Ligand for cereblon (CRBN)

Abstract

To provide compounds, compositions and methods to treat diseases or disorders caused by dysfunctional protein activity.SOLUTION: The present invention provides a pharmaceutical composition that comprises a compound of the following formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 692,167, filed June 29, 2018, which is incorporated herein by reference in its entirety.

[0002] Government Licensing Rights This invention was made with Government support under Grant No. R01CA214608 awarded by the National Institutes of Health. The Government has certain rights in this invention. [Background technology]

[0003] The gene encoding cereblon (CRBN) was first identified in the course of genetic research into memory and learning, and the gene was assigned the name CRBN based on its hypothesized role in the development of cerebral tissue, because its expression in the hippocampus, among other compartments, is associated with memory and learning processes. Higgins et al., Neurol. 63(10):1927-31 (2004)

[0004] Cereblon is a 442 amino acid multifunctional protein located in the cytoplasm, nucleus and superficial membrane of human brain and other tissues (Wada et al., Biochem. & Biophys. Res. Comm. 477:388-94 (2016)). It interacts with DNA damage binding protein-1 (DDB1), cullin 4 (Cul4A and Cul4B), and regulator of Cullins 1 (RoC1) to mediate CRL4 expression. CRBNIt forms a functional E3 ubiquitin ligase complex known as the E3 ubiquitin ligase complex. The role of cereblon as part of this complex includes targeting proteins for proteolysis (degradation) via the ubiquitin-proteasome pathway. See, e.g., Chang et al., Int. J. Biochem. Mol. Biol. 2(3):287-94 (2011).

[0005] Cereblon is closely associated with the metabolism and proliferation of normal as well as tumor cells. On the one hand, its presence ensures the normal metabolic and physiological functions of ion channels, which are important for maintaining cell growth and proliferation. On the other hand, cereblon is also involved in the development of many diseases, such as cancer. See generally Shi et al., J. Immunol. Res. Article ID 9130608 (2017).

[0006] Immunomodulatory drugs ("IMiDs") are a new class of anti-cancer drugs derived from thalidomide, a drug approved by the FDA for the treatment of multiple myeloma. In addition to thalidomide itself, two such thalidomide analogs, lenalidomide and pomalidomide, are approved by the FDA for the treatment of multiple myeloma (among other diseases) (and are sold under the names REVLIMID® and POMALYST®, respectively). As suggested by the nomenclature, one of the first known properties of IMiDs was their immunomodulatory capabilities, including cytokine modulation and T cell co-stimulation (Schafer et al., J. Pharmacol. & Exper. Ther. 305:1222-32 (2003)), which results in the production of interleukin-2 in T cells. Subsequently, IMiDs have been shown to have pleiotropic effects on a wide range of immune cells, including natural killer (NK) cell activation and B cell and monocyte inhibition (Corral et al., J. Immunol. 163:380-6 (1999)). More recently, cereblon has been identified as a common primary target of IMiDs.

[0007] For example, members of the Ikaros family of transcription factors, Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3, respectively), upregulate CRL4 in T cells in response to treatment with lenalidomide and pomalidomide. CRBN It has been reported that lenalidomide, but not pomalidomide, induces degradation of the protein kinase casein kinase 1α (CK1α), which exploits CK1α haploinsufficiency associated with 5q deletion-associated myelodysplastic syndrome. Kronke et al., Nature 523:183-8 (2015).

[0008] More recently, CRBN-binding compounds named "cereblon modulators" have been developed. For example, CC-122, a new chemical entity termed a "pleiotropic pathway modifier," binds to cereblon and promotes the degradation of Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and T cells in vitro, in vivo, and in patients, resulting in both cell-autonomous and immunostimulatory effects. See Hagner et al., Blood 126(6):779-89 (2016). CC-885 is another new cereblon modulator. The antitumor activity of this drug, which is broader than that of thalidomide, lenalidomide, and pomalidomide, has been reported to be mediated by cereblon-dependent ubiquitination and degradation of the translation termination factor glutathione S-transferase pi gene 1 (GSTP1). See Matyskiela et al., Nature 535:252-7 (2016).

[0009] Utilizing cereblon as a mediator in disease treatment could also be used to mediate disease by targeting proteins that are themselves disease mediators (e.g., bromodomain-containing protein 4 (BRD4)) to CRL4. CRBN This has led to the development of heterobifunctional PROTACs (PROteolysis TArgeting Chimeras) that recruit E3 ubiquitin ligases to lead to the degradation of targeted proteins. See, e.g., Lu et al., Cell Cancer Biol. 22(6):755-63 (2015). [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Higgins et al., Neurol.63(10):1927-31(2004) [Non-Patent Document 2] Wada et al.,Biochem.&Biophys.Res.Comm.477:388-94(2016) [Non-Patent Document 3] Chang et al.,Int.J.Biochem.Mol.Biol.2(3):287-94(2011) [Non-Patent Document 4] Shi et al.,J.Immunol.Res.Article ID 9130608(2017) [Non-Patent Document 5] Schafer et al.,J.Pharmacol.&Exper.Ther.305:1222-32(2003) [Non-Patent Document 6] Corral et al., J. Immunol. 163:380-6 (1999) [Non-Patent Document 7] Gandhi et al.,Br.J.Hematol.164:811-21(2014) [Non-Patent Document 8] Kronke et al.,Nature 523:183-8(2015) [Non-Patent Document 9] Hagner et al.,Blood 126(6):779-89(2016) [Non-Patent Document 10] Matyskiela et al.,Nature 535:252-7(2016) [Non-Patent Document 11] Lu et al.,Cell Cancer Biol.22(6):755-63(2015) Summary of the Invention [Means for solving the problem]

[0011] The first aspect of the present invention relates to a compound of formula (I): [ka] (Wherein, Z is CH2 or C(O), m and m 1 are independently an integer from 0 to 8, R is H or A, X is H or C(O), Y is absent or NRA (wherein R is H or C1-C2 alkyl), and when R is H, X is C(O), and m 1 is 1, and Y is NR1A, and R is A, then X is H, and m 1 is 0, Y does not exist, and A is (A1) to (A5): [ka] (wherein R2 is H or C1-C2 alkyl, R3 is optionally substituted C1-C5 alkyl, an optionally substituted ring (e.g., optionally substituted C6-C14 aryl, optionally substituted C6-C14 heteroaryl, optionally substituted C5-14 carbocycle and optionally substituted C5-14 heterocycle), or R2 and R3 together with the N to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group), [ka] (wherein R4 represents an optionally substituted cyclic group (e.g., an optionally substituted C5-C14 carbocyclic group, an optionally substituted C6-C14 aryl group, an optionally substituted C5-C14 heterocyclic group, or an optionally substituted C6-C14 heteroaryl group), [ka] (wherein R5 represents hydrogen or halo (F, Cl, Br, or I), and R6 represents NR7R8 (wherein R7 represents H, and R8 represents an optionally substituted C6-C14 aryl group), [ka] (wherein R2 and R3 are as defined above, and R9 and R 10 each represents H, or each independently represents C or N, provided that R and R 10 at least one of represents N and together with the atom to which they are attached form an optionally substituted C5-C6 heterocyclic group, e.g., an optionally substituted membered C6 heteroaryl group; or [ka] (Wherein, R4, R9 and R 10 represents a group selected from (wherein R represents a group selected from R, R and R are as defined above), or a pharma- ceutically acceptable salt or stereoisomer thereof (sometimes referred to herein as "compounds of the invention").

[0012] In some embodiments, m and m 1 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, m and m 1 is independently 0, 1, 2, 3, 4, 5 or 6.

[0013] In some embodiments, Z is CH2.

[0014] Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

[0015] A further aspect of the present invention is directed to methods of making the compounds of the present invention.

[0016] A further aspect of the present invention is directed to a method of treating a disease or disorder associated with abnormal activity of a protein that may be a substrate for cereblon and complexes containing the compound, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[0017] Without intending to be bound by any theory of operation, the compounds of the present invention exert therapeutic (e.g., anti-cancer) effects or benefits through a combination of antiproliferative and immunomodulatory effects. Specifically, binding of the compounds to cereblon inhibits CRL4 CRBNIt is believed that the compounds of the present invention confer differentiated substrate specificity to E3 ubiquitin ligase. This diversified substrate specificity substantially expands the variety and number of potential targets, thus providing a wide range of therapeutic applications. For example, in addition to or in addition to the expression products of Ikaros family zinc finger protein 1 (IKZF1), and IKZF3, and casein kinase 1 alpha (CK1α), the compounds of the present invention may indirectly target a host of different substrates for cereblon-dependent ubiquitination and degradation. Such substrates include, for example, family with sequence similarity 83 member F (FAM83F), DTW domain containing 1 (DTWD1), IKZF2, IKZF4, IKZF5, zinc finger protein 91 homolog (ZFP91), ZFP62, ZFP36 ring finger protein like (ZFP36L2), ring finger protein 166 (RNF166), Ras-related protein Rab-28 (RAB28), glutathione S-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membrane translocase subunit Tim10, and the like. Tim10 (TIMM10), GDNF-inducible zinc finger protein 1 (GZF1), early growth response 1 (EGR1), hyper-methylated in cancer 1 (HIC1), HIC2, insulinoma-associated protein 2 (INSM2), odd-skipped-related transcription factor 2 (OSR2), protein polybromo-1 (PB1), PR domain zinc finger protein 15 (PRD15), spalt like transcription factor 1 (SALL1), SALL3, SALL4, WIZ, zinc finger and BTB domain-containing protein 17 (Zinc finger and BTB domain-containing protein 17)domain-containing protein 17 (ZBT17), ZBTB39, ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, zinc finger protein interacting with K protein 1 ( 1) (ZIK1), zinc finger protein 3 (ZNF3), ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZN6F54, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, zinc finger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827, and zinc finger with UFM1-specific peptidase domain Examples of such proteins include ZUFSP (UFM1-specific peptidase domain).

[0018] A method for treating or inhibiting the progression of cancer including the administration of a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt or stereoisomer thereof, to a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt or stereoisomer thereof, protein 1 (IKZF1), IKZF2, IKZF3, IKZF4, IKZF5, Ras-related protein Rab-28 (RAB28), glutathione S-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membrane translocase subunit Tim10 (TIMM10), GDNF-inducible zinc finger protein 1 (GZF1), early growth response 1 (EGR1), cancer hypermethylation 1 (HIC1), HIC2, insulinoma-associated protein 2 (INSM2), odd- skipped-related transcription factor 2 (OSR2), protein polybromo-1 (PB1), PR domain zinc finger protein 15 (PRD15), spalt-like transcription factor 1 (SALL1), SALL3, SALL4, WIZ, zinc finger and BTB domain-containing protein 17 (ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, ZBTB39, zinc finger protein interacting with K protein 1 (ZIK1), zinc finger protein 3 (ZNF3 ), ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, zinc finger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827,Also provided are methods for treating a disease or disorder characterized or mediated by abnormal activity of a protein selected from the group consisting of zinc finger containing UFM1-specific peptidase domain (ZUFSP).

[0019] In some embodiments, the disease or disorder is characterized or mediated by aberrant activity of IKZF2.

[0020] One advantage of the present invention is that the compounds can provide effective therapy in cases where the target may not otherwise be "druggable" in that it is directly targeted by any of the current generation IMiDs. The compounds of the present invention may also be advantageous compared to cereblon-targeted PROTACS, which may cause pharmacokinetic challenges due to their large flexible linkers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] 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 herein belongs. As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated to facilitate understanding of the invention.

[0022] As used in this description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. So, for example, reference to "a composition" includes a mixture of two or more such compositions, reference to "an inhibitor" includes a mixture of two or more such inhibitors, etc.

[0023] Unless otherwise stated, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value that is modified by the term "about."

[0024] The transitional phrase "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not "materially affect the basic and novel characteristics" of the claimed invention.

[0025] The term "abnormal" as used herein refers to an activity that is different from the normal activity of a protein in a non-pathological condition. Such an abnormal activity may be dysfunctional or deregulated. Thus, the term abnormal may refer to a greater or lesser activity or function of a protein compared to a normal healthy subject.

[0026] With respect to 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.

[0027] As used herein, the term "alkyl" refers to a saturated, straight or branched chain, monovalent hydrocarbon radical. In one embodiment, the alkyl radical is a C1-C 18 In other embodiments, the alkyl radical is a C0-C6, C0-C5, C0-C3, C1-C 12, C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3 group (C0 alkyl represents 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.

[0028] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists only of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, such as, for example, methylene, ethylene, propylene, and n-butylene. The alkylene chain may be attached to the rest of the molecule through a single bond and to the radical group through 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 1-5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1-4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1-3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1-2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0029] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more (eg, 1, 2, 3, or 4) halo groups.

[0030] As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, an alkenyl radical is a C2-C 18 In another embodiment, the alkenyl radical is a C2-C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.

[0031] As used herein, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, an alkynyl radical is a C2-C 18 In another example, the alkynyl radical is a group of C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3. Examples include ethynyl prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0032] The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. An "ether" is two hydrocarbons covalently linked by an oxygen. Thus, the substituent of an alkyl that makes the alkyl an ether is or resembles an alkoxyl, and can be represented, for example, by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0033] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0034] As used herein, the term "ester" refers to an ester of the formula --OC(O)Z 1 or --C(O)OZ 1 and Z 1 may be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.

[0035] As used herein, the term “ether” refers to a group of the formula Z 1 OZ 2 and Z 1 and Z 2 can be independently an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.

[0036] As used herein, the term "ketone" refers to a compound of formula Z 1 C(O)Z 2 and A 1 and A 2independently represent an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.

[0037] As used herein, the term "sulfonyl" refers to a group of the formula --S(O)Z 1 Z refers to a sulfo-oxo group represented by 1 may be hydrogen, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all as described herein.

[0038] The term "sulfonylamino" (or "sulfonamide") as used herein is represented by the formula --S(O)2NH2.

[0039] As used herein, the term "cyclic group", used alone or as part of a larger moiety, broadly refers to any group containing a saturated, partially saturated or aromatic ring system, such as carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl and heteroaryl groups. A cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl or heteroaryl groups.

[0040] As used herein, the term "carbocycle" (and "carbocyclyl"), used alone or as part of a larger moiety, refers to a group containing a saturated, partially unsaturated, or aromatic ring system having from 3 to 20 carbon atoms, alone or as part of a larger moiety (e.g., an alkcarbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, a carbocyclyl is a ring system having from 3 to 15 carbon atoms (C 15 In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C 12 In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5~C 10 In another embodiment, the carbocyclyl as a monocycle includes C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl as a bicycle includes C7-C 12 In another embodiment, the carbocyclyl as a spiro system is a C5-C 12Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclohex ... Examples of carbocyclyl include cycloalkyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl, and bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic, or spirocarbocycles). 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 rings), where the radical or point of attachment is on the carbocyclic ring.

[0041] Thus, the term carbocycle, as used herein, also includes carbocyclylalkyl groups, which have the formula --R c -carbocyclyl (wherein R c is an alkylene chain. The term carbocycle also includes carbocyclylalkoxy groups, which as used herein refer to groups of the formula --O--R c -carbocyclyl (wherein R c refers to a group bonded through an oxygen atom of an alkylene chain.

[0042] As used herein, the term "heterocyclyl", used alone or as part of a larger moiety, refers to "carbocyclyl" containing saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In some embodiments, heterocyclyl refers to a 3-15 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3-12 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, e.g., a 3-12 membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, e.g., a 5-14 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.

[0043] In some embodiments, heterocyclyl groups contain 3-12 ring atoms, and include monocyclic, bicyclic, tricyclic, and spirocyclic ring systems, where the ring atoms are carbon and 1-5 ring atoms are heteroatoms, e.g., nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3-7 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 4-6 membered monocyclic rings having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, heterocyclyls contain 3 membered monocyclic rings. In some embodiments, heterocyclyls contain 4 membered monocyclic rings. In some embodiments, heterocyclyls contain 5-6 membered monocyclic rings. In some embodiments, heterocyclyls contain 0-3 double bonds. In any of the above embodiments, heterocyclyls contain 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2) and any nitrogen heteroatom may be optionally 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, oxahydropyridine ... Sajinanil, thiajinanil, thioxanil, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydro pyrrolo[d]imidazolyl, 1,6-dihydroimidazole[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, 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, pyrazolinyl, pyrazolinyl Zolidinyl, dithianyl, dithiolanyl, pyrimidinoyl, pyrimidindionyl, pyrimidin-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-onyl (1-azaspiro[4.5]decan-2-only), azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are 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. Exemplary 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, e.g., imidazol-2-yl; triazolyl, e.g., 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, e.g., 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Exemplary 6-membered heterocyclyls contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, such as pyridyl, e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, e.g., pyrimidyl-2-yl and pyrimidyl-4-yl; triazinyl, e.g., 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, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl, pyrimidyl, pyridazinyl, and 1,3,4-triazin-2-yl groups are further examples of heterocyclyl groups. In some embodiments, heterocyclic groups include heterocyclic rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the radical or point of attachment is on the heterocyclic ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0044] Thus, the term heterocycle includes N-heterocyclyl groups, which as used herein refers to heterocyclyl groups that contain at least one nitrogen and the attachment point of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group.Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl.The term heterocycle also includes C-heterocyclyl groups, which as used herein refers to heterocyclyl groups that contain at least one heteroatom and the attachment point of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group.Representative examples of C-heterocyclyl radicals include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl and 2- or 3-pyrrolidinyl. The term heterocycle also encompasses heterocyclylalkyl groups, which are of the formula --R c -heterocyclyl (wherein R c is an alkylene chain). The term heterocycle as used herein also includes heterocyclylalkoxy groups of the formula --O--R c -heterocyclyl (wherein R c refers to a radical bonded through an oxygen atom of an alkylene group.

[0045] As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl" where the terminal carbon atom on an alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an aryl group) refers to a group that contains a monocyclic, bicyclic, or tricyclic carbocyclic ring system, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, an aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring." In one embodiment, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, and 2,3-dihydro-1H-indenyl, which may be substituted or independently substituted by one or more substituents described herein. A specific aryl is phenyl. In some embodiments, aryl groups include aryl rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the radical or point of attachment is on the aryl ring.

[0046] Thus, the term aryl includes aralkyl groups (e.g., benzyl), which are of the formula --R c -aryl (wherein R c is an alkylene chain such as methylene or ethylene. In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, also encompasses aralkoxy groups, which have the formula --O--R c -aryl (wherein R c refers to a group attached through an oxygen atom of an alkylene chain such as methylene or ethylene.

[0047] As used herein, the term "heteroaryl," used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (and "heteroaralkyl"), or "heteroarylalkoxy" (and "heteroaralkoxy"), refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes a 4-6 membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen, which may be independently substituted. In another embodiment, heteroaryl includes a 5-6 membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxazolyl ... Sadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriarolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4- Examples include 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 a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic, bicyclic, or tricyclic. In some embodiments, heteroaryl groups include heteroaryl rings fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings) where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0048] Thus, the term heteroaryl includes N-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above that contain at least one nitrogen and the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl also includes C-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above that contain at least one nitrogen and the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl also includes heteroarylalkyl groups, which as disclosed above refer to heteroarylalkyl groups of the formula --R c -heteroaryl (wherein R c is an alkylene chain as defined above. The term heteroaryl also includes heteroaralkoxy (or heteroarylalkoxy) groups, which as used herein have the formula -O-R c -heteroaryl (wherein R c refers to a group attached through an oxygen atom of an alkylene group, as defined above.

[0049] Any group described herein may be substituted or unsubstituted. As used herein, the term "substituted" refers broadly to all permissible substituents, with the implicit caveat that such substitution is subject to the permissible valence of the atom and substituent being substituted, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. Representative substituents include halogens, hydroxyl groups, and any other organic groupings, which may contain any number of carbon atoms, e.g., 1-14 carbon atoms, and may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms, e.g., oxygen, sulfur, and nitrogen, and may be grouped into linear, branched, or cyclic structural formats.

[0050] Representative examples of substituents include alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ring, substituted ring, carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, halo, hydroxyl, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, amino acid, and peptide groups.

[0051] Generally speaking, the compounds of the present invention have the formula (I): [ka] (Wherein, Z is CH2 or C(O), m and m 1are independently an integer from 0 to 8, R is H or A, X is H or C(O), Y is absent or NRA (wherein R is H or C1-C2 alkyl), and when R is H, X is C(O), and m 1 is 1, and Y is NR1A, and R is A, then X is H, and m 1 is 0, Y is absent, and A is [ka] (wherein R2 is H or C1-C2 alkyl, R3 is optionally substituted C1-C5 alkyl, optionally substituted C6-C14 aryl, optionally substituted C6-C14 heteroaryl, optionally substituted C5-C14 carbocycle or optionally substituted C5-C14 heterocycle, or R2 and R3 together with the N to which they are attached form an optionally substituted C6-C14 heterocycle or an optionally substituted C6-C14 heteroaryl group), [ka] (wherein R4 represents an optionally substituted cyclic group, for example, an optionally substituted C5-C14 carbocyclic group, an optionally substituted C6-C14 aryl group, an optionally substituted C5-C14 heterocyclic group, or an optionally substituted C6-C14 heteroaryl group), [ka] (wherein R5 represents hydrogen or halo, and R6 represents NR7R8 (wherein R7 represents H, and R8 represents an optionally substituted C6-C14 aryl group), [ka] (wherein R2 and R3 are as defined above, and R9 and R 10 each represents H, or each independently represents C or N, provided that R and R 10at least one of represents N and together with the atom to which they are attached form an optionally substituted C5-C6 heterocyclic group, for example an optionally substituted C6 heteroaryl group, or [ka] (Wherein, R4, R9 and R 10 represents a group selected from: wherein R is as defined above; or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0052] In some embodiments, m and m 1 is independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, m and m 1 is independently 0, 1, 2, 3, 4, 5 or 6.

[0053] m is 0, R is H, X is C(O), and m 1 In some embodiments where R is 1, Y is NR1A, and R1 is H, the compound of formula (I) has formula (Ia): [ka] wherein A and Z are as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0054] In some embodiments where A is represented by A1, the compound of formula (Ia) has the formula (Ia1): [ka] wherein R2 and R3 are as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0055] In some embodiments, where R3 represents aryl (e.g., phenyl) or substituted aryl (e.g., substituted phenyl), the compound of formula (Ia1) has the formula (Ia1a): [ka] (Wherein, m1 is 0 or 1, and R 11 and R 12 independently represent H, halo, CF, or C-C alkoxy, or R 11 and R 12 each independently represent a C or a heteroatom (e.g., O, N, or S) and together with the atom to which they are attached form an optionally substituted cyclic group, e.g., a C5-C14 carbocycle, a C5-C14 heterocycle, a C6-C14 aryl, or a C6-C14 heteroaryl group (provided that, consistent with the use of the term "aryl", the overall ring structure is defined as an optionally substituted aryl group), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0056] In some embodiments where R3 represents an optionally substituted heterocyclic group, the compound of formula (Ia1) has the formula (Ia1b): [ka] (wherein R2 is as defined above and R 13 represents H or an optionally substituted C1-C5 alkyl, an optionally substituted C6-C14 aryl, an optionally substituted C6-C14 heteroaryl, an optionally substituted C5-C14 carbocycle, or an optionally substituted C5-C14 heterocycle), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0057] In some embodiments, where m is 0 and R2 and R3 together with the atom to which they are attached optionally form a C5-C14 heterocycle, e.g., an optionally substituted C6-C14 heteroaryl group, the compound of formula (Ia1) has the formula (Ia1c): [ka] (In the formula, R 13is as defined above), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0058] In some embodiments where A is represented by A2, the compound of formula (Ia) has the formula (Ia2): [ka] wherein R4 is as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0059] m and m 1 In some embodiments where R is 0, X is H, Y is absent, and R is A, the compound of formula (I) has formula (Ib): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0060] In some embodiments where A is represented by A1, the compound of formula (Ib) has the formula (Ib1): [ka] wherein R2 and R3 are as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0061] In some embodiments, where R3 is optionally substituted aryl (e.g., phenyl), the compound of Formula (Ib1) has the formula (Ib1a): [ka] (Wherein, m1 is 0 or 1, and R2, R 11 and R 12 is as defined above), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0062] In some embodiments, the compound of Formula (Ib1) has the formula (Ib1b): [ka] (wherein m1 is 0 or 1, R2 is as defined above, and R3 represents an optionally substituted C5-C14 heterocyclic group), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0063] In some embodiments, where R2 and R3 together with the atom to which they are attached form an optionally substituted heterocyclic group, e.g., an optionally substituted heteroaryl group, the compound of formula (Ib1) has the formula (Ib1c): [ka] (In the formula, R 13 is as defined above), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0064] In some embodiments where A is represented by A2, the compound of formula (Ib) has the formula (Ib2): [ka] wherein R4 is as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0065] In some embodiments where A is represented by A3, the compound of formula (Ib) has the formula (Ib3): [ka] wherein R5 and R6 are as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0066] In some embodiments where A is represented by A4, the compound of formula (Ib) has the formula (Ib4): [ka] (Wherein, R2, R3, R9 and R 10 is as defined above), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0067] In some embodiments where A is represented by A5, the compound of formula (Ib) has the formula (Ib5): [ka] (Wherein, R4, R9 and R 10 is as defined above), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0068] X is H, m 1 In some embodiments where R is 0, R is A, and Y is absent, the compound of Formula (I) has the formula (Ic): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0069] In some embodiments where A is represented by A3, the compound of formula (Ic) has the formula (Ic1): [ka] wherein R5 and R6 are as defined above, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0070] Representative examples of R3, R4 and R8 for the compounds of the present invention are as follows: [ka] .

[0071] Representative examples of NR2R3 groups for the compounds of the present invention are as follows: [ka] .

[0072] With respect to the compounds of the present invention, R and R 10 Representative examples of optionally substituted C5-C6 heterocyclic groups formed by the formula: [ka] .

[0073] In some embodiments, Z is CH2.

[0074] In some embodiments, the compound of the invention is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0075] The compounds of the present application may be in the form of free acid or free base, or pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable" in the context of salt refers to a salt of a compound that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, i.e., the compound in salt form can be administered to a subject without causing undesirable biological effects (e.g., dizziness or stomach upset) or interacting in a harmful manner with any other components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to the product obtained by reacting a compound of the present invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic bases, such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples of pharma- ceutically 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, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate, etc. Certain compounds of the present invention can form pharma- ceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine or metformin.

[0076] In some embodiments, the compounds of the present invention are isotopically derivatives in that they have at least one desired isotopic substitution of an atom at a higher amount than the natural abundance of that isotope, i.e., enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. Deuterium, i.e. 2Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances.

[0077] The compounds of the present invention may have at least one chiral center and therefore may be in the form of stereoisomers, which as used herein encompasses all isomers of individual compounds that differ only in the orientation of the atoms in space. The term stereoisomer includes enantiomers (enantiomers containing the (R-) or (S-) configuration of a compound), mixtures of enantiomers of a compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of a compound, and isomers of a compound with more than one chiral center that are not mirror images of each other (diastereoisomers). The chiral centers of the compounds may undergo epimerization in vivo, such that 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 application may be prepared and used in the form of individual isomers substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0078] Additionally, the compounds of the present invention encompass the use of N-oxides, crystalline forms (also known as polymorphs), active metabolites of compounds having the same type of activity, tautomers, and solvated forms with pharma- ceutically acceptable solvents such as water and ethanol, as well as unsolvated forms of the compounds. Solvated forms of the conjugates presented herein are also considered to be disclosed herein.

[0079] Synthesis method In another aspect, the present invention is directed to a method for preparing the compounds of the present invention, or their pharma- ceutically acceptable salts or stereoisomers. Generally speaking, the compounds of the present invention, or their pharma- ceutically acceptable salts or stereoisomers, may be prepared by any method known to be applicable to the preparation of chemically related compounds. The compounds of the present invention will be better understood in conjunction with the synthetic schemes described in the various examples and illustrating non-limiting methods by which the compounds of the present invention can be prepared.

[0080] Pharmaceutical Compositions Another aspect of the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle suitable for administering the compounds of the present invention to a mammal, as known in the art. Suitable carriers can include, for example, liquids (both aqueous and non-aqueous as well as 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 body part to another. A carrier is "acceptable" in the sense of being physiologically inert and compatible with the other ingredients of the formulation, and not toxic to the subject or patient. Depending on the type of formulation, the composition may contain one or more pharmaceutically acceptable excipients.

[0081] Generally speaking, the compounds of the present invention may be formulated into a given type of composition according to conventional pharmaceutical practice, e.g., conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping and compressing methods (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 can include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im) and intrasternal injection or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation and inhalation) and topical (e.g., transdermal). In general, the most suitable route of administration will depend on various factors, including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration can also be advantageous in that the compound can be administered relatively quickly, such as in the case of single-dose treatment and / or acute conditions.

[0082] In some embodiments, the compositions are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0083] Thus, the compounds of the present invention may 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 may also be formulated for immediate, intermediate, or sustained release.

[0084] Oral solid dosage forms include capsules, tablets, pills, powders, and granules.In these solid dosage forms, the active compound is mixed with carriers such as sodium citrate or dicalcium phosphate and additional carriers or excipients such as a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrants such as crosslinked polymers (such as crosslinked polyvinylpyrrolidinone ( crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders 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 glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings. They may further contain an opacifying agent.

[0085] In some embodiments, the compound of the present invention may be incorporated into hard or soft gelatin capsules.Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose and croscarmellose sodium.Gelatin shells may include gelatin, titanium dioxide, iron oxide and coloring agents.

[0086] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs.In addition to the compound, liquid dosage forms may contain aqueous or non-aqueous carriers commonly used in the art, (depending on the solubility of the compound), such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.Oral compositions may also contain excipients, such as wetting agents, suspending agents, colorants, sweeteners, flavoring agents and aromatic agents.

[0087] Injectable preparations may include sterile aqueous solutions or oily suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable solvents and vehicles that may be used are water, Ringer's solution, USP and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectable solutions. Injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use. The effect of the compound may be prolonged by slowing its absorption, which may be accomplished by the use of liquid suspensions or crystalline or amorphous material with poor water solubility. Prolonged absorption of a compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oil vehicle.

[0088] In certain embodiments, the compounds of the present invention may be administered in a local rather than systemic manner, for example, via injection of the conjugate directly into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Injectable depot forms are prepared by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The release rate of the compound may be controlled by varying the ratio of compound to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

[0089] The compounds of the present invention may also be formulated for buccal or sublingual administration and include, for example, tablets, lozenges and gels.

[0090] The compound may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosol, mist or powder. The pharmaceutical composition may be delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol may be determined by providing a valve to provide a metered amount. In some embodiments, capsules and cartridges containing gelatin, for example, for use in an inhaler or insufflator, may be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0091] The compounds of the present invention may be formulated for topical administration, which as used herein 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.

[0092] Representative examples of carriers useful in formulating compositions for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffered solutions (e.g., hypotonic or buffered saline). For example, creams may be formulated using saturated or unsaturated fatty acids, such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl, or oleyl alcohol. Creams may also contain non-ionic surfactants, such as polyoxy-40 stearate.

[0093] In some embodiments, topical formulations may also include excipients, examples of which are permeation enhancers. These agents are preferably capable of transporting pharmacologically active compounds through the stratum corneum to the epidermis or dermis with little or no systemic absorption. A variety of compounds have been evaluated for their effectiveness in enhancing the permeation rate of drugs through the skin.

[0094] See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which reviews the use and testing of various skin permeation enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Representative examples of permeation 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-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0095] Representative examples of other excipients that can be included in other types of formulations (as long as they are compatible) besides in topical formulations include preservatives, antioxidants, moisturizers, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citric acid. Suitable moisturizers include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citric acid, hydrochloric acid, and lactic acid buffers. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0096] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches in which the compound is dissolved and / or dispersed in a polymer or adhesive and formulated in a lipophilic emulsion or buffered aqueous solution. Patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. Transdermal delivery of compounds may be achieved by means of iontophoretic patches. Transdermal patches may provide controlled delivery of compounds with slow absorption rates by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Absorption enhancers may be used to increase absorption, examples of which include absorbable pharmacologic acceptable solvents that aid passage through the skin.

[0097] Ophthalmic formulations include eye drops.

[0098] 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, and the like. Compositions for rectal or vaginal administration may also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity to release the compound. Dosage As used herein, the term "therapeutically effective amount" refers to an amount of any of the following proteins that are capable of binding to, or inhibit, the activity of, any of the following proteins: casein kinase 1 alpha (CK1α), sequence similarity 83 family member F (FAM83F), DTW domain containing 1 (DTWD1), zinc finger protein 91 homolog (ZFP91), ZFP62, ZFP36 RING finger protein-like (ZFP36L2), RING finger protein 166 (RNF166), Ikaros family zinc finger protein 1 (IKZF1), IKZF2, IKZ F3, IKZF4, IKZF5, Ras-related protein Rab-28 (RAB28), glutathione S-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membrane translocase subunit Tim10 (TIMM10), GDNF-inducible zinc finger protein 1 (GZF1), early growth response 1 (EGR1)-, hypermethylation in cancer 1 (HIC1)-, HIC2-, insulinoma-associated protein 2 (INSM2)-, odd-skipped-associated transcription factor child 2 (OSR2), protein polybromo-1 (PB1), PR domain zinc finger protein 15 (PRD15), spalt-like transcription factor 1 (SALL1), SALL3, SALL4, WIZ, zinc finger and BTB domain containing protein 17 (ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, ZBTB39, zinc finger protein interacting with K protein 1 (ZIK1), zinc finger protein 3 (ZNF3), ZNF2 17, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, zinc finger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827,and Zinc finger containing UFM1 specific peptidase domain (ZUFSP), and the amount of the compound of the present invention or a pharma- ceutical acceptable salt or stereoisomer thereof effective to produce a desired therapeutic response in a particular patient suffering from a disease or disorder characterized or mediated by the abnormal activity of a protein selected from the group consisting of zinc finger containing UFM1 specific peptidase domain (ZUFSP), In some embodiments, the disease or disorder is characterized or mediated by the abnormal activity of IKZF2. The term "therapeutically effective amount" includes an amount of the compound of the present invention or its pharma- ceutically acceptable salt or stereoisomer that is administered to induce a positive modification (e.g., amelioration) in the disease or disorder to be treated, or to prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject, or simply kill or inhibit the proliferation of disease (e.g., cancer) cells.

[0099] The total daily dosage of the compound of the present invention and its usage can be determined according to standard medical practice, for example, by the attending physician using sound medical judgment.The specific therapeutically effective dose for any specific patient depends on various factors, including the disease or disorder being treated and its severity (e.g., its current state); the activity of the specific compound being used; the specific composition being used; the age, weight, general health condition, sex and diet of the patient; the time of administration, route of administration and the excretion rate of the specific compound being used; the duration of treatment; the drugs used in combination with or simultaneously with the specific compound being used; and similar factors well known in the medical field (for example, see 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).

[0100] The compounds of the present invention may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for an adult human) may be in the range of about 0.001 to about 1600 mg, 0.01 to about 1000 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100 to 400 mg / day, about 1 to about 50 mg / day, and about 5 to about 40 mg / day, and in still other embodiments, about 10 to about 30 mg / day. Individual dosages may be formulated to contain the desired dosage depending on the number of times the compound is administered per day. As an example, capsules may be formulated to contain about 1 to about 200 mg of the compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, the individual doses may be compounded to contain a desired dosage depending on the number of times the compound is administered per day.

[0101] How to use In some aspects, the compounds of the present invention may be useful in the treatment of diseases and disorders characterized by abnormal activity of a protein that participates in the initiation, manifestation, severity or progression of one or more symptoms or markers of the disease or disorder, which may be targeted for degradation by cereblon, and where degradation of the targeted protein may confer a therapeutic benefit. The disease or disorder may be said to be characterized or mediated by abnormal protein activity, which may involve elevated protein levels compared to non-pathological conditions, as disclosed above. A "disease" is generally considered as an animal's health condition in which the animal is unable to maintain homeostasis and the animal's health condition continues to worsen if the disease is not remitted. In contrast, a "disorder" in an animal is a health condition in which the animal is able to maintain homeostasis, but the animal's health condition is not more favorable than in the absence of the disorder. If left untreated, the disorder does not necessarily cause a further decrease in the animal's health condition. In some embodiments, the compounds of the present application may be useful in the treatment of proliferative diseases and disorders (e.g., cancer or benign neoplasms). As used herein, the term "cell proliferative disease or disorder" refers to conditions characterized by uncontrolled or abnormal cell proliferation, or both, including non-cancerous conditions, pre-cancerous conditions, and cancer.

[0102] The term "subject" (or "patient"), as used herein, includes all members of the animal kingdom susceptible to or afflicted with the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., a human or a non-human mammal. The method is also applicable to companion animals, e.g., dogs and cats, as well as livestock, e.g., cows, horses, sheep, goats, pigs, and other domesticated and wild animals. A subject "in need" of treatment according to the present invention may be one who is "suffering or suspected of suffering from" a particular disease or disorder, who has been positively diagnosed or who otherwise shows a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional may diagnose or suspect that the subject suffers from the disease or disorder. Thus, subjects who are suffering from or suspected of suffering from a particular disease or disorder are not necessarily two separate groups.

[0103] Exemplary types of non-cancerous (e.g., cell proliferative) diseases or disorders that may be suitable for treatment with the compounds of the invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, cardiac diseases, viral diseases, chronic and acute kidney diseases or injuries, metabolic diseases, allergic and genetic diseases.

[0104] Representative examples of specific non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative conditions, autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ecodermal dysplasia, pure red cell aplasia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndrome (CAPS), endotoxic shock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pneumonia, chronic graft rejection, hidradenitis suppurativa, Inflammatory bowel disease, Crohn's disease, Behçet's syndrome, systemic lupus erythematosus, glomerulonephritis, multiple sclerosis, early-onset diabetes mellitus, autoimmune uveitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, autoimmune thyroiditis or Hashimoto's disease, Sjögren's syndrome, vitiligo, Wegener's disease Bronchiectasis, granulomatous orchitis, autoimmune oophoritis, sarcoidosis, rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, dermatitis herpetiformis, ulcerative colitis, pancreatic fibrosis, hepatitis, liver fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, fever, restenosis, cerebral malaria, cervicitis, stroke and ischemic injury, neurotrauma , acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndromes, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendinitis, tendonitis, herniated, ruptured, or prolapsed disc syndrome, osteopetrosis, rhinosinusitis, thrombosis, silicosis, pulmonary sarcosissarcosis, bone resorption disorders such as osteoporosis, graft-versus-host reaction, fibromyalgia, AIDS and other viral diseases such as herpes zoster, herpes simplex type I or II, influenza virus and cytomegalovirus, diabetes mellitus type I and type II, obesity, insulin resistance and diabetic retinopathy, 22q11.2 deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, colour blindness, meowing, Down's syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefleter's syndrome syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sudden infant death syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, cystic fibrosis, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, arteriosclerosis, amyotrophic lateral sclerosis, asocality, immune response, venous distension, vaginitis including chronic recurrent yeast vaginitis, depression, and sudden infant death syndrome.

[0105] In other embodiments, the method is directed to treating a subject with cancer.Generally speaking, the compounds of the present invention can be effective in treating carcinomas (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers that affect the blood, including lymphocytes, bone marrow, and / or lymph nodes), including leukemia, lymphoma, and multiple myeloma.Included are adult tumors / cancers and pediatric tumors / cancers.Cancers may be vascularized or not yet substantially vascularized or non-vascularized tumors.

[0106] Representative examples of cancer include adrenal cortical carcinoma, AIDS-related cancer (e.g., Kaposi's and AIDS-related lymphoma), appendix cancer, childhood cancer (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, brain cancer (e.g., glioma and glioblastoma, e.g., brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumor, etc.) tumors), visual pathway and hypothalamic gliomas), breast cancer, bronchial adenoma / carcinoid, carcinoid tumors, nervous system cancers (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancers (e.g., colon cancer, rectal cancer), lymphatic neoplasms, mycosis fungoids, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancers (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), cholangiocarcinoma, germ cell tumors, ovarian germ cell tumors, gestational trophoblastic tumors Glioma, Head and neck cancer, Neuroendocrine tumors, Hodgkin's lymphoma, Ann Arbor stage III and stage IV pediatric non-Hodgkin's lymphoma, ROS1 positive refractory non-Hodgkin's lymphoma, Leukemia, Lymphoma, Multiple myeloma, Hypopharyngeal cancer, Intraocular melanoma, Eye cancer, Islet cell tumors (endocrine pancreas), Kidney cancer (e.g. Wilms' tumor, renal cell carcinoma), Liver cancer, Lung cancer (e.g. non-small cell lung cancer and small cell lung cancer), ALK positive anaplastic large cell lymphoma, ALK positive advanced malignant solid neoplasms, Waldenstrom's macroglobulinemia macroglobulinema, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of occult primary, multiple endocrine neoplasia (MEN), myelodysplastic syndromes, myelodyplastic / myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, cancer of the mouth (e.g., mouth cancer, lip cancer, oral cavity cancer)cancer, tongue cancer, oropharyngeal cancer, pharyngeal cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumors, ovarian low malignant potential tumors), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, metastatic anaplastic thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, pituitary tumors, plasma cell neoplasms / multiple myeloma, pulmonary pleuroblastoma, prostate cancer, retinoblastoma rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial cancer) cancer), uterine sarcoma, uterine cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, juvenile xanthogranuloma, transitional cell carcinoma of the renal pelvis and ureters and other urinary organs, urethral cancer, gestational trophoblastic neoplasia, vaginal cancer, vulvar cancer, hepatoblastoma, rhabdoid tumor, and Wilms' tumor.

[0107] Sarcomas that may be treatable using the compounds of the invention include both soft tissue and bone cancers as well, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelioma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (fatty tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), mesenchymous or mixed mesodermal tumor (mixed connective tissue type), and histiocytic sarcoma (immune cancer).

[0108] In some embodiments, the methods of the invention involve treatment of subjects with cell proliferative diseases or disorders of the blood system, liver (hepatocytes), brain, lung, colorectal (e.g., colon), pancreas, prostate, ovary, breast, skin (e.g., melanoma), and endometrium.

[0109] As used herein, "cell proliferative diseases or disorders of the blood system" include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia, myelodysplasia of unknown etiology, and essential thrombocythemia. Representative examples of hematological cancers include: multiple myeloma, lymphomas (T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., diffuse large B-cell lymphoma (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma), Burkitt's lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenström's macroglobulinemia, refractory and B-cell non-Hodgkin's lymphoma selected from recurrent B-cell non-Hodgkin's lymphoma, childhood lymphoma, and lymphomas of lymphocytic and cutaneous origin, such as small lymphocytic lymphoma, primary CNS lymphoma (PCNSL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, and leukemia, myeloid neoplasms and mast cell neoplasms.

[0110] As used herein, "hepatic cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the liver.Hepatic cell proliferation disorder can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), precancerous or precancerous conditions of the liver, benign growths or lesions of the liver, and malignant growths or lesions of the liver, as well as metastatic lesions in tissues and organs in the body other than the liver.Brain cell proliferation disorder can include hepatic hyperplasia, metaplasia, and dysplasia.

[0111] As used herein, "brain cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the brain.Brain cell proliferation disorder can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and primitive neuroectodermal tumor (medulloblastoma)), brain precancer or precancerous condition, brain benign growth or lesion, and brain malignant growth or lesion, as well as metastatic lesion in tissues and organs in the body other than the brain.Brain cell proliferation disorder can include brain hyperplasia, metaplasia, and dysplasia.

[0112] As used herein, "pulmonary cell proliferative disease or disorder" includes all forms of cell proliferative disorders that affect lung cells. Pulmonary cell proliferative disorders include lung cancer, precancerous or precancerous conditions of the lung, benign growths or lesions of the lung, and metastatic lesions in tissues and organs in the body other than the lung. Lung cancer includes all forms of cancer of the lung, such as malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer includes small cell lung cancer ("SLCL"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma. Lung cancer can include "scar carcinoma", bronchioloalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer includes lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0113] As used herein, "colon cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect colon cells, including colon cancer, colon precancer or precancerous condition, colon adenomatous polyp and metachronous lesion of colon.Colon cancer includes sporadic and hereditary colon cancer, malignant colon neoplasm, carcinoma in situ, typical carcinoid tumor, and atypical carcinoid tumor, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma.Colon cancer can be associated with hereditary syndromes, such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis.Colon cell proliferation disorder can also be characterized by colon hyperplasia, metaplasia, and dysplasia.

[0114] As used herein, "pancreatic cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect pancreatic cells.Pancreatic cell proliferation disorder can include pancreatic cancer, pancreatic precancer or precancerous condition, pancreatic hyperplasia and pancreatic dysplasia, pancreatic benign growth or lesion, pancreatic malignant growth or lesion, and metastatic lesion in tissues and organs in the body other than pancreas.Pancreatic cancer includes all forms of cancer of the pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, and pancreatic neoplasm with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0115] As used herein, "prostate cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect prostate.Prostate cell proliferation disorder can include prostate cancer, prostate precancer or precancerous condition, prostate benign growth or lesion, prostate malignant growth or lesion, and metastatic lesion in body tissue and organ other than prostate.Prostate cell proliferation disorder can include prostate hyperplasia, metaplasia, and dysplasia.

[0116] As used herein, "cell proliferative disease or disorder of the ovary" includes all forms of cell proliferative disorders that affect cells of the ovary.Cell proliferative disorders of the ovary can include ovarian precancer or precancerous conditions, ovarian benign growths or lesions, ovarian cancer, and metastatic lesions in tissues and organs of the body other than the ovary.Cell proliferative disorders of the ovary can include ovarian hyperplasia, metaplasia, and dysplasia.

[0117] As used herein, "breast cell proliferative disease or disorder" includes all forms of cell proliferative disorders that affect breast cells. Breast cell proliferative disorders can include breast cancer, pre-cancer or pre-cancerous conditions of the breast, benign growths or lesions of the breast, and metastatic lesions in tissues and organs of the body other than the breast. Breast cell proliferative disorders can include breast hyperplasia, metaplasia, and dysplasia.

[0118] As used herein, "cell proliferative disease or disorder of the skin" includes all forms of cell proliferative disorders that affect skin cells.Cell proliferative disorders of the skin can include precancerous or precancerous conditions of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions in tissues and organs of the body other than the skin.Cell proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.

[0119] As used herein, "endometrial cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the endometrium.Endometrial cell proliferation disorder can include endometrial cancer, endometrial precancer or precancerous condition, endometrial benign growth or lesion, endometrial malignant growth or lesion, and metastatic lesion in tissues and organs in the body other than endometrium.Endometrial cell proliferation disorder can include endometrial hyperplasia, metaplasia, and dysplasia.

[0120] The compounds of the present invention may be administered to patients, e.g., cancer patients, as monotherapy or in combination therapy, and as frontline or follow-on therapy for patients unresponsive to frontline therapy. The therapy may be a "first line" treatment, either alone or in combination with other therapies, i.e., as an initial treatment in patients who have not received a previous anti-cancer treatment regimen, or a "second line" treatment, either alone or in combination with other therapies, in patients who have received a previous anti-cancer treatment regimen, or a "third line," "fourth line," etc. treatment, either alone or in combination with other therapies. The therapy may also be given to patients who have received previous therapies that have been partially successful but are intolerant to the specific treatment. The therapy may also be given as adjuvant therapy, i.e., to prevent recurrence of cancer in patients who currently have no detectable disease or after surgical removal of a tumor. Thus, in some embodiments, the compounds may be administered to patients who have received another therapy, e.g., chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof.

[0121] The method of the present application may involve administration of the compound of the present invention or a pharmaceutical composition thereof to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). For example, the frequency of administration may range from once a day to about once every 8 weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments involves a 28-day cycle that includes daily administration for 3 weeks (21 days).

[0122] Combination therapy The compounds of the present invention may be used in combination with at least one other active agent, such as an anti-cancer agent or regimen, in the treatment of diseases and disorders. The term "in combination" in this context means that the agents are administered together, including administration in the same or separate dosage forms for substantially the same time, or sequentially, such as as part of the same treatment regimen or by a continuous treatment regimen. Thus, when given sequentially, at the start of administration of the second compound, the first of the two compounds may still be detectable at effective concentrations at the site of treatment in some cases. The order and time interval may be determined so that they can act together (e.g., synergistically to provide increased benefits than if they were administered otherwise). For example, the therapeutic agents may be administered simultaneously or sequentially in any order at different times, but if not administered simultaneously, they may be administered close enough in time to provide the desired therapeutic effect, which may be in a synergistic manner. Thus, the term is not limited to administration of the active agents at exactly the same time.

[0123] In some embodiments, the treatment regimen may include administration of the compounds of the present invention in combination with one or more additional therapeutic agents known for use in treating a disease or condition (e.g., cancer). The dosage of the additional anti-cancer therapeutic agent may be the same as or even lower than the known or recommended dose. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anti-cancer agents that may be used in combination with the compounds of the present invention are known in the art. See, for example, U.S. Pat. No. 9,101,622 (section 5.2 thereof) and U.S. Pat. No. 9,345,705 B2 (columns 12-18 thereof). Representative examples of additional active agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogens, signal transduction pathway inhibitors, antimicrotubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0124] In some embodiments, the compounds of the invention and the additional (e.g., anti-cancer) therapeutic agent may be administered in parts less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. Two or more anti-cancer therapeutic agents may be administered within the same patient visit.

[0125] In some embodiments, the compound of the present invention and the additional agent or therapeutic agent (e.g., anti-cancer therapeutic agent) are administered periodically. Cycling therapy involves the administration of one anti-cancer therapeutic agent for a period of time, followed by the administration of a second anti-cancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one or both of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one or both of the anti-cancer therapeutic agents, and / or to improve the efficacy of the therapy. In one example in the context of cancer treatment, cycling therapy involves the administration of a first anti-cancer therapeutic agent for a period of time, followed by the administration of a second anti-cancer therapeutic agent for a period of time, optionally followed by the administration of a third anti-cancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one of the anti-cancer therapeutic agents, and / or to improve the efficacy of the anti-cancer therapeutic agents.

[0126] Pharmaceutical Kits The composition of the present invention may be assembled into a kit or pharmaceutical system.The kit or pharmaceutical system according to this aspect of the present invention comprises a carrier or package, such as a box, carton, or tube, having one or more containers, such as vials, tubes, ampoules, or bottles, containing the compound of the present invention or its pharmaceutical composition in close confinement therein.The kit or pharmaceutical system of the present invention may also comprise printed instructions for using the compound and composition.

[0127] These and other aspects of the present application will be further understood in consideration of the following examples, which are intended to illustrate certain specific embodiments of the present application and are not intended to limit its scope as defined by the claims. EXAMPLES

[0128] Example 1: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)amino)acetamide (1). [ka] [ka] tert-Butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2-oxoethyl)-carbamate

[0129] To a solution of (tert-butoxycarbonyl)glycine (2.1 g, 12 mmol), DIEA (5 mL, 30 mmol) in DMF (30 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (4.94 g, 13 mmol) and stirred for 0.5 h, then lenalidomide (2.59 g, 10 mmol) was added and the mixture was then stirred at room temperature for another 1 h. The mixture was then purified by silica gel (MeOH / DCM=0-10%) to give the title compound.

[0130] LCMS(m / z):417[M+H] + . [ka] 2-Amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0131] To a solution of tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2-oxoethyl)-carbamate in DCM (30 mL) was added TFA (10 mL) and stirred at room temperature for 3 h. The mixture was then concentrated in vacuo and purified by silica gel (MeOH / DCM=0-30%) to give the title compound (972 mg, 23% for two steps).

[0132] LCMS(m / z):317[M+H] + . [ka] 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0133] To a solution of 2-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (972 mg, 2.26 mmol) and 2,4-dichloropyrimidine (332 mg, 2.26 mmol) in THF (20 mL) was added DIEA (1.1 mL, 6.78 mmol) and then stirred overnight. The mixture was then concentrated in vacuo and purified by silica gel (MeOH / DCM=0-10%) to give the title compound (693 mg, 72%).

[0134] LCMS(m / z):429[M+H] + . [ka]

[0135] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and 2-fluoroaniline (13 mg, 0.12 mmol) in BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 1 (4.6 mg, 6%).

[0136] 1H NMR(500MHz,DMSO-d6)δ 11.05(s,1H),10.18(s,1H),10.06(s,1H),9.38(t,J=5.7Hz,1H),7.90(d,J=7.2Hz,1H),7 .83-7.74(m,2H),7.57-7.49(m,2H),7.26-7.16(m,1H),7.08-6.97(m,1H),6.45(d,J=7.2 Hz,1H),5.16(dd,J=13.3,5.2Hz,1H),4.31-4.22(m,4H),2.93(ddd,J=17.4,13.6,5.4Hz, 1H),2.65-2.56(m,1H),2.24(qd,J=13.2,4.5Hz,1H),2.03(ddd,J=10.3,5.4,2.8Hz,1H).

[0137] LCMS(m / z):504[M+H] + .

[0138] Example 2: Synthesis of 2-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (2). [ka]

[0139] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and 2,3-dihydro-1H-inden-5-amine (16 mg, 0.12 mmol) in BuOH (1 mL) was added TFA (18 μL, 0.24 mmol) and the mixture was heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 2 (4.4 mg, 6%).

[0140] 1H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.32(s,1H),10.11(s,1H),9.30(t,J=5.9Hz,1H),7.82(d,J=7.2H z,1H),7.58-7.48(m,2H),7.34(s,1H),7.26-7.18(m,2H),7.08(d,J=8.0Hz,1H),6 .39(d,J=7.2Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.33-4.25(m,4H),2.85(dt,J= 14.5,7.7Hz,2H),2.73(q,J=7.5Hz,4H),2.07-1.96(m,2H),1.91(p,J=7.0Hz,2H).

[0141] LCMS(m / z):526[M+H] + .

[0142] Example 3: Synthesis of 2-((2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (3). [ka]

[0143] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and benzo[d][1,3]dioxol-5-ylmethanamine (18 mg, 0.12 mmol) in BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 3 (6.5 mg, 4%).

[0144] 1H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),9.85(d,J=4.6Hz,1H),7.78(dd,J=7.6,1.4Hz,1H),7.68(d,J=5.7Hz,1H),7.5 4-7.43(m,2H),7.32(s,1H),6.94(s,1H),6.82(s,1H),6.76-6.65(m,2H),5.90(s,2H),5.86 (d,J=6.0Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.36-4.22(m,4H),4.09(d,J=5.9Hz,2H),2. 92(ddd,J=17.2,13.6,5.4Hz,1H),2.69-2.57(m,1H),2.32-2.18(m,1H),2.03-1.96(m,1H).

[0145] LCMS(m / z):544[M+H] + .

[0146] Example 4: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)acetamide (4). [ka]

[0147] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and (S)-pyrrolidin-2-ylmethanol (12 mg, 0.12 mmol) in BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 4 (1.9 mg, 3%).

[0148] 1H NMR (500MHz, DMSO-d6) δ 11.88(s,1H),11.04(s,1H),10.13(s,1H),9.12(s,1H),7.83(dd,J=7.6,1.4Hz, 1H),7.73(d,J=7.3Hz,1H),7.57-7.46(m,2H),6.29(d,J=7.2Hz,1H),5.18(dd,J= 13.3,5.1Hz,1H),4.42-4.26(m,4H),3.64-3.34(m,4H),2.94(ddd,J=18.1,13.5 ,5.4Hz,1H),2.67-2.60(m,1H),2.30(dd,J=13.1,4.6Hz,1H),2.10-1.90(m,6H).

[0149] LCMS(m / z):494[M+H] + .

[0150] Example 5: Synthesis of 2-((2-(benzo[d][1,3]dioxol-5-ylamino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (5). [ka]

[0151] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (60 mg, 0.14 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (21 mg, 0.14 mmol) in BuOH (1 mL) was added TFA (21 μL, 0.28 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 5 (5.2 mg, 6%).

[0152] 1H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),10.25(s,1H),10.12(s,1H),9.28(s,1H),7.83-7.74(m,2H),7.56-7.4 7(m,2H),7.01(d,J=2.5Hz,1H),6.97(d,J=8.6Hz,1H),6.74(d,J=8.7Hz,1H),6.37(d, J=7.2Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.32(s,2H),4.16-4.05(m,4H),2.92(dd d,J=17.2,13.5,5.4Hz,1H),2.64-2.56(m,1H),2.32-2.20(m,1H),2.06-1.95(m,1H).

[0153] LCMS(m / z):530[M+H] + .

[0154] Example 6: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((3-(2-oxopyrrolidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)acetamide (6). [ka]

[0155] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (60 mg, 0.14 mmol) and 1 1-(3-aminopropyl)pyrrolidin-2-one (20 mg, 0.14 mmol) in BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 6 (4.1 mg, 5%).

[0156] 1H NMR(500MHz,DMSO-d6)δ 11.94(s,1H),11.04(d,J=2.3Hz,1H),10.20-10.08(m,1H),8.04-7.93(m,1H),7.85(ddd,J=17.0,7 .4,1.6Hz,1H),7.74(d,J=7.3Hz,1H),7.58-7.46(m,2H),6.30-6.23(m,1H),5.17(ddd,J=13.3,5.2, 2.9Hz,1H),4.49-4.21(m,4H),3.31(d,J=22.6Hz,2H),3.19-3.08(m,2H),2.98-2.90(m,1H),2.67- 2.59(m,1H),2.34-2.25(m,1H),2.14(d,J=7.8Hz,1H),2.08-1.99(m,1H),1.81(s,1H),1.62(s,1H).

[0157] LCMS(m / z):535[M+H] + .

[0158] Example 7: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)acetamide (7). [ka]

[0159] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.234 mmol) and 4-methoxyaniline (29 mg, 0.234 mmol) in BuOH (1 mL) was added TFA (36 μL, 0.468 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 7 (10.9 mg, 7%).

[0160] 1H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),10.46(s,1H),10.15(s,1H),9.32(d,J=5.7Hz,1H),7.81(td,J=9.1,7.7,4.1Hz ,2H),7.58-7.47(m,2H),7.42(d,J=8.5Hz,2H),6.78(d,J=8.5Hz,2H),6.38(d,J=7.2Hz,1H),5 .14(dd,J=13.3,5.1Hz,1H),4.33-4.23(m,4H),3.60(s,3H),2.93(ddd,J=17.2,13.5,5.4Hz, 1H),2.65-2.56(m,1H),2.23(qd,J=13.2,4.4Hz,1H),2.01(dtd,J=12.4,7.4,6.2,3.7Hz,1H).

[0161] LCMS(m / z):516[M+H] + .

[0162] Example 8: Synthesis of 2-((2-([1,1'-biphenyl]-4-yl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (8). [ka] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (110 mg, 0.24 mmol) and [1,1'-biphenyl]-4-ylboronic acid (54 mg, 0.28 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (52 mg, 0.26 mmol), Pd2dba3 (22 mg, 0.024 mmol) and tri-tert-butylphosphonium tetrafluoroborate (20 mg, 0.048 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 8 (4.4 mg, 3%).

[0163] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.30(s,1H),8.77(dd,J=4.4,1.4Hz,1H),8.36(d,J=8.2Hz,2H),8 .31-8.27(m,1H),7.90-7.72(m,5H),7.56-7.50(m,4H),7.49-7.39(m,1H),6.88(d ,J=6.7Hz,1H),5.11(dd,J=13.4,5.0Hz,1H),4.49(d,J=5.4Hz,2H),4.37(s,2H),2 .87(t,J=13.9Hz,1H),2.64(d,J=5.1Hz,1H),2.17(d,J=13.4Hz,1H),1.96(s,1H).

[0164] LCMS(m / z):547[M+H] + .

[0165] Example 9: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(3-methoxyphenyl)pyrimidin-4-yl)amino)acetamide (9). [ka]

[0166] tTo a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (3-methoxyphenyl)boronic acid (43 mg, 0.28 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (49 mg, 0.25 mmol), Pd2dba3 (21 mg, 0.023 mmol) and tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 9 (4.0 mg, 3%).

[0167] 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),10.31(s,1H),9.79(s,1H),8.24(d,J=7.2Hz,1H),8.19-8.17(m,1H),7.81(dd,J=7.6,1. 5Hz,1H),7.68(ddd,J=8.9,7.3,1.8Hz,1H),7.56-7.52(m,2H),7.32(d,J=8.4Hz,1H),7.11(t,J=7.6Hz, 1H),6.98(d,J=7.2Hz,1H),5.14(dd,J=13.3,5.2Hz,1H),4.50(d,J=5.5Hz,2H),4.36-4.25(m,2H),3.9 8(s,3H),2.92(ddd,J=18.3,13.4,5.5Hz,1H),2.62-2.56(m,1H),2.15-2.07(m,1H),2.00-1.96(m,1H).

[0168] LCMS(m / z):501[M+H] + .

[0169] Example 10: Synthesis of 2-((2-(2,5-dimethoxyphenyl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (10). [ka]

[0170] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (2,5-dimethoxyphenyl)boronic acid (51 mg, 0.28 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (49 mg, 0.25 mmol), Pd2dba3 (21 mg, 0.023 mmol) and tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 10 (2.8 mg, 1%).

[0171] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.30(s,1H),9.60(s,1H),8.23(d,J=9.3Hz,1H),8.16(d,J=7.2Hz,1H),7.84-7.7 8(m,1H),7.59-7.49(m,2H),6.88(d,J=7.1Hz,1H),6.80(d,J=2.4Hz,1H),6.66(dt,J=8.9,2.0Hz, 1H),5.13(dd,J=13.3,5.1Hz,1H),4.47(d,J=5.5Hz,2H),4.32(s,2H),4.01(s,3H),3.89(s,3H),2 .92(ddd,J=18.3,13.5,5.4Hz,1H),2.58(d,J=17.5Hz,1H),2.20-2.08(m,1H),2.01-1.90(m,1H).

[0172] LCMS(m / z):531[M+H] + .

[0173] Example 11: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(4-fluorophenyl)pyrimidin-4-yl)amino)acetamide (11). [ka]

[0174] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (4-fluorophenyl)boronic acid (50 mg, 0.28 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (49 mg, 0.25 mmol), Pd2dba3 (21 mg, 0.023 mmol) and tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 11 (10.0 mg, 3%).

[0175] 1 H NMR (500MHz, DMSO-d6) δ 11.02(s,1H),10.30(s,1H),9.30(s,1H),8.36-8.23(m,2H),7.81(d,J=7.2Hz ,1H),7.57-7.49(m,3H),7.42(t,J=8.6Hz,2H),6.88(d,J=6.8Hz,1H),5.13(dd ,J=13.3,5.1Hz,1H),4.47(d,J=5.3Hz,2H),4.34(s,2H),2.92(ddt,J=18.1,1 3.6,4.7Hz,1H),2.65-2.57(m,1H),2.19-2.12(m,1H),1.98(d,J=10.2Hz,1H).

[0176] LCMS(m / z):489[M+H] + .

[0177] Example 12: Synthesis of 2-((2-(4-acetylphenyl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (12). [ka]

[0178] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (4-acetylphenyl)boronic acid (45 mg, 0.28 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (49 mg, 0.25 mmol), Pd2dba3 (21 mg, 0.023 mmol) and tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give 12 (3.6 mg, 3%).

[0179] 1 H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),10.22(s,1H),8.75(s,1H),8.40(d,J=8.4Hz,2H),8.29(d,J=6.4Hz,1H),8 .06(d,J=8.1Hz,2H),7.81(d,J=7.4Hz,1H),7.57-7.47(m,2H),6.82(d,J=6.4Hz,1H),5. 11(dd,J=13.1,5.1Hz,1H),4.43-4.38(m,2H),4.33(s,2H),2.90(ddd,J=18.2,13.5,5.4 Hz,1H),2.63(s,3H),2.57(d,J=19.1Hz,1H),2.14(d,J=13.6Hz,1H),2.00-1.91(m,1H).

[0180] LCMS(m / z):513[M+H]+ .

[0181] Example 13: Synthesis of 2-((2-(benzofuran-2-yl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (13). [ka]

[0182] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (150 mg, 0.35 mmol) and benzofuran-2-ylboronic acid (68 mg, 0.42 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (75 mg, 0.39 mmol), Pd2dba3 (32 mg, 0.035 mmol) and tri-tert-butylphosphonium tetrafluoroborate (20 mg, 0.07 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give 13 (12.3 mg, 6%).

[0183] 1 H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),10.20(s,1H),8.22(d,J=5.8Hz,1H),8.14(s,1H),7.83(dd,J=7.4,1.6 Hz,1H),7.72(d,J=7.8Hz,1H),7.66(s,1H),7.63(d,J=8.3Hz,1H),7.56-7.49(m,2H) ,7.43-7.38(m,1H),7.29(s,1H),6.67(s,1H),5.07(dd,J=13.4,4.9Hz,1H),4.36(d, J=22.3Hz,4H),2.92-2.79(m,1H),2.46(s,1H),2.13(d,J=13.9Hz,1H),1.89(s,1H).

[0184] LCMS(m / z):511[M+H] + .

[0185] Example 14: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)acetamide (14). [ka]

[0186] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (210 mg, 0.5 mmol) and (R)-pyrrolidin-2-ylmethanol (50 mg, 0.5 mmol) in BuOH (2 mL) was added TFA (76 μL, 1.0 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 14 (5.1 mg, 2%).

[0187] 1 H NMR(500MHz,DMSO-d6)δ 11.04(s,1H),10.15(s,1H),9.13(s,1H),7.83(d,J=7.6Hz,1H),7.74(d,J=7.2Hz,1H ),7.60-7.47(m,2H),6.29(d,J=7.2Hz,1H),5.18(dd,J=13.3,5.2Hz,1H),4.44-4.27 (m,4H),3.60-3.36(m,5H),2.94(ddd,J=18.1,13.5,5.5Hz,1H),2.68-2.58(m,1H),2 .30(tt,J=13.1,6.7Hz,1H),2.06-2.00(m,1H),1.91(dqd,J=18.5,12.4,6.4Hz,4H).

[0188] LCMS(m / z):494[M+H] + .

[0189] Example 15: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((2-methoxyphenyl)amino)pyrimidin-4-yl)amino)acetamide (15). [ka]

[0190] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (140 mg, 0.33 mmol) and 2-methoxyaniline (40 mg, 0.33 mmol) in BuOH (2 mL) was added TFA (50 μL, 0.66 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 15 (9.5 mg, 5%).

[0191] 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),10.18(s,1H),9.64(s,1H),9.38(t,J=5.8Hz,1H),7.94-7.77(m,3H),7.5 6-7.49(m,2H),7.12(t,J=7.7Hz,1H),7.09-7.07(m,1H),6.80(t,J=7.7Hz,1H),5.14(dd ,J=13.3,5.2Hz,1H),4.34-4.20(m,4H),3.83(s,3H),2.92(ddd,J=17.2,13.5,5.4Hz,1 H),2.66-2.54(m,1H),2.19(qd,J=13.1,4.4Hz,1H),2.00(dtd,J=12.8,5.4,2.2Hz,1H).

[0192] LCMS(m / z):516[M+H] + .

[0193] Example 16: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)amino)acetamide (16). [ka]

[0194] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (135 mg, 0.316 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (73 mg, 0.316 mmol) in BuOH (2 mL) was added TFA (48 μL, 0.632 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 16 (12.1 mg, 5%).

[0195] 1 H NMR(500MHz,DMSO-d6)δ 11.04(s,1H),10.27(s,1H),9.27(t,J=5.6Hz,1H),7.88(dd,J=7.4,1.6Hz,1H),7.80(dd,J=7.2,2.1Hz,1H),7. 59-7.51(m,2H),7.47-7.43(m,1H),7.29-7.22(m,1H),7.17(t,J=6.9Hz,1H),7.11(d,J=7.5Hz,1H),5.18(dd,J =13.3,5.1Hz,1H),4.36(dd,J=34.4,7.4Hz,4H),3.85(t,J=5.1Hz,4H),3.37(dt,J=48.5,5.2Hz,4H),2.93(ddd ,J=18.0,13.5,5.3Hz,1H),2.64-2.57(m,1H),2.31(qd,J=13.2,4.4Hz,1H),2.04(ddd,J=13.3,5.8,3.4Hz,1H).

[0196] LCMS(m / z):623[M+H] + .

[0197] Example 17: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(methyl(phenyl)amino)pyrimidin-4-yl)amino)acetamide (17). [ka]

[0198] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (135 mg, 0.316 mmol) and N-methylaniline (34 mg, 0.316 mmol) in BuOH (2 mL) was added TFA (48 μL, 0.632 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 17 (16.5 mg, 6%).

[0199] 1 H NMR(500MHz,DMSO-d6)δ 11.04(s,1H),10.20(s,1H),9.35(t,J=5.7Hz,1H),7.86(dd,J=7.4,1.6Hz,1H),7.60( d,J=7.2Hz,1H),7.57-7.53(m,2H),7.49(d,J=7.4Hz,2H),7.45(dt,J=8.2,2.6Hz,3H) ,6.38(d,J=7.2Hz,1H),5.18(dd,J=13.3,5.1Hz,1H),4.46-4.28(m,4H),3.44(s,3H), 2.99-2.87(m,1H),2.67-2.58(m,1H),2.31(qd,J=13.2,4.5Hz,1H),2.13-1.96(m,1H).

[0200] LCMS(m / z):500[M+H] + .

[0201] Example 18: Synthesis of 2-((2-(benzyl(ethyl)amino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (25). [ka]

[0202] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (98 mg, 0.23 mmol) and N-benzylethanamine (31 mg, 0.23 mmol) in BuOH (2 mL) was added TFA (36 μL, 0.46 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 25 (1.4 mg, 0.8%).

[0203] 1 H NMR(500MHz,DMSO-d6)δ 11.04(s,1H),10.05(s,1H),7.77(dt,J=13.2,7.1Hz,2H),7.54-7.46(m,2H),7.4 0-7.18(m,6H),6.33(d,J=6.6Hz,1H),5.15(dd,J=13.2,5.2Hz,1H),4.78(d,J=16 .6Hz,2H),4.30(d,J=5.7Hz,4H),3.52(s,2H),2.93(ddd,J=17.4,13.6,5.4Hz,1H ),2.68-2.57(m,1H),2.17(d,J=16.2Hz,1H),2.01(s,1H),1.03(t,J=7.0Hz,3H).

[0204] LCMS(m / z):528[M+H] + .

[0205] Example 19: Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(4-fluoro-2-methoxyphenyl)pyrimidin-4-yl)amino)acetamide (34). [ka]

[0206] t To a solution of 2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (60 mg, 0.28 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (49 mg, 0.25 mmol), Pd2dba3 (21 mg, 0.023 mmol) and tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 34 (1.6 mg, 1%).

[0207] LCMS(m / z):519[M+H] + .

[0208] Example 20: Synthesis of 3-(4-((2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (18). [ka] [ka] 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0209] To a solution of lenalidomide (777 mg, 3 mmol) and 2,4-dichloropyrimidine (882 mg, 6 mmol) in DMF (6 mL) was added DIEA (1.5 mL, 9 mmol), then the mixture was heated to 110° C. overnight. The mixture was concentrated in vacuo and then purified by silica gel (MeOH / DCM=0-6%) to give the title compound (321 mg, 29%) as a pale white solid.

[0210] LCMS(m / z):372[M+H] + . [ka]

[0211] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (112 mg, 0.3 mmol) and 4-methoxyaniline (37 mg, 0.3 mmol) in BuOH (2 mL) was added TFA (45 μL, 0.6 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 18 (64.3 mg, 38%).

[0212] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.36(d,J=51.4Hz,2H),7.94(dd,J=41.2,7.4Hz,2H),7.65(d,J=7.5Hz,1H),7 .56(t,J=7.7Hz,1H),7.32(d,J=8.4Hz,2H),6.85(d,J=8.4Hz,2H),6.43(d,J=6.9Hz,1H),5.1 4(dd,J=13.2,5.2Hz,1H),4.46(d,J=17.5Hz,1H),4.33(d,J=17.4Hz,1H),3.74(s,3H),2.90( ddd,J=18.1,13.6,5.4Hz,1H),2.62-2.53(m,1H),2.35-2.24(m,1H),1.87(d,J=11.2Hz,1H).

[0213] LCMS(m / z):459[M+H] + .

[0214] Example 21: Synthesis of 3-(4-((2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (19). [ka]

[0215] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (98 mg, 0.26 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (40 mg, 0.26 mmol) in BuOH (2 mL) was added TFA (40 μL, 0.52 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 19 (15.9 mg, 10.1%).

[0216] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.41(d,J=52.9Hz,2H),7.94(dd,J=57.8,7.2Hz,2H),7.6 9-7.49(m,2H),6.99(s,1H),6.85-6.71(m,2H),6.43(d,J=6.9Hz,1H),5. 14(dd,J=13.3,5.3Hz,1H),4.46(d,J=17.5Hz,1H),4.30(d,J=17.4Hz,1H ),4.20(s,4H),2.97-2.85(m,1H),2.57(s,1H),2.25(s,1H),1.82(s,1H).

[0217] LCMS(m / z):487[M+H] + .

[0218] Example 22: Synthesis of 3-(4-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (21). [ka]

[0219] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (83 mg, 0.22 mmol) and 2-fluoroaniline (25 mg, 0.22 mmol) in BuOH (2 mL) was added TFA (33 μL, 0.44 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 21 (11.0 mg, 9%).

[0220] 1 H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),10.31(s,1H),10.01(s,1H),8.07(d,J=6.8Hz,1H),7.89(d,J=7.9Hz,1H),7.59(dd,J=9.9,7.0Hz, 2H),7.46(t,J=7.7Hz,1H),7.30(ddd,J=10.5,8.3,1.4Hz,1H),7.24(tdd,J=7.9,5.2,1.6Hz,1H),7.11(t,J=7.7H z,1H),6.49(d,J=6.7Hz,1H),5.14(dd,J=13.3,5.1Hz,1H),4.45(d,J=17.5Hz,1H),4.33(d,J=17.4Hz,1H),2.96- 2.84(m,1H),2.59(dt,J=17.0,3.3Hz,1H),2.31(qd,J=13.2,4.4Hz,1H),1.97-1.84(m,1H).LCMS(m / z):447[M+H] + .

[0221] Example 23: Synthesis of 3-(1-oxo-4-((2-((3-(2-oxopyrrolidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione (22). [ka]

[0222] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.24 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (34 mg, 0.24 mmol) in BuOH (2 mL) was added TFA (36 μL, 0.48 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 22 (8.6 mg, 6%).

[0223] 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),10.58(s,1H),8.32(s,1H),7.93(d,J=6.9Hz,2H),7.65(dd,J=18.8,7.5Hz, 2H),6.38(s,1H),5.19(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.7Hz,1H),4.38(d,J=17.8Hz, 1H),3.17(d,J=21.2Hz,6H),2.94(ddd,J=18.0,13.7,5.4Hz,1H),2.60(d,J=17.2Hz,1H), 2.39(qd,J=13.2,4.5Hz,1H),2.14(s,2H),2.02(d,J=12.2Hz,1H),1.73(d,J=83.3Hz,4H).

[0224] LCMS(m / z):478[M+H] + .

[0225] Example 24: Synthesis of 3-(1-oxo-4-((2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione (23). [ka]

[0226] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (85 mg, 0.23 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (53 mg, 0.23 mmol) in BuOH (2 mL) was added TFA (35 μL, 0.46 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 23 (10.9 mg, 7%).

[0227] 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),10.53(s,1H),8.00(d,J=6.9Hz,1H),7.84(d,J=7.8Hz,1H),7.68(d,J=7.4Hz,1H),7.62(t,J=7.7Hz,1H),7. 44(t,J=8.0Hz,1H),7.28-7.23(m,1H),7.22(t,J=1.9Hz,1H),7.10(d,J=7.6Hz,1H),6.41(d,J=6.9Hz,1H),5.19(dd,J=13. 3,5.2Hz,1H),4.47(d,J=17.6Hz,1H),4.37(d,J=17.5Hz,1H),3.76(q,J=4.0Hz,4H),3.39(t,J=4.3Hz,4H),2.93(ddd,J=1 7.4,13.7,5.4Hz,1H),2.58(dt,J=17.2,3.1Hz,1H),2.38(qd,J=13.2,4.4Hz,1H),2.02(ddq,J=10.5,5.6,3.3,2.7Hz,1H).

[0228] LCMS(m / z):566[M+H] + .

[0229] Example 25: Synthesis of 3-(4-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24). [ka]

[0230] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.24 mmol) and 2,3-dihydro-1H-inden-5-amine (33 mg, 0.24 mmol) in BuOH (2 mL) was added TFA (36 μL, 0.48 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 24 (15.6 mg, 11%).

[0231] 1 H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),10.47(d,J=32.6Hz,2H),8.03(d,J=6.9Hz,1H),7.87(d,J=7.9Hz,1H),7.68(d,J=7.4Hz,1H),7.5 8(t,J=7.7Hz,1H),7.32(s,1H),7.09(q,J=8.2Hz,2H),6.45(d,J=6.9Hz,1H),5.12(dd,J=13.3,5.1Hz,1H),4.4 6(d,J=17.5Hz,1H),4.31(d,J=17.5Hz,1H),2.88(ddd,J=18.0,13.6,5.4Hz,1H),2.79(t,J=7.4Hz,2H),2.68(t ,J=6.8Hz,2H),2.57-2.55(m,1H),2.22(qd,J=13.3,4.4Hz,1H),1.98(p,J=7.4Hz,2H),1.75(d,J=12.2Hz,1H).

[0232] LCMS(m / z):469[M+H] + .

[0233] Example 26: Synthesis of 3-(4-((2-(benzyl(ethyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (26). [ka]

[0234] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.24 mmol) and N-benzylethanamine (33 mg, 0.24 mmol) in BuOH (2 mL) was added TFA (36 μL, 0.48 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 26 (7.6 mg, 5%).

[0235] 1 H NMR (500MHz, DMSO-d6) δ 11.04(s,1H),10.38(s,1H),7.96(d,J=7.0Hz,1H),7.64-7.55(m,1H),7.38-7.2 4(m,4H),7.18(s,2H),6.43(s,1H),5.17(dd,J=13.3,5.1Hz,1H),4.74(s,2H),4 .50-4.28(m,2H),3.55(s,2H),2.93(ddd,J=17.3,13.6,5.4Hz,1H),2.61(dt,J= 17.2,3.3Hz,1H),2.36(qd,J=12.9,4.4Hz,1H),2.07-1.93(m,1H),1.10(s,3H).

[0236] LCMS(m / z):471[M+H] + .

[0237] Example 27: Synthesis of 3-(4-((2-(methyl(phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (27). [ka]

[0238] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.22 mmol) and N-methylaniline (23 mg, 0.22 mmol) in BuOH (2 mL) was added TFA (33 μL, 0.44 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 27 (17.4 mg, 14%).

[0239] 1 H NMR(500MHz,DMSO-d6)δ 11.05(s,1H),10.50(s,1H),7.86(dd,J=22.4,7.5Hz,2H),7.58(d,J=7.5Hz,1H),7.53(t,J= 7.6Hz,2H),7.47-7.39(m,4H),6.50(d,J=7.0Hz,1H),5.18(dd,J=13.3,5.1Hz,1H),4.47(d, J=17.5Hz,1H),4.37(d,J=17.5Hz,1H),3.39(s,3H),2.94(ddd,J=17.3,13.6,5.4Hz,1H),2. 62(dt,J=17.2,3.4Hz,1H),2.37(qd,J=13.2,4.4Hz,1H),2.02(dtd,J=12.8,5.3,2.3Hz,1H).

[0240] LCMS(m / z):443[M+H] + .

[0241] Example 28: Synthesis of 3-(4-((2-(mesitylamino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (28). [ka]

[0242] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (86 mg, 0.23 mmol) and 2,4,6-trimethylaniline (31 mg, 0.23 mmol) in BuOH (2 mL) was added TFA (35 μL, 0.46 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 28 (4.7 mg, 4%).

[0243] LCMS(m / z):471[M+H] + .

[0244] Example 29: Synthesis of 3-(4-((2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (29). [ka]

[0245] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82 mg, 0.22 mmol) and (S)-pyrrolidin-2-ylmethanol (23 mg, 0.22 mmol) in BuOH (2 mL) was added TFA (33 μL, 0.44 mmol) and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give 29 (6.3 mg, 5%).

[0246] 1 H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),10.46(s,2H),8.12-7.87(m,2H),7.63(dd,J=20.9,7.6H z,2H),6.44(s,1H),5.19(dt,J=13.3,5.2Hz,1H),4.57-4.31(m,2H),4. 11(s,1H),3.47(d,J=38.9Hz,4H),2.94(ddd,J=18.2,13.9,5.0Hz,1H) ,2.66-2.56(m,1H),2.40-2.31(m,1H),2.09(s,1H),2.05-1.84(m,4H).

[0247] LCMS(m / z):437[M+H] + .

[0248] Example 30: Synthesis of 3-(4-((2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30). [ka]

[0249] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82 mg, 0.22 mmol) and (R)-pyrrolidin-2-ylmethanol (23 mg, 0.22 mmol) in BuOH (2 mL) was added TFA (33 μL, 0.44 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 30 (12.0 mg, 10%).

[0250] 1H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),10.49(s,1H),8.22-7.88(m,2H),7.74-7.37(m,2H),6.44(s,1H),5.18(dt,J=13.3,5.2Hz,1H),4.56-4.28(m,2H),4 .11(s,1H),3.63-3.37(m,4H),2.99-2.85(m,1H),2.67-2.56(m,1H),2.43-2.32(m,1H),2.11(d,J=15.7Hz,1H),2.06-1.83(m,5H).

[0251] LCMS(m / z):437[M+H] + .

[0252] Example 31: Synthesis of 3-(4-((2-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (37). [ka]

[0253] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.27 mmol) and (R)-2-amino-3-methylbutan-1-ol (28 mg, 0.27 mmol) in BuOH (2 mL) was added TFA (41 μL, 0.54 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 37 (4.5 mg, 3%).

[0254] 1H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),10.50(s,1H),8.21(s,1H),7.94(d,J=7.3Hz,2H),7.66(d,J=7.1Hz ,1H),7.60(t,J=7.7Hz,1H),6.37(s,1H),5.17(dd,J=13.1,5.1Hz,1H),4.59-4.3 4(m,2H),3.48(d,J=9.0Hz,2H),2.99-2.87(m,1H),2.62(dd,J=15.3,11.7Hz,1H) ,2.44-2.31(m,1H),2.01(d,J=16.2Hz,1H),1.84(s,1H),0.86(d,J=42.6Hz,6H).

[0255] LCMS(m / z):439[M+H] + .

[0256] Example 32: Synthesis of 3-(4-((2-((2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (38). [ka]

[0257] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.27 mmol) and 2-methoxyaniline (33 mg, 0.27 mmol) in BuOH (2 mL) was added TFA (41 μL, 0.54 mmol) and then the mixture was heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 38 (20.6 mg, 13%).

[0258] 1H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),10.64(s,1H),9.86-9.75(m,1H),8.04(d,J=7.0Hz,1H),7.88(d,J=7.9Hz,1H),7.65(dd,J=7.5,0. 9Hz,1H),7.53(t,J=7.6Hz,2H),7.20(t,J=7.6Hz,1H),7.11(dd,J=8.4,1.4Hz,1H),6.82(t,J=7.8Hz,1H),6.51(d ,J=7.1Hz,1H),5.14(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.5Hz,1H),4.34(d,J=17.5Hz,1H),3.82(s,3H),2.90(d dd,J=17.3,13.7,5.4Hz,1H),2.57(dt,J=17.2,3.4Hz,1H),2.28(qd,J=13.2,4.4Hz,1H),1.87(d,J=12.6Hz,1H).

[0259] LCMS(m / z):459[M+H] + .

[0260] Example 33: Synthesis of 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pyrimidin-2-yl)amino)benzenesulfonamide (40). [ka]

[0261] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60 mg, 0.16 mmol) and 4-aminobenzenesulfonamide (28 mg, 0.16 mmol) in BuOH (2 mL) was added TFA (24 μL, 0.32 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 40 (9.0 mg, 9%).

[0262] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.39(s,1H),10.17(s,1H),8.12(d,J=6.5Hz,1H),7.97(d,J=7.7Hz,1H), 7.72-7.55(m,6H),7.24(s,2H),6.48(d,J=6.6Hz,1H),5.15(dd,J=13.3,5.2Hz,1H),4.4 8(d,J=17.5Hz,1H),4.37(d,J=17.5Hz,1H),2.90(ddd,J=17.3,13.6,5.4Hz,1H),2.56(d t,J=16.9,3.4Hz,1H),2.30(qd,J=13.2,4.5Hz,1H),1.90(dtd,J=12.9,5.4,2.3Hz,1H).

[0263] LCMS(m / z):508[M+H] + .

[0264] Example 34: Synthesis of 3-(4-((2-(indolin-5-ylamino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (43). [ka]

[0265] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.135 mmol) and tert-butyl 5-aminoindoline-1-carboxylate (32 mg, 0.135 mmol) in BuOH (2 mL) was added TFA (21 μL, 0.27 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 43 (10.4 mg, 13%).

[0266] 1H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.48(d,J=30.2Hz,2H),8.02(d,J=6.9Hz,1H),7.95(d,J=7.8Hz,1H),7.66(dd,J=7.5,1.1H z,1H),7.61(t,J=7.6Hz,1H),7.07(s,1H),7.01(s,2H),6.46(d,J=6.9Hz,1H),5.15(dd,J=13.2,5.1Hz,1H ),4.49(d,J=17.5Hz,1H),4.34(d,J=17.5Hz,1H),3.56(t,J=8.2Hz,2H),2.99(t,J=8.1Hz,2H),2.94-2.85 (m,1H),2.64-2.55(m,1H),2.33(ddd,J=26.6,13.2,3.2Hz,1H),2.25(s,1H),1.90(dd,J=11.1,5.2Hz,1H).

[0267] LCMS(m / z):470[M+H] + .

[0268] Example 35: Synthesis of 3-(4-((2-(((3s,5s,7s)-adamantan-1-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (44). [ka]

[0269] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.135 mmol) and (3s,5s,7s)-adamantan-1-amine (24 mg, 0.162 mmol) in BuOH (2 mL) was added TFA (67 μL, 0.405 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 44 (4.1 mg, 3%).

[0270] 1H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),10.61(s,1H),7.99(s,1H),7.93(d,J=7.2Hz,1H),7.72(dd,J=10.6,7.6Hz,2H),7.62 (t,J=7.6Hz,1H),6.33(d,J=7.2Hz,1H),5.16(dd,J=13.3,5.2Hz,1H),4.40(d,J=17.6Hz,1H),4.30( d,J=17.6Hz,1H),2.92(ddd,J=17.3,13.6,5.4Hz,1H),2.64-2.53(m,1H),2.44-2.36(m,1H),2.09( s,1H),1.96-1.91(m,1H),1.86(s,3H),1.76(s,6H),1.50(d,J=12.2Hz,3H),1.33(d,J=11.9Hz,3H).

[0271] LCMS(m / z):487[M+H] + .

[0272] Example 36: Synthesis of 3-(4-((2-(naphthalen-2-ylamino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (45). [ka]

[0273] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.135 mmol) and tert-butyl 5-aminoindoline-1-carboxylate (23 mg, 0.162 mmol) in BuOH (2 mL) was added TFA (21 μL, 0.27 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 45 (16.8 mg, 21%).

[0274] 1H NMR(500MHz,DMSO-d6)δ 10.98(s,1H),10.79(s,1H),10.61(s,1H),8.11(d,J=7.0Hz,1H),8.03-8.00(m,1H),7.95(d,J=7 .9Hz,1H),7.84(t,J=8.3Hz,2H),7.71(d,J=7.5Hz,1H),7.58(d,J=7.7Hz,1H),7.55-7.39(m,4H) ,6.52(d,J=6.9Hz,1H),5.08(dd,J=13.2,5.2Hz,1H),4.49(d,J=17.6Hz,1H),4.35(d,J=17.6Hz, 1H),2.81(ddd,J=17.2,13.7,5.4Hz,1H),2.45(s,1H),2.16(dt,J=11.5,5.3Hz,1H),1.62(s,1H).

[0275] LCMS(m / z):479[M+H] + .

[0276] Example 37: Synthesis of 3-(4-((2-((9H-fluoren-3-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (46). [ka]

[0277] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.135 mmol) and 9H-fluoren-3-amine (24 mg, 0.135 mmol) in BuOH (2 mL) was added TFA (21 μL, 0.27 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 46 (30.0 mg, 37%).

[0278] 1H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),10.79(s,1H),10.64(s,1H),8.10(d,J=6.9Hz,1H),7.92(d,J=7.9Hz,1H),7.82(d,J=7.5Hz,1H) ,7.79-7.74(m,1H),7.74-7.70(m,2H),7.63(t,J=7.7Hz,1H),7.55(d,J=7.4Hz,1H),7.39-7.33(m,2H),7.28(t d,J=7.4,1.2Hz,1H),6.50(d,J=7.0Hz,1H),5.12(dd,J=13.2,5.2Hz,1H),4.51(d,J=17.6Hz,1H),4.36(d,J=1 7.5Hz,1H),2.85(ddd,J=17.3,13.6,5.4Hz,1H),2.54(d,J=11.7Hz,1H),2.30-2.15(m,1H),1.80-1.67(m,1H).

[0279] LCMS(m / z):517[M+H] + .

[0280] Example 38: Synthesis of 3-(1-oxo-4-((2-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione (52). [ka]

[0281] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.27 mmol) and 5,6,7,8-tetrahydronaphthalen-2-amine (40 mg, 0.27 mmol) in BuOH (2 mL) was added TFA (41 μL, 0.54 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 52 (70.4 mg, 44%).

[0282] 1 H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),10.62(s,1H),10.54(s,1H),8.03(d,J=7.0Hz,1H),7.85(d,J=7.9Hz,1H),7.68(d,J=7.5Hz,1H),7.58(t,J =7.7Hz,1H),7.09(d,J=2.2Hz,1H),7.04(dd,J=8.3,2.2Hz,1H),6.93(d,J=8.3Hz,1H),6.46(d,J=7.0Hz,1H),5.12(dd,J =13.2,5.2Hz,1H),4.45(d,J=17.6Hz,1H),4.29(d,J=17.5Hz,1H),2.89(ddd,J=17.3,13.7,5.4Hz,1H),2.64(d,J=6.2Hz ,2H),2.55(d,J=2.6Hz,1H),2.45(s,2H),2.20(qd,J=13.4,4.3Hz,1H),1.68(dd,J=7.6,4.3Hz,4H).LCMS(m / z):483[M+H] + .

[0283] Example 39: Synthesis of 3-(4-((2-(4-acetylphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20). [ka]

[0284] tTo a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (115 mg, 0.3 mmol) and (4-acetylphenyl)boronic acid (61 mg, 0.36 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (64 mg, 0.33 mmol), Pd2dba3 (27 mg, 0.03 mmol) and tri-tert-butylphosphonium tetrafluoroborate (18 mg, 0.06 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 20 (10.0 mg, 6%).

[0285] 1 H NMR(500MHz,DMSO-d6)δ 11.00(s,1H),9.65(s,1H),8.49(d,J=5.8Hz,1H),8.37(d,J=8.3Hz,2H),8.13(d,J=7.8Hz,1H ),8.07(d,J=8.3Hz,2H),7.67-7.53(m,2H),6.87(d,J=5.9Hz,1H),5.17(dd,J=13.3,5.1Hz,1 H),4.52(d,J=17.3Hz,1H),4.43(d,J=17.3Hz,1H),2.92(ddd,J=17.2,13.6,5.4Hz,1H),2.63 (s,3H),2.61-2.55(m,1H),2.35(qd,J=13.2,4.4Hz,1H),2.01(dtd,J=12.7,5.3,2.2Hz,1H).

[0286] LCMS(m / z):456[M+H] + .

[0287] Example 40: Synthesis of 3-(4-((2-([1,1'-biphenyl]-4-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (31). [ka]

[0288] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.27 mmol) and [1,1'-biphenyl]-4-ylboronic acid (80 mg, 0.41 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (58 mg, 0.30 mmol), Pd2dba3 (25 mg, 0.027 mmol) and tri-tert-butylphosphonium tetrafluoroborate (16 mg, 0.054 mmol). The mixture was heated to 80° C. and stirred under N2 atmosphere overnight. The mixture was then filtered, concentrated in vacuo, and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 31 (4.0 mg, 2%).

[0289] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),9.99(s,1H),8.47(d,J=6.1Hz,1H),8.30(d,J=8.5Hz,2H),8.10(dd,J=7.3,1.6Hz,1H),7. 85(d,J=8.5Hz,2H),7.79-7.75(m,2H),7.67-7.61(m,2H),7.51(dd,J=8.4,7.0Hz,2H),7.44-7.39(m,1H ),6.88(d,J=6.2Hz,1H),5.18(dd,J=13.4,5.1Hz,1H),4.54(d,J=17.4Hz,1H),4.44(d,J=17.4Hz,1H),2 .92(ddd,J=18.0,13.6,5.4Hz,1H),2.64-2.54(m,1H),2.35(qd,J=13.2,4.5Hz,1H),2.07-1.96(m,1H).

[0290] LCMS(m / z):490[M+H] + .

[0291] Example 41: Synthesis of 3-(4-((2-(3-methoxyphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (32). [ka]

[0292] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (78 mg, 0.21 mmol) and (3-methoxyphenyl)boronic acid (48 mg, 0.32 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (45 mg, 0.23 mmol), Pd2dba3 (19 mg, 0.021 mmol) and tri-tert-butylphosphonium tetrafluoroborate (12 mg, 0.042 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 32 (13.7 mg, 12%).

[0293] 1 H NMR(500MHz,DMSO-d6)δ 11.19(s,1H),11.02(s,1H),8.44(d,J=7.1Hz,1H),7.96(d,J=7.8Hz,1H),7.86(d,J=7.8Hz,1H),7.73(dd,J=7. 5,1.1Hz,1H),7.67(td,J=7.8,7.3,1.3Hz,2H),7.32(dd,J=8.5,0.9Hz,1H),7.17(td,J=7.5,1.0Hz,1H),7.06( d,J=6.9Hz,1H),5.18(dd,J=13.3,5.1Hz,1H),4.52(d,J=17.6Hz,1H),4.42(d,J=17.6Hz,1H),3.98(s,3H),2.9 3(ddd,J=17.3,13.7,5.4Hz,1H),2.64-2.55(m,1H),2.38-2.29(m,1H),2.00(ddq,J=10.3,5.4,3.1,2.6Hz,1H).

[0294] LCMS(m / z):444[M+H] + .

[0295] Example 42: Synthesis of 3-(4-((2-(4-fluoro-2-methoxyphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33). [ka]

[0296] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (96 mg, 0.26 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (66 mg, 0.39 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (56 mg, 0.29 mmol), Pd2dba3 (22 mg, 0.026 mmol) and tri-tert-butylphosphonium tetrafluoroborate (15 mg, 0.052 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 33 (17.1 mg, 11%).

[0297] 1 H NMR(500MHz,DMSO-d6)δ 11.14(s,1H),11.03(s,1H),8.43(d,J=7.0Hz,1H),7.94(d,J=7.8Hz,1H),7.89(dd,J=8.8,6.7Hz,1H),7.7 2(dd,J=7.6,1.0Hz,1H),7.66(t,J=7.7Hz,1H),7.26(dd,J=11.3,2.4Hz,1H),7.03(td,J=8.5,4.1Hz,2H), 5.18(dd,J=13.3,5.1Hz,1H),4.50(d,J=17.6Hz,1H),4.41(d,J=17.6Hz,1H),3.98(s,3H),2.93(ddd,J=17 .3,13.6,5.4Hz,1H),2.64-2.56(m,1H),2.33(qd,J=13.2,4.4Hz,1H),2.00(dtd,J=12.6,5.1,2.1Hz,1H).

[0298] LCMS(m / z):462[M+H] + .

[0299] Example 43: Synthesis of 3-(4-((2-(2,4-dimethoxyphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (35). [ka]

[0300] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.27 mmol) and (2,4-dimethoxyphenyl)boronic acid (74 mg, 0.41 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (58 mg, 0.30 mmol), Pd2dba3 (25 mg, 0.027 mmol) and tri-tert-butylphosphonium tetrafluoroborate (16 mg, 0.054 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 35 (9.3 mg, 6%).

[0301] 1H NMR(500MHz,DMSO-d6)δ 11.11(s,1H),11.02(s,1H),8.35(d,J=7.1Hz,1H),7.93(d,J=8.5Hz,2H),7.74(d,J=7.5Hz,1H),7 .68(t,J=7.7Hz,1H),6.99(s,1H),6.82(d,J=2.3Hz,1H),6.80-6.76(m,1H),5.18(dd,J=13.3,5.1 Hz,1H),4.51(d,J=17.6Hz,1H),4.40(d,J=17.6Hz,1H),4.03(s,3H),3.89(s,3H),2.92(ddd,J=17 .3,13.6,5.4Hz,1H),2.63-2.55(m,1H),2.33(qd,J=12.9,4.2Hz,1H),2.00(td,J=6.0,2.3Hz,1H).

[0302] LCMS(m / z):474[M+H] + .

[0303] Example 44: Synthesis of 3-(4-((2-(benzofuran-2-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (36). [ka]

[0304] t To a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.27 mmol) and benzofuran-2-ylboronic acid (65 mg, 0.41 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (58 mg, 0.30 mmol), Pd2dba3 (25 mg, 0.027 mmol) and tri-tert-butylphosphonium tetrafluoroborate (16 mg, 0.054 mmol). The mixture was heated to 80° C. and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 36 (5.0 mg, 3%).

[0305] 1 H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),9.75(s,1H),8.44(d,J=5.9Hz,1H),8.08(d,J=7.7Hz,1H),7.78(dt,J=7.8,1.0Hz,1H),7.68(dq,J=8 .3,0.9Hz,1H),7.63(t,J=7.6Hz,1H),7.61-7.57(m,2H),7.43(ddd,J=8.4,7.2,1.4Hz,1H),7.34-7.30(m,1H),6.8 3(d,J=6.0Hz,1H),5.16(dd,J=13.2,5.1Hz,1H),4.60(d,J=17.4Hz,1H),4.44(d,J=17.4Hz,1H),2.90(ddd,J=17.3 ,13.6,5.4Hz,1H),2.59-2.53(m,1H),2.37(ddd,J=15.6,12.4,4.5Hz,1H),2.03(ddq,J=10.6,5.6,3.3,2.7Hz,1H).

[0306] LCMS(m / z):454[M+H] + .

[0307] Example 45: Synthesis of 3-(4-((2-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39). [ka]

[0308] tTo a solution of 3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60 mg, 0.16 mmol) and (4-fluorophenyl)boronic acid (34 mg, 0.24 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (34 mg, 0.18 mmol), Pd2dba3 (15 mg, 0.016 mmol) and tri-tert-butylphosphonium tetrafluoroborate (10 mg, 0.032 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give compound 39 (1.5 mg, 2%).

[0309] 1 H NMR(500MHz,DMSO-d6)δ 11.01(s,1H),9.96(s,1H),8.44(d,J=6.1Hz,1H),8.25(dd,J=8.6,5.7Hz,1H),8.04(dd,J=7.0,1.9Hz ,1H),7.84(dd,J=8.3,6.3Hz,1H),7.62(d,J=7.0Hz,2H),7.36(t,J=8.7Hz,1H),7.15(t,J=8.9Hz,1H), 6.86(d,J=6.1Hz,1H),5.17(dd,J=13.3,5.1Hz,1H),4.50(d,J=17.4Hz,1H),4.42(d,J=17.4Hz,1H),2. 92(ddd,J=18.2,13.5,5.4Hz,1H),2.66-2.55(m,1H),2.34(qd,J=13.3,4.6Hz,1H),2.03-1.97(m,1H).

[0310] LCMS(m / z):432[M+H] + .

[0311] Example 46: Synthesis of 3-(4-((2-((2,3-dihydro-1H-inden-5-yl)amino)-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (53). [ka] [ka] 3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0312] To a solution of lenalidomide (78 mg, 0.34 mmol) and 2,6-dichloro-9-isopropyl-9H-purine (88 mg, 0.34 mmol) in DMF (2 mL) was added DIEA (169 μL, 1.02 mmol), then the mixture was heated to 100° C. overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / H2O, 0.05% TFA) to give the title compound.

[0313] LCMS(m / z):454[M+H] + . [ka]

[0314] t To a solution of 3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60 mg, 0.13 mmol) and 2,3-dihydro-1H-inden-5-amine (18 mg, 0.13 mmol) in BuOH (1 mL) was added TFA (20 μL, 0.26 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 53 (19.8 mg, 23%).

[0315] 1H NMR(500MHz,DMSO-d6)δ 10.93(s,1H),9.74(s,1H),9.03(s,1H),8.31(s,1H),7.85(d,J=7.7Hz,1H),7.69-7.50(m,3H),7.28(d,J =8.3Hz,1H),6.96(d,J=8.2Hz,1H),5.08(dd,J=13.2,5.2Hz,1H),4.78-4.68(m,1H),4.57(d,J=17.3Hz,1H ),4.34(d,J=17.3Hz,1H),2.85(ddd,J=18.3,13.6,5.4Hz,1H),2.74(t,J=7.3Hz,2H),2.64(t,J=7.5Hz,2H ),2.48(s,1H),2.20(dd,J=13.3,4.5Hz,1H),1.98-1.88(m,2H),1.74-1.67(m,1H),1.57(d,J=6.7Hz,6H).

[0316] LCMS(m / z):551[M+H] + .

[0317] Example 47: Synthesis of 3-(4-((9-isopropyl-2-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (55). [ka]

[0318] t To a solution of 3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (45 mg, 0.1 mmol) and 5,6,7,8-tetrahydronaphthalen-2-amine (15 mg, 0.1 mmol) in BuOH (1 mL) was added TFA (15 μL, 0.2 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 55 (11.0 mg, 16%).

[0319] 1 H NMR(500MHz,DMSO-d6)δ 10.94(s,1H),9.82(s,1H),9.01(s,1H),8.40(s,1H),7.91(d,J=7.6Hz,1H),7.63-7.50(m,2H),7.4 1(s,1H),7.26(dd,J=8.3,2.3Hz,1H),6.80(d,J=8.3Hz,1H),5.08(dd,J=13.2,5.1Hz,1H),4.71(p, J=6.8Hz,1H),4.59(d,J=17.3Hz,1H),4.35(d,J=17.3Hz,1H),3.08(qd,J=7.3,4.7Hz,4H),2.91-2. 81(m,1H),2.56-2.52(m,1H),1.77(d,J=12.2Hz,1H),1.68(t,J=3.3Hz,4H),1.58(d,J=6.7Hz,6H).

[0320] LCMS(m / z):565[M+H] + .

[0321] Example 48: Synthesis of 3-(4-((9-isopropyl-2-(mesitylamino)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (56). [ka]

[0322] t To a solution of 3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (45 mg, 0.1 mmol) and 2,4,6-trimethylaniline (14 mg, 0.1 mmol) in BuOH (1 mL) was added TFA (15 μL, 0.2 mmol), and the mixture was then heated to reflux overnight. The mixture was then concentrated in vacuo and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 56 (0.5 mg, 0.8%).

[0323] LCMS(m / z):553[M+H]+ .

[0324] Example 49: Synthesis of 3-(4-((2-(2-methoxyphenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (47). [ka] [ka] 2,6-Dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

[0325] To a solution of 2,6-dichloro-9H-purine (1.89 g, 10 mmol) and NaOH (1.2 g, 30 mmol) in DMF (30 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (3.5 mL, 20 mmol), and the mixture was stirred for 4 h. The mixture was then extracted with EtOAc, washed with brine, dried over Na2SO4, concentrated in vacuo and used in the next step without any purification.

[0326] LCMS(m / z):319[M+H] + . [ka] 3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0327] To a solution of 2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (10 mmol) and lenalidomide (2.6 g, 10 mmol) in DMF (30 mL) was added DIEA (3.3 mL, 20 mmol), then heated to 110° C. and stirred overnight. The mixture was purified by silica gel (MeOH / DCM=0-4%) directly to give the title compound (1.0 g, 19% for two steps) as a yellow solid.

[0328] LCMS(m / z):542[M+H] + . [ka]

[0329] t To a solution of 3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (83 mg, 0.15 mmol) and (2-methoxyphenyl)boronic acid (27 mg, 0.18 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (32 mg, 0.17 mmol), Pd2dba3 (14 mg, 0.015 mmol) and tri-tert-butylphosphonium tetrafluoroborate (9 mg, 0.03 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuum and purified by silica gel (MeOH / DCM=0-4%) to give the intermediate. The intermediate was then concentrated in vacuo, dissolved in TFA / DCM=1 / 1, stirred for 2 h, and then concentrated in vacuo again and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 47 (26.0 mg, 29%).

[0330] 1H NMR(500MHz,DMSO-d6)δ 10.99(s,1H),8.50(s,1H),8.05(dd,J=6.9,2.1Hz,1H),7.62-7.50(m,4H),7.45(ddd,J=8.9,7.5 ,1.8Hz,1H),7.17-7.12(m,1H),7.04(td,J=7.5,0.9Hz,1H),5.15(dd,J=13.3,5.1Hz,1H),4.60(d ,J=17.5Hz,1H),4.45(d,J=17.4Hz,1H),2.92(ddd,J=17.2,13.6,5.4Hz,1H),2.60(d,J=3.3Hz,1 H),2.55(s,3H),2.32(qd,J=13.3,4.6Hz,1H),1.95(dt,J=10.0,4.0Hz,1H).LCMS(m / z):484[M+H] + .

[0331] Example 50: Synthesis of 3-(4-((2-([1,1'-biphenyl]-4-yl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (48). [ka]

[0332] tTo a solution of 3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72 mg, 0.13 mmol) and [1,1'-biphenyl]-4-ylboronic acid (32 mg, 0.16 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (27 mg, 0.14 mmol), Pd2dba3 (12 mg, 0.013 mmol) and tri-tert-butylphosphonium tetrafluoroborate (8 mg, 0.026 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuum and purified by silica gel (MeOH / DCM=0-4%) to give the intermediate. The intermediate was then concentrated in vacuo, dissolved in TFA / DCM=1 / 1, stirred for 2 h, then concentrated again and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 48 (1.7 mg, 2%).

[0333] 1 H NMR(500MHz,DMSO-d6)δ 10.94(s,1H),9.91(s,1H),8.36-8.24(m,3H),8.01-7.96(m,1H),7.75(dd,J=9.9,7. 9Hz,4H),7.64-7.59(m,2H),7.49(dd,J=8.3,7.1Hz,2H),7.42-7.35(m,1H),5.13(dd ,J=13.1,5.1Hz,1H),4.64(d,J=17.4Hz,1H),4.51(d,J=17.4Hz,1H),2.93-2.78(m,1 H),2.51(d,J=1.9Hz,1H),2.34(qd,J=13.2,4.8Hz,1H),1.96(dd,J=14.9,8.4Hz,1H).

[0334] LCMS(m / z):530[M+H] + .

[0335] Example 51: Synthesis of 3-(4-((2-(4-fluoro-2-methoxyphenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (49). [ka]

[0336] t To a solution of 3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82 mg, 0.15 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (31 mg, 0.18 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (32 mg, 0.17 mmol), Pd2dba3 (14 mg, 0.015 mmol) and tri-tert-butylphosphonium tetrafluoroborate (9 mg, 0.03 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuum and purified by silica gel (MeOH / DCM=0-4%) to give the intermediate. The intermediate was then concentrated in vacuo, dissolved in TFA / DCM=1 / 1, stirred for 2 h, then concentrated again and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 49 (16.4 mg, 18%).

[0337] 1H NMR(500MHz,DMSO-d6)δ 10.98(s,1H),9.74(s,1H),8.30(s,1H),8.11-7.99(m,1H),7.58-7.48(m,3H),6.98 (dd,J=11.6,2.4Hz,1H),6.82(td,J=8.4,2.4Hz,1H),5.13(dd,J=13.3,5.1Hz,1H),4 .59(d,J=17.4Hz,1H),4.45(d,J=17.3Hz,1H),3.77(s,3H),2.91(ddd,J=17.9,13.5, 5.4Hz,1H),2.63-2.55(m,1H),2.36(qd,J=13.2,4.5Hz,1H),1.94(d,J=12.8Hz,1H).

[0338] LCMS(m / z):502[M+H] + .

[0339] Example 52: Synthesis of 3-(4-((2-(4-fluorophenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (50). [ka]

[0340] tTo a solution of 3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (82 mg, 0.15 mmol) and (4-fluorophenyl)boronic acid (25 mg, 0.18 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (32 mg, 0.17 mmol), Pd2dba3 (14 mg, 0.015 mmol) and tri-tert-butylphosphonium tetrafluoroborate (9 mg, 0.03 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuum and purified by silica gel (MeOH / DCM=0-4%) to give the intermediate. The intermediate was then concentrated in vacuo, dissolved in TFA / DCM=1 / 1, stirred for 2 h, then concentrated again and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 50 (6.3 mg, 7%).

[0341] 1 H NMR (500MHz, DMSO-d6) δ 10.94(s,1H),9.89(s,1H),8.34(s,1H),8.27-8.20(m,2H),7.95(dd,J=6.0,2 .9Hz,1H),7.61(q,J=3.9,3.1Hz,2H),7.31-7.19(m,2H),5.13(dd,J=13.2,5. 1Hz,1H),4.58(d,J=17.4Hz,1H),4.48(d,J=17.3Hz,1H),2.88(ddd,J=18.0,1 1.5,5.4Hz,1H),2.55(s,1H),2.33(qd,J=13.1,4.4Hz,1H),2.01-1.91(m,1H).

[0342] LCMS(m / z):472[M+H] + .

[0343] Example 53: Synthesis of 3-(4-((2-(3,5-dimethoxyphenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (51). [ka]

[0344] t To a solution of 3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.17 mmol) and (3,5-dimethoxyphenyl)boronic acid (36 mg, 0.2 mmol) in BuOH (2 mL) was added N,N-dicyclohexylmethylamine (36 mg, 0.18 mmol), Pd2dba3 (15 mg, 0.017 mmol) and tri-tert-butylphosphonium tetrafluoroborate (10 mg, 0.03 mmol). The mixture was heated to 80 °C and stirred overnight under N2 atmosphere. The mixture was then filtered, concentrated in vacuum and purified by silica gel (MeOH / DCM=0-4%) to give the intermediate. The intermediate was then concentrated in vacuo, dissolved in TFA / DCM=1 / 1, stirred for 2 h, then concentrated in vacuo again and purified by preparative HPLC (MeOH / HO, 0.05% TFA) to give compound 51 (4.5 mg, 4%).

[0345] LCMS(m / z):514[M+H] + .

[0346] Example 54: Synthesis of 4-(3-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (57). [ka] [ka] 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0347] To a solution of 4-bromoisobenzofuran-1,3-dione (2.27 g, 10 mml) and 3-aminopiperidine-2,6-dione hydrochloride (1.8 g, 11 mmol) in AcOH (30 mL) was added NaOAc (984 mg, 12 mmol), and the mixture was then heated to reflux at 140° C. overnight. The mixture was cooled, and then the mixture was filtered, washed with water, and then air-dried to give the crude product without any purification.

[0348] LCMS(m / z):337[M+H] + . [ka] tert-Butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)carbamate

[0349] To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (336 mg, 1 mmol) and tert-butyl prop-2-yn-1-ylcarbamate (310 mg, 2 mmol) in DMF (5 mL) was added CuI (38 mg, 0.2 mmol), Et3N (2.5 mL) and Pd(PPh3)2Cl2 (70 mg, 0.1 mmol). The resulting mixture was then heated to 70 °C and stirred under N2 atmosphere for 3 h. The mixture was then filtered, concentrated in vacuo and purified by silica gel (MeOH / DCM=0-4%) to give the title compound.

[0350] LCMS(m / z):412[M+H] + . [ka] tert-Butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)carbamate

[0351] To a solution of tert-butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)carbamate in MeOH was added Pd / C (10% by weight loading, matrix carbon), and the mixture was then hydrogenated at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound.

[0352] LCMS(m / z):415[M+H] + . [ka] 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0353] A solution of tert-butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)carbamate in TFA / DCM=1 / 2 (v / v) was stirred at room temperature for 3 h and then concentrated in vacuo. The crude title compound was used in the next step without any purification.

[0354] LCMS(m / z):315[M+H] + . [ka] 4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0355] To a solution of 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and 2,4-dichloropyrimidine (1 eq) in isopropanol was added DIEA (3 eq), then the mixture was stirred for 3 h at 50° C. The mixture was then concentrated in vacuo and purified by silica gel (MeOH / DCM=0-10%) to give the title compound (115 mg).

[0356] LCMS(m / z):428[M+H] + . [ka]

[0357] t To a solution of 4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg, 0.12 mmol) and 2,3-dihydro-1H-inden-5-amine (16 mg, 0.12 mmol) in BuOH (2 mL) was added TFA (18 μL, 0.24 mmol), then the mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo and purified by preparative HPLC to give compound 57 (13.3 mg, 17%).

[0358] 1 H NMR(500MHz,DMSO-d6)δ 11.12(s,1H),10.42(s,1H),9.05(t,J=5.6Hz,1H),7.82(d,J=7.6Hz,1H), 7.79-7.65(m,3H),7.39(s,1H),7.27-7.15(m,2H),6.19(d,J=7.2Hz,1H), 5.14(dd,J=12.9,5.4Hz,1H),3.39(q,J=6.4Hz,2H),2.94-2.88(m,1H),2. 84(qd,J=7.4,2.8Hz,8H),2.65-2.56(m,1H),1.99(dq,J=29.1,7.4Hz,6H).

[0359] LCMS(m / z):525[M+H] + .

[0360] Example 56: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-((2-(mesitylamino)pyrimidin-4-yl)amino)propyl)isoindoline-1,3-dione (58). [ka]

[0361] t To a solution of 4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg, 0.12 mmol) and 2,4,6-trimethylaniline (16 mg, 0.12 mmol) in BuOH (2 mL) was added TFA (18 μL, 0.24 mmol), then the mixture was stirred at 100° C. overnight. The mixture was concentrated and purified by preparative HPLC to give compound 58 (6.3 mg, 8%).

[0362] LCMS(m / z):527[M+H] + .

[0363] Example 57: Synthesis of 4-(6-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (59). [ka] [ka] tert-Butyl (6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hex-5-yn-1-yl)carbamate

[0364] To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (672 mg, 2 mmol) and tert-butyl hex-5-yn-1-ylcarbamate (788 mg, 4 mmol) in DMF (10 mL) was added CuI (76 mg, 0.4 mmol), Et3N (5 mL) and Pd(PPh3)2Cl2 (140 mg, 0.2 mmol). The resulting mixture was then heated to 70 °C and stirred under N2 atmosphere for 3 h. The mixture was then filtered, concentrated in vacuo and purified by silica gel (MeOH / DCM=0-6%) to give the title compound.

[0365] LCMS(m / z):454[M+H] + . [ka] tert-Butyl (6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexyl)carbamate

[0366] To a solution of tert-butyl (6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hex-5-yn-1-yl)carbamate in MeOH was added Pd / C (10% by weight loading, matrix carbon), and the mixture was then hydrogenated at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound.

[0367] LCMS(m / z):458[M+H] + . [ka] 4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0368] A solution of tert-butyl (6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexyl)carbamate in TFA / DCM=1 / 2 (v / v) was stirred at room temperature for 3 h and then concentrated in vacuo. The crude title compound was used in the next step without any purification.

[0369] LCMS(m / z):358[M+H] + . [ka] 4-(6-((2-chloropyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0370] To a solution of 4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and 2,4-dichloropyrimidine (1 eq) in isopropanol was added DIEA (3 eq), then the mixture was stirred for 3 h at 50° C. The mixture was then concentrated in vacuo and purified by silica gel (MeOH / DCM=0-10%) to give the title compound (120 mg).

[0371] LCMS(m / z):470[M+H] + . [ka]

[0372] t To a solution of 4-(6-((2-chloropyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (40 mg, 0.085 mmol) and 2,3-dihydro-1H-inden-5-amine (11 mg, 0.085 mmol) in BuOH (2 mL) was added TFA (13 μL, 0.17 mmol), then the mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo and purified by preparative HPLC to give compound 59 (3.2 mg, 6%).

[0373] 1 H NMR(500MHz,DMSO-d6)δ 11.12(d,J=3.5Hz,1H),8.83(s,1H),7.97-7.62(m,5H),7.42(s,1H),7.08-6.99(m,1H), 6.65-6.57(m,1H),5.94-5.85(m,1H),5.22-5.06(m,1H),2.90(ddd,J=16.9,13.8,5.4Hz ,1H),2.77(td,J=15.8,13.9,7.2Hz,4H),2.61(d,J=19.1Hz,1H),2.34(dt,J=46.4,7.0H z,2H),2.13-2.03(m,1H),2.03-1.90(m,2H),1.69-1.49(m,4H),1.38(d,J=18.4Hz,2H).

[0374] LCMS(m / z):567[M+H] + .

[0375] Example 58: Synthesis of 4-(6-((2-((9H-fluoren-2-yl)amino)pyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60). [ka]

[0376] t To a solution of 4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and 2,4-dichloropyrimidine (40 mg, 0.085 mmol) and 9H-fluoren-3-amine (15 mg, 0.085 mmol) in BuOH (2 mL) was added TFA (13 μL, 0.17 mmol), then the mixture was stirred at 100° C. overnight. The mixture was concentrated in vacuo and purified by preparative HPLC to give compound 60. (5.6 mg, 9%).

[0377] LCMS(m / z):615[M+H] + .

[0378] Example 59: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(6-((2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)amino)hexyl)isoindoline-1,3-dione (61). [ka]

[0379] tTo a solution of 4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and 2,4-dichloropyrimidine (40 mg, 0.085 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (19 mg, 0.085 mmol) in BuOH (2 mL) was added TFA (13 μL, 0.17 mmol), then the mixture was stirred overnight at 100° C. The mixture was concentrated in vacuo and purified by preparative HPLC to give compound 61 (5.5 mg, 8%).

[0380] 1 H NMR(500MHz,DMSO-d6)δ 11.30-10.99(m,1H),8.84(s,1H),8.00-7.75(m,3H),7.70(td,J=6.7,2.4Hz,1H),7.48-7.4 0(m,1H),7.22(s,1H),7.10(d,J=3.4Hz,1H),6.68-6.60(m,1H),6.18-6.07(m,1H),5.14(ddd ,J=13.2,5.2,3.3Hz,1H),3.85(d,J=5.6Hz,4H),3.48(s,4H),2.98-2.85(m,1H),2.67-2.55 (m,1H),2.31(q,J=6.9Hz,1H),2.05(dt,J=11.6,5.0Hz,1H),1.71-1.49(m,4H),1.24(s,4H).

[0381] LCMS(m / z):664[M+H] + .

[0382] Example 60: Synthesis of 3-(5-(((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (41). [ka]

[0383] To a solution of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (67 mg, 0.19 mmol) and 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TFA (50 mg, 0.13 mmol) in DMA (2 mL) was added DIEA (67 mg, 0.52 mmol) at room temperature. The reaction mixture was heated to 130° C. overnight. The crude mixture was purified by HPLC to give compound 41 (18 mg, 0.031 mmol, 24%).

[0384] 1 H NMR(500MHz,DMSO-d6)δ 10.98(s,1H),9.50(s,1H),8.30-7.93(m,3H),7.90-7.54(m,3H),7.50-7 .27(m,3H),5.09(dd,J=13.3,5.1Hz,1H),4.54(d,J=48.2Hz,2H),4.42-4 .16(m,2H),3.39(d,J=58.0Hz,1H),2.90(ddd,J=17.3,13.6,5.5Hz,1H), 2.59(dd,J=17.1,3.8Hz,1H),2.37(qd,J=13.2,4.4Hz,1H),1.14(m,6H).

[0385] LCMS(m / z):583[M+H] + .

[0386] Example 61: Synthesis of 3-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (42) [ka]

[0387] To a solution of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (67 mg, 0.19 mmol) and lenalidomide (50 mg, 0.19 mmol) in s-BuOH (2 mL) was added TFA (33 mg, 0.29 mmol) at room temperature. The reaction mixture was heated to 100° C. overnight. The crude mixture was purified by HPLC to give compound 42 (21 mg, 0.037 mmol, 19%). (M+H) + Calculated value: 569.13, Found value 569.14.

[0388] 1 H NMR(500MHz,DMSO-d6)δ 10.97(s,1H),9.60(s,1H),9.43(s,1H),8.47(d,J=8.4Hz,1H),8.29(s,1H),7.82(td,J=7 .7,7.1,2.1Hz,2H),7.61-7.46(m,3H),7.35-7.26(m,1H),5.10(dd,J=13.3,5.1Hz,1H),4 .51-4.28(m,2H),3.47(p,J=6.8Hz,1H),2.87(ddd,J=17.3,13.7,5.4Hz,1H),2.54(d,J=4 .0Hz,1H),2.28(qd,J=13.3,4.5Hz,1H),1.88-1.76(m,1H),1.17(dd,J=10.0,6.8Hz,6H).

[0389] LCMS(m / z):569[M+H] + .

[0390] Example 62: Lenalidomide dissociation assay

[0391] Various compounds of the present invention were analyzed for cereblon binding. In the Atto565-Lenalidomide dissociation assay, compounds were dispensed in 384-well microplates (Corning, 4514) using a D300e Digital Dispenser (HP) normalized to 1% DMSO at 10 nM Atto565-Leanlidomide, 100 nM DDB1ΔB-CRBN, 50 mM Tris (pH 7.5), 200 mM NaCl, 0.1% Pluronic® F-68 solution (Sigma). Compound titrations were incubated at room temperature for 60 minutes. Changes in fluorescence polarization were monitored for 1 h at 120 s cycles using a PHERAstar® FS microplate reader (BMG Labtech). Data from two independent replicates (n=2) were used to calculate IC using a variable slope equation in GraphPad Prism 7. 50 Values ​​were estimated. Ki was calculated using a probe Kd of 40 nM for the above conditions according to the formula described in Nikolovska-Coleska et al., Analytical Biochemistry 332(2):261-273 (2004) for the competition model using free concentrations.

[0392] I C 50 The results, expressed in terms of K i values, are shown in Table 1 below.

[0393] Example 63: Cellular CRBN dBET6 dissociation assay

[0394] BRD4BD2 was subcloned into a mammalian pcDNA5 / FRT Vector (ampicillin and hygromycin B resistant) modified to contain MCS-eGFP-P2A-mCherry. Stable cell lines expressing eGFP-protein fusions and mCherry reporters were generated using the Flip-In™ 293 system. Plasmid (0.3 μg) and pOG44 (4.7 μg) DNA were pre-incubated for 20 minutes in 100 μl of Opti-MEM I (Gibco™, Life Technologies™) medium containing 0.05 mg / ml Lipofectamine™ 2000 (Invitrogen™) and added to Flip-In™ 293 cells (Gibco™, Life Technologies™) containing 1.9 ml of DMEM medium per well in a 6-well plate format (Falcon™, 353046). Cells were propagated after 48 hours and transferred to DMEM medium containing 50 μg / ml hygromycin B (REF 10687010, Invitrogen™) as a selection marker in 10 cm2 plates (Corning, 430165). After 2-3 passage cycles, cells expressing eGFP and mCherry were enriched using FACS (FACSAria™ II, BD).

[0395] Cells stably expressing BRD4BD2-GFP with mCherry reporter were seeded at 30-50% confluency in 96-well plates (3596, Costar) with 100 μl of DMEM medium containing 10% FBS per well one day before compound treatment. Compounds and 100 nM dBET6 were dispensed using a D300e Digital Dispenser (HP) normalized to 0.5% DMSO and incubated with cells for 5 h after trypsinization and resuspension in DMEM medium, transferred to 96-well plates (353910, Falcon®) and analyzed by flow cytometer (guava easyCyte™ HT, Millipore™). Signal was acquired from a minimum of 3000 events per well to monitor eGFP and mCherry fluorescence. Data was analyzed using FlowJo® (FlowJo®, LCC). Forward and side scatter outliers, frequently associated with cellular debris, were removed leaving >90% of the total cells, followed by removal of eGFP and mCherry signal outliers leaving 88-90% of the total cells to generate the set used for quantification. The amount of eGFP protein relative to mCherry was then quantified as a 10-fold amplification ratio for each individual cell using the formula: 10×eGFP / mCherry. Median ratios were then calculated per set and normalized to the median DMSO ratio. [Table 1-1] [Table 1-2]

[0396] As shown in Table 1, compounds 1–17, which share the same amine-based linkage to the lenalidomide moiety, have in vitro K values ​​ranging from 13 to 0.13 μM. i It bound to CRBN. Compounds 14, 16, and 17 were used to measure the affinity (K i The affinity of the antibody was higher than 1.49 μM.

[0397] These molecules were further evaluated in a cellular CRBN engagement assay, which relies on the dissociation of the CRBN-based decomposer molecule dBET6 from CRBN by competitive ligands, thus rescuing the degradation of the second bromodomain of BRD4. This assay provided a readout of cellular CRBN binding that was influenced by the permeability of the tested molecules. The data are shown in Table 1.

[0398] As indicated in Table 1, cellular CRBN engagement was suppressed by a wide range of agents, from inactive compounds (compounds 22, 34, and 40) to the FDA-approved lenalidomide (EC of 0.82 μM). 50 )'s EC50 More than EC 50 The EC values ​​ranged from 0.66, 0.67, 0.742, and 0.46 μM for compounds 23, 26, 39, and 52, respectively. 50 The same pyrimidine-based bond of the IMiD core is shared by the most potent compounds, compounds 23, 26, 39 and 52. The remaining compounds tested in this assay showed good to moderate cellular CRBN engagement compared to lenalidomide.

[0399] All patent and non-patent publications are indicative of the level of skill of those skilled in the art to which this invention pertains, and all such 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.

[0400] Although the invention herein has been described with reference to specific embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. Formula (Ia1) or (Ib1): 【Chemistry 1】 (Wherein, Z is CH ２ and R ２ is H or C1-C2 alkyl, R ３ is an optionally substituted C1-C5 alkyl, an optionally substituted C6-C14 aryl, an optionally substituted C6-C14 heteroaryl, an optionally substituted C5-C14 carbocycle or an optionally substituted C5-C14 heterocycle, or R ２ and R ３ form, together with the N to which they are attached, an optionally substituted C6-C14 heterocyclic group or an optionally substituted C6-C14 heteroaryl group; When substituted, the substituents are each independently alkyl, alkoxy, alkenyl, alkynyl, carbocycle, heterocycle, aryl, heteroaryl, aralkyl, halo, hydroxyl, aryloxy, alkylthio, arylthio, cyano, carboxyl, amino, or amido, provided that the compound is: 【Chemistry 2】 (except where or a pharma- ceutically acceptable salt or stereoisomer thereof.

2. The compound of formula (Ia1) has the formula (Ia1a): 【Chemistry 9】 (In the formula, m １ is 0 or 1, and R １１ and R １２ are each independently H, halo, or CF ３ or C1-C2 alkoxy, or R １１ and R １２ are each independently a C or a heteroatom, and together with the atom to which they are attached form an optionally substituted C5-C14 carbocycle, an optionally substituted C5-C14 heterocycle, an optionally substituted C6-C14 aryl, or an optionally substituted C6-C14 heteroaryl group.

2. The compound of claim 1 having a structure represented by:

3. The compound of formula (Ia1) has the formula (Ia1c): 【Chemistry 11】 (wherein R 13 is H or an optionally substituted C1-C5 alkyl, an optionally substituted C6-C14 aryl, an optionally substituted C6-C14 heteroaryl, an optionally substituted C5-C14 carbocycle or an optionally substituted C5-C14 heterocycle).

2. The compound of claim 1 having a structure represented by:

4. The compound of formula (Ib1) has the formula (Ib1a): 【Chemistry 15】 (In the formula, m １ is 0 or 1, R 11 and R 12 are each independently H, halo, CF 3 , or C1-C2 alkoxy, or R 11 and R 12 are each independently C or a heteroatom and together with the atom to which they are attached form an optionally substituted C5-C14 carbocycle, an optionally substituted C5-C14 heterocycle, an optionally substituted C6-C14 aryl, or an optionally substituted C6-C14 heteroaryl group.

2. The compound of claim 1 having a structure represented by:

5. The compound of formula (Ib1) has the formula (Ib1c): 【Chemistry 17】 (wherein R 13 is H or an optionally substituted C1-C5 alkyl, an optionally substituted C6-C14 aryl, an optionally substituted C6-C14 heteroaryl, an optionally substituted C5-C14 carbocycle or an optionally substituted C5-C14 heterocycle).

2. The compound of claim 1 having a structure represented by:

6. R ３ The compound according to claim 1, wherein represents an optionally substituted C6-C14 aryl or an optionally substituted C6-14 heteroaryl group.

7. R ３ 2. The compound of claim 1, wherein represents an optionally substituted C5-14 carbocyclic or an optionally substituted C5-14 heterocyclic group.

8. R ３ The compound according to claim 1, wherein is an optionally substituted C6-14 aryl group or a substituted C6-14 heteroaryl group.

9. R ３ The compound of claim 8 , wherein is an optionally substituted phenyl group. 【Request 10】 【Chemical 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 2. The compound of claim 1, selected from the group consisting of:

11. 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11 in the form of a capsule or tablet.

13. 12. The pharmaceutical composition of claim 11, which is a solution or suspension.

14. 13. A pharmaceutical composition for treating cancer comprising a therapeutically effective amount of a compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof.

15. 15. The pharmaceutical composition of claim 14, wherein the cancer is a blood cancer selected from leukemia, lymphoma and multiple myeloma.

16. The pharmaceutical composition of claim 15, wherein the cancer is multiple myeloma.

Images