,

Chem.

[14] R 1 Is ethyl, isopropyl, tert-butyl, phenyl, benzyl, pyrazolyl, imidazolyl, tetrazolyl, pyridinyl or pyrimidinyl, the compound according to

[13] .

[15] Y is absent, and the compound has the structure of formula Ib:

Chem.

[16]

Chem.

Chem.

[15] .

[17]

Chem.

[15] .

[18]

Chem.

Chem.

[17] .

[19] Z is

Chem.

Chem.

[18] , which represents.

[20] Ar is

Chem.

[19] .

[21] R 3 Independently represents methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, chloro or fluoro, the compound according to

[20] .

[22] Ar is

Chem.

[20] , which represents.

[23] Said any substituent is independently methyl, chloro, fluoro, phenyl, benzyl,

Chem.

[15] .

[24]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[25] A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of [1] to

[24] or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

[26] A method for treating a disease or disorder characterized by or mediated by the dysfunctional activity of a protein that is a substrate of a complex of CRBN and the compound according to any one of [1] to

[24] , the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of [1] to

[24] or a pharmaceutically acceptable salt or stereoisomer thereof.

[27] The method according to

[26] , wherein the disease or disorder is characterized by or mediated by the dysfunctional activity of FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1α, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1 or ZKSC5.

[28] The method according to

[27] , wherein the disease or disorder is mediated by dysfunctional IKZF2 (Helios) activity.

[29] The method according to

[27] or

[28] , wherein the disease or disorder is coronary heart disease.

[30] The method according to

[27] or

[28] , wherein the disease is cancer.

[31] The method according to

[30] , wherein the disease or disorder is leukemia.

[32] The method according to

[30] , wherein the disease or disorder is carcinoma.

[33] The method according to

[30] , wherein the cancer is T-cell leukemia or T-cell lymphoma.

[34] The method according to

[30] , wherein the cancer is Hodgkin lymphoma or non-Hodgkin lymphoma.

[35] The method according to

[30] , wherein the cancer is myeloid leukemia.

[36] The method according to

[30] , wherein the cancer is non-small cell lung cancer (NSCLC).

[37] The method according to

[30] , wherein the cancer is melanoma. [38 The method according to

[30] , wherein the cancer is triple-negative breast cancer (TNBC).

[39] The method according to

[30] , wherein the cancer is nasopharyngeal carcinoma (NPC).

[40] A method for treating a disease or disorder caused by a decrease in TXNIP protein level, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of [1] to

[24] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[41] The method according to

[40] , wherein the disease or disorder is gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, non-alcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy or diabetic cardiomyopathy.

[42] A compound represented by the structure of formula II:

Chem.

Chem.

Chem.

Chem.

[43]

Chem.

Chem.

[42] .

[44] R 4 The compound according to

[42] , wherein it is alkyl, halo, hydroxyl, amino, amide, substituted carbamate or substituted carbamide.

[45] Ar 1 The compound according to

[42] , wherein it is optionally substituted phenyl.

[46]

Chem.

Chem.

Chem.

Chem.

Chem.

[42] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[47] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of

[42] to

[46] , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[48] A method for treating a disease or disorder characterized by or mediated by a dysfunctional activity of a protein that is a substrate of a complex of CRBN and a compound according to any one of

[42] to

[46] , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of

[42] to

[46] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[49] The method according to

[48] , wherein the disease or disorder is characterized by or mediated by a dysfunctional activity of FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1α, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1 or ZKSC5.

[50] The method according to

[49] , wherein the disease or disorder is mediated by a dysfunctional IKZF2 (Helios) activity.

[51] The method according to

[49] or

[50] , wherein the disease or disorder is coronary heart disease.

[52] The method according to

[49] or

[50] , wherein the disease or disorder is cancer.

[53] The method according to

[52] , wherein the disease or disorder is leukemia.

[54] The method according to

[52] , wherein the disease or disorder is carcinoma.

[55] The method according to

[52] , wherein the cancer is T-cell leukemia or T-cell lymphoma.

[56] The method according to

[52] , wherein the cancer is Hodgkin lymphoma or non-Hodgkin lymphoma.

[57] The method according to

[52] , wherein the cancer is myeloid leukemia.

[58] The method according to

[52] , wherein the cancer is non-small cell lung cancer (NSCLC).

[59] The method according to

[52] , wherein the cancer is melanoma.

[60] The method according to

[52] , wherein the cancer is triple-negative breast cancer (TNBC).

[61] The method according to

[52] , wherein the cancer is nasopharyngeal carcinoma (NPC).

[62] A method for treating a disease or disorder caused by a decrease in TXNIP protein level, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of

[42] to

[46] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[63] The method according to

[62] , wherein the disease or disorder is selected from gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, non-alcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy.

[64] A compound represented by the structure of formula III:

Chem.

[65] W 5 and W 6 are both -NH-, the compound according to

[64] .

[66] Ar 2 is phenyl substituted with one or more groups selected from alkyl, halo and haloalkyl, the compound according to

[64] .

[67]

Chem.

Chem.

[64] selected from the group consisting of, or a pharmaceutically acceptable salt or stereoisomer thereof.

[68] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of

[64] to

[67] , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[69] A method for treating a disease or disorder characterized by or mediated by a dysfunctional activity of a protein that is a substrate of a complex of CRBN and a compound according to any one of

[64] to

[67] , comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of

[64] to

[67] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[70] The method according to

[69] , wherein the disease or disorder is characterized by or mediated by a dysfunctional activity of FAM83F, DTWD1, ZFP62, ZFP91, RNF166, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, CK1α, ZN653, ZN654, ZN827, ZN692, ZBTB2, ZBTB39, RAB28, GSTP1, ZFP36L2, GZF1, GSPT2, EGR1, HIC1, HIC2, INSM2, OSR1, OSR2, PRD15, SALL1, SALL3, SALL4, WIZ, Z324B, ZBT17, ZBT41, ZBT49, ZBT7A, ZBT7B, ZIK1, ZNF3, ZNF217, ZNF276, ZNF316, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, ZNF517, ZNF526, ZNF581, ZNF582, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF787, ZNF814, ZNF827, ZSC10, ZSC22, ZUFSP, E4F1, BCL6, BCL6B, PATZ1 or ZKSC5.

[71] The method according to

[70] , wherein the disease or disorder is mediated by a dysfunctional IKZF2 (Helios) activity.

[72] The method according to

[70] or

[71] , wherein the disease or disorder is coronary heart disease.

[73] The method according to

[70] or

[71] , wherein the disease or disorder is cancer.

[74] The method according to

[73] , wherein the disease or disorder is leukemia.

[75] The method according to

[73] , wherein the disease or disorder is carcinoma.

[76] The method according to

[73] , wherein the cancer is T cell leukemia or T cell lymphoma.

[77] The method according to

[73] , wherein the cancer is Hodgkin lymphoma or non-Hodgkin lymphoma.

[78] The method according to

[73] , wherein the cancer is myeloid leukemia.

[79] The method according to

[73] , wherein the cancer is non-small cell lung cancer (NSCLC).

[80] The method according to

[73] , wherein the cancer is melanoma.

[81] The method according to

[73] , wherein the cancer is triple negative breast cancer (TNBC).

[82] The method according to

[73] , wherein the cancer is nasopharyngeal carcinoma (NPC).

[83] A method for treating a disease or disorder caused by a decrease in TXNIP protein level, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of

[64] to

[67] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[84] The method according to

[83] , wherein the disease or disorder is gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, non-alcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy or diabetic cardiomyopathy.

Claims

1. A compound represented by the structure of Formula I: 【Chemical 1】 [wherein, Q represents CH ２ or C=O; X represents NR, O or S, and R is H or Me; Y is absent or represents phenyl, benzyl, 【Chemical Formula 15】 (Here, R １ represents alkyl, aryl or heteroaryl) ; [Chemical Formula 2] is absent or [Chemical Formula 3] 【Chemical 80】 or 【Chemical 81】 (wherein, n is 2 or 3; n' is 0 or 1; R' is halo, optionally substituted C1-C2 alkyl, optionally substituted aryl, or optionally substituted heteroaryl; R'' represents optionally substituted C1-C2 alkyl; Z is 【Chemical Formula 4】 represents, where W １ and W ２ are each independently, absent or independently, CH, CH ２ , O, O-CH ２ , NH-CH ２ or an optionally substituted amino; M represents a 5- or 6-membered cyclic group; and Ar is 【Chemical 23】 represents, where each R ３ is independently alkyl, halo, trifluoromethyl, aryl, heteroaryl, or benzyl, and n'' is 0, 1, or 2) ; 【Chemical Formula 5】 or either Y is absent], or a pharmaceutically acceptable salt or stereoisomer thereof, or a compound represented by the structure of Formula II: 【Chemical Formula 10】 [wherein, 【Chemical 11】 is 【Chemical 12】 represents, where R ４ is H or a substituent; R ５ is H, -Me, -Et, 【Chemical Formula 13】 ; W ３ and W ４ each independently does not exist or each independently represents CH ２ , NH or NH-CH ２ ; Ar １ which may be optionally substituted and is aryl or heteroaryl], or a pharmaceutically acceptable salt or stereoisomer thereof, or a compound represented by the structure of Formula III: 【Chemical Formula 14】 [wherein, W ５ and W ６ each independently represents -CH ２ - or -NH-, provided that one of W ５ and W ６ is -NH-; Ar ２ which may be optionally substituted and is aryl or heteroaryl], or a pharmaceutically acceptable salt or stereoisomer thereof, when the substituents in the above-mentioned optionally substituted Formula (I), (II), or (III) are independently C1-C6 alkyl, C1-C6 alkoxy, haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 carbocyclic, C3-C12 heterocyclic, phenyl, benzyl, pyridyl, pyrimidinyl, halo, hydroxyl, C6-C12 aryloxy, C1-C6 alkylthio, C3-C12 arylthio, cyano, carboxyl, amino, amide, sulfinamide, sulfonamide or urea, the compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound according to Claim 1, wherein Q is C=O.

3. Q is CH ２ The compound according to claim 1, wherein Q is CH

4. The compound according to any one of Claims 1 to 3, wherein X is NH or NMe.

5. The compound according to any one of Claims 1 to 3, wherein X is O or S.

6. R １ The compound according to claim 1, wherein R represents ethyl, isopropyl, tert-butyl, phenyl, benzyl, pyrazolyl, imidazolyl, tetrazolyl, pyridinyl or pyrimidinyl.

7. 【Fig. 16】 is 【Chemical 17】 or 【Chemical Formula 18】 is an optionally substituted fused 5,6- or 6,6-ring system, or 【Chemical Formula 19】 is 【Chemical 20】 , the compound according to Claim 1.

8. Z is 【Chemical 21】 【Chemical 22】 , the compound according to Claim 7.

9. R ３ is independently methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, chloro or fluoro, or Ar is 【Chemical 24】 , the compound according to Claim 8.

10. 【Fig. 25】 is 【Chemical 26】 (Here, R ５ ’ is H, Me or Et) , the compound according to Claim 1.

11. R ４ is alkyl, halo, hydroxyl, amino, amide, substituted carbamate or substituted urea, or Ar １ The compound according to claim 1, wherein Ar is phenyl which may be optionally substituted.

12. W ５ and W ６ are both -NH-, or Ar ２ The compound according to claim 1, wherein Ar is phenyl substituted with one or more groups selected from alkyl, halo and haloalkyl.

13. Formula Ia: [Chemical Formula 7] or, Formula Ib: 【Chemical 8】 having the structure, When the substituents in the above formula Ia or formula Ib are optionally substituted, they are independently methyl, chloro, fluoro, phenyl, benzyl, 【Chemical Formula 9】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. 【Fig. 27】 ​ 【Chemical 29】 【Chemical Formula 30】 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 【Chemical Formula 36】 【Chemical 37】 【Chemical Formula 38】 【Chemical 39】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a disease or disorder characterized by or mediated by a dysfunctional activity of a protein that is a substrate of a complex of CRBN and the compound according to any one of claims 1 to 14, wherein the disease or disorder is mediated by a dysfunctional IKZF2 (Helios) activity, or wherein the disease or disorder is caused by a decrease in TXNIP protein level.

17. The pharmaceutical composition according to claim 16, wherein the disease or disorder is coronary heart disease or cancer.

18. wherein the cancer is leukemia, carcinoma, T-cell leukemia, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloid leukemia, non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), or nasopharyngeal cancer (NPC), or The pharmaceutical composition according to claim 17, wherein the disease or disorder is gout, idiopathic pulmonary fibrosis, silicosis, asbestosis, non-alcoholic steatohepatitis, atherosclerosis, diabetes, diabetic nephropathy, diabetic retinopathy or diabetic cardiomyopathy.

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