Compounds that modulate protein recruitment and / or degradation

Abstract

To provide cereblon binding agents for the degradation of proteins by the ubiquitin proteasome pathway for therapeutic applications.SOLUTION: Compositions comprising a compound described below and a pharmaceutically effective amount and a pharmaceutically acceptable carrier are provided.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention provides cereblon-binding agents for the degradation of proteins by the ubiquitin-proteasome pathway for therapeutic uses, as further described herein.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 949,027, filed December 17, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins occurs via the ubiquitin-proteasome pathway (UPP). The UPP is essential for the regulation of almost all cellular processes.

[0004] Covalent attachment of multiple ubiquitin molecules by E3 ubiquitin ligases to terminal lysine residues marks the protein for proteasomal degradation, where it is digested into small peptides and ultimately into its constituent amino acids that function as building blocks for new proteins.

[0005] Thalidomide and its analogs have been shown to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (Ito, T. et al., Science, 2010, 327:1345). Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding proteins and forms an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1), which functions as a substrate receptor to select proteins for ubiquitination. Binding of lenalidomide to cereblon facilitates subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and proteasomal degradation (Lu, G. et al., Science, 2014, 343:305-309; Kronke, J. et al., Science, 2014, 343:301-305).

[0006] It is an object of the present invention to provide novel compounds that bind to cereblon and their use for the treatment of various diseases and disorders, for example, by modulating protein degradation. Summary of the Invention [Problem to be solved by the invention]

[0007] Novel compounds that bind cereblon are provided, along with their uses and production methods. Without wishing to be bound by theory, it is believed that binding of the disclosed compounds to cereblon increases or decreases the interaction of cereblon with one or more of IKZF1, SALL4, and ASS1, leading to their subsequent ubiquitination and degradation in the proteasome. Selected compounds have been found to be strong binders of cereblon and also exhibit potential therapeutic uses. Thus, in various embodiments, the compounds are "molecular glues" that can bind protein surfaces or interfaces, for example, on cereblon, and stabilize its interaction(s) with another protein, potentially activating or inhibiting a cellular response (e.g., ubiquitination and degradation in the proteasome).

[0008] The compounds disclosed herein, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof can be used to treat disorders mediated by cereblon, IKZF1, SALL4, or ASS1, such as various cancers and autoimmune diseases or disorders.

[0009] In one aspect, the compounds of the present invention have formula I: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is aryl, -N(R 5 )-XR 6 , -SO2R 5 , or -O(CH2) m R 5 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0010] In one aspect, the compounds of the present invention have formula II: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 is aryl, -NH-(C3-C 10 ) heteroaryl, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0011] In one aspect, the compounds of the present invention have formula III: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 3 is cyano, aryl, -NH-(C3-C 10 ) heteroaryl, (C3-C 10 ) heterocyclo, or -N(R 5 )-(CH2) m-X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0012] In one aspect, the compounds of the present invention have formula IV: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 4 is halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0013] In one aspect, the compounds of the present invention have formula V: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 17 is cyano, heteroaryl, -(CH2) m -C(O)OR 6 , or -N(R 5 )-(CH2) m -X-(CH2) n-R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0014] In one aspect, the compounds of the present invention have formula VI: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 16 is NH2 or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence.w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0015] In one aspect, the compounds of the present invention have formula VII: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 18 , R 19 , R 20 , R 21 are each independently H, halo, (C-C)alkyl, or -N(R 5 )-XR 6 where R 18 , R 19 , R 20 , R 21 wherein no more than two of the substituents are H; or R 18 , R 19 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) to form a heterocycle, or R 19 , R 20 together with the carbon to which they are attached (C3-C10 ) cycloalkyl or (C3-C 10 ) to form a heterocycle, or R 20 , R 21 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) heterocycles, any of which may contain one or more R w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0016] In one aspect, the compounds of the present invention have formula VIII: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 8 , R 9 , R 10 , R 11are each independently H, halo, OH, cyano, (C-C) alkyl, (C-C) alkoxy, aryl, or heteroaryl, any of which may be present in combination with one or more R as allowed by valence. w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; where n is 0, 1, 2, 3, or 4).

[0017] In one aspect, the compounds of the present invention have formula IX: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 12 , R 13 , R 14 , R 15 are each independently H, NH, (C-C) alkyl, -N(R 5 )-(CH2)mN(R 5 )-XR 6where R 12 , R 13 , R 14 , and R 15 Not more than three substituents of R are H, and any of them may be substituted with one or more R as allowed by the valences. w may be optionally substituted with a group; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0018] In one aspect, the compounds of the present invention have the formula X: [ka] or a pharmaceutically acceptable salt thereof (Wherein, Y is —NHR 33 , -NHC(O)R 33 , or -CHR 33 R 34 and; R 7 is H, (C1-C3) alkyl, or R7 and R 34 together with the carbon to which it is attached to form a carbon-carbon double bond; R 33 is an aryl, heteroaryl, (C3-C 10 ) heterocyclo, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; where n is 0, 1, 2, 3, or 4).

[0019] In one aspect, the compound of the present invention is selected from the group consisting of: 3-[1-oxo-5-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidin-2-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]acetamide; 3-[5-[(2-aminopyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetyl]amino]benzamide; 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindolin-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-methyl-acetamide; Acetic acid;3-[1-oxo-6-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxo-pyrazin-2-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxalin-2-ylamino)isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione 3-[6-(5,7-dihydrofuro[3,4-d]pyrimidin-2-ylamino)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-phenyl-acetamide; 3-[6-[[2-(2,4-dimethylpiperazin-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-(dimethylamino)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindolin-2-yl)piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N,N-dimethylacetamide; 3-[6-[[2-(2-methylmorpholin-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-methyl-N-[(1-methylpyrazol-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]pyridazine-3-carbonitrile; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-(Dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; N-cyclopropyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 3-[1-oxo-6-(2-oxoimidazolidin-1-yl)isoindolin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]propanoic acid; 2-Acetamido-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 3-[6-[[2-(3-methyl-5-oxo-piperazin-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetic acid; 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindolin-2-yl]piperidine-2,6-dione; 3-(1-oxo-7-phenyl-isoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-4-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-4-yl]amino]acetic acid; 3-(7-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione; 3-(5-amino-1-oxo-3,4-dihydroisoquinolin-2-yl)piperidine-2,6-dione; t-Butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-1-yl]acetate; 3-[1-(2H-indol-3-yl)-3-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-carbonitrile; 3-[1-(dimethylamino)-3-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidin-1-yl)piperidine-2,6-dione; 3-(Quinazolin-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(quinoxalin-2-ylamino)piperidine-2,6-dione; 3-(pyrimidin-2-ylamino)piperidine-2,6-dione; N-(2,6-dioxo-3-piperidyl)-2-oxo-3H-pyridine-6-carboxamide; 3-(4-methyl-1,1,3-trioxo-1,2-benzothiazol-2-yl)piperidine-2,6-dione; 3-(8-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(6-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; and 3-(8-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione.

[0020] In one aspect, the invention relates to a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0021] In one aspect, the present invention relates to a method of treating a disease, comprising administering to a subject in need thereof a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0022] In one aspect, the present invention relates to a method of treating or preventing cancer, comprising administering to a subject in need thereof a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, uterine cancer, leukemia, lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, e.g., Ewing's sarcoma, The tumor is selected from the group consisting of angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, schwannoma, testicular tumor, thyroid carcinoma, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. In one embodiment, the subject is a human.

[0023] In another aspect, the present invention relates to a method of treating or preventing one or more autoimmune diseases or disorders, comprising administering to a subject in need thereof a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the autoimmune disease or disorder is selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., allograft rejection prevention), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, and other autoimmune diseases or disorders, and the like.

[0024] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings. Reference to various compounds is made with reference to Table 1 in Example 4. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding to 5HPP-3 compared to lenalidomide (LEN). [Figure 2] Figure 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C98696 compared to LEN. Lenalidomide is the top curve in the right panel. [Figure 3] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C36126 compared to LEN. [Figure 4] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C44292 compared to LEN. [Figure 5] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C97402 compared to LEN. [Figure 6] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C51830 compared to LEN. [Figure 7] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C55468 compared to LEN. [Figure 8] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28661 compared to LEN. [Figure 9] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29137 compared to LEN. [Figure 10] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29408 compared to LEN. [Figure 11] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47997 compared to LEN. [Figure 12] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48009 compared to LEN. [Figure 13] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48020 compared to LEN. [Figure 14] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C66979 compared to LEN. [Figure 15] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C68121 compared to LEN. [Figure 16] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C49708 compared to LEN. [Figure 17] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C96622 compared to LEN. [Figure 18] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C45748 compared to LEN. [Figure 19] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84961 compared to LEN. [Figure 20] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84964 compared to LEN. [Figure 21]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84966 compared to LEN. [Figure 22] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84971 compared to LEN. [Figure 23] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C56572 compared to LEN. [Figure 24] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64324 compared to LEN. [Figure 25] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64376 compared to LEN. [Figure 26] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80370 compared to LEN. [Figure 27] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80375 compared to LEN. [Figure 28] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80382 compared to LEN. [Figure 29] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80383 compared to LEN. [Figure 30] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80384 compared to LEN. [Figure 31] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80386 compared to LEN. [Figure 32]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80387 compared to LEN. [Figure 33] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80389 compared to LEN. [Figure 34] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80392 compared to LEN. [Figure 35] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C98053 compared to LEN. [Figure 36] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C49713 compared to LEN. [Figure 37] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C11892 compared to LEN. [Figure 38] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12581 compared to LEN. [Figure 39] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12583 compared to LEN. [Figure 40] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12584 compared to LEN. [Figure 41] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12586 compared to LEN. [Figure 42] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12595 compared to LEN. [Figure 43]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12597 compared to LEN. [Figure 44] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12598 compared to LEN. [Figure 45] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C95330 compared to LEN. [Figure 46] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C95333 compared to LEN. [Figure 47] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C95338 compared to LEN. [Figure 48] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C74668 compared to LEN. [Figure 49] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C73349 compared to LEN. [Figure 50] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35833 compared to LEN. [Figure 51] FIG. 1 shows the changes in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with 5′-OH-THL compared to LEN. [Figure 52] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C60651 compared to LEN. [Figure 53] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C58181 compared to LEN. [Figure 54]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with CC-122 compared to LEN. [Figure 55] FIG. 1 shows the changes in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding to CC-220 compared to LEN. [Figure 56] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with CC-885 compared to LEN. [Figure 57] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C15352 compared to LEN. [Figure 58] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C36124 compared to LEN. [Figure 59] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C36128 compared to LEN. [Figure 60] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with glutarimide compared to LEN. [Figure 61] FIG. 1 shows the effect of LEN on the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding. [Figure 62] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C10001 compared to LEN. [Figure 63] FIG. 1 shows the changes in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding to POM compared to LEN. [Figure 64] FIG. 1 shows the changes in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding to THL compared to LEN. [Figure 65]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with CC07128 compared to LEN. [Figure 66] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C38930 compared to LEN. [Figure 67] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C38935 compared to LEN. [Figure 68] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C75987 compared to LEN. [Figure 69] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C87699 compared to LEN. [Figure 70] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C24031 compared to LEN. [Figure 71] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C07207 compared to LEN. [Figure 72] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C89676 compared to LEN. [Figure 73] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28558 compared to LEN. [Figure 74] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28577 compared to LEN. [Figure 75] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28620 compared to LEN. [Figure 76]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28891 compared to LEN. [Figure 77] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28928 compared to LEN. [Figure 78] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C28973 compared to LEN. [Figure 79] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29330 compared to LEN. [Figure 80] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29361 compared to LEN. [Figure 81] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29457 compared to LEN. [Figure 82] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29490 compared to LEN. [Figure 83] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C14950 compared to LEN. [Figure 84] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C24191 compared to LEN. [Figure 85] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C02896 compared to LEN. [Figure 86] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47927 compared to LEN. [Figure 87]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47928 compared to LEN. [Figure 88] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47930 compared to LEN. [Figure 89] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47932 compared to LEN. [Figure 90] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47933 compared to LEN. [Figure 91] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47959 compared to LEN. [Figure 92] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47995 compared to LEN. [Figure 93] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47998 compared to LEN. [Figure 94] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48003 compared to LEN. [Figure 95] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48005 compared to LEN. [Figure 96] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48007 compared to LEN. [Figure 97] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48014 compared to LEN. [Figure 98]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48016 compared to LEN. [Figure 99] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C48018 compared to LEN. [Figure 100] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C22548 compared to LEN. [Figure 101] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C22564 compared to LEN. [Figure 102] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C22586 compared to LEN. [Figure 103] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C22594 compared to LEN. [Figure 104] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C22622 compared to LEN. [Figure 105] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C30231 compared to LEN. [Figure 106] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C29737 compared to LEN. [Figure 107] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C67858 compared to LEN. [Figure 108] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C68126 compared to LEN. [Figure 109]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C55859 compared to LEN. [Figure 110] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C23258 compared to LEN. [Figure 111] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C47935 compared to LEN. [Figure 112] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C05955 compared to LEN. [Figure 113] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C49278 compared to LEN. [Figure 114] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C39453 compared to LEN. [Figure 115] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C51383 compared to LEN. [Figure 116] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C99884 compared to LEN. [Figure 117] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C34491 compared to LEN. [Figure 118] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C98103 compared to LEN. [Figure 119] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C96413 compared to LEN. [Figure 120]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35745 compared to LEN. [Figure 121] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35751 compared to LEN. [Figure 122] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35754 compared to LEN. [Figure 123] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35797 compared to LEN. [Figure 124] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35811 compared to LEN. [Figure 125] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35856 compared to LEN. [Figure 126] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C23066 compared to LEN. [Figure 127] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C39772 compared to LEN. [Figure 128] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C51647 compared to LEN. [Figure 129] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C40531 compared to LEN. [Figure 130] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84963 compared to LEN. [Figure 131]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84965 compared to LEN. [Figure 132] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84967 compared to LEN. [Figure 133] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C84970 compared to LEN. [Figure 134] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64319 compared to LEN. [Figure 135] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64329 compared to LEN. [Figure 136] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64340 compared to LEN. [Figure 137] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64344 compared to LEN. [Figure 138] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64348 compared to LEN. [Figure 139] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C64372 compared to LEN. [Figure 140] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C89940 compared to LEN. [Figure 141] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12697 compared to LEN. [Figure 142]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C16899 compared to LEN. [Figure 143] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80369 compared to LEN. [Figure 144] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80373 compared to LEN. [Figure 145] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80374 compared to LEN. [Figure 146] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80376 compared to LEN. [Figure 147] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80378 compared to LEN. [Figure 148] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80379 compared to LEN. [Figure 149] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80380 compared to LEN. [Figure 150] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80385 compared to LEN. [Figure 151] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80390 compared to LEN. [Figure 152] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80391 compared to LEN. [Figure 153]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80393 compared to LEN. [Fig. 154] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80394 compared to LEN. [Figure 155] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80395 compared to LEN. [Figure 156] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C80396 compared to LEN. [Figure 157] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C33779 compared to LEN. [Figure 158] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C46003 compared to LEN. [Figure 159] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with CC08493 compared to LEN. [Figure 160] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C09063 compared to LEN. [Figure 161] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C09563 compared to LEN. [Figure 162] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C10239 compared to LEN. [Figure 163] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C10537 compared to LEN. [Fig. 164]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C10981 compared to LEN. [Figure 165] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12582 compared to LEN. [Figure 166] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12589 compared to LEN. [Figure 167] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12693 compared to LEN. [Figure 168] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12694 compared to LEN. [Figure 169] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C12695 compared to LEN. [Figure 170] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C95329 compared to LEN. [Figure 171] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C95334 compared to LEN. [Fig. 172] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C95336 compared to LEN. [Figure 173] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C59904 compared to LEN. [Fig. 174] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C75688 compared to LEN. [Figure 175]FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C35830 compared to LEN. [Figure 176] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C13247 compared to LEN. [Figure 177] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C16463 compared to LEN. [Figure 178] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C17800 compared to LEN. [Figure 179] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with C21223 compared to LEN. [Figure 180] FIG. 1 shows the change in the ability of cereblon to recruit ASS1, IKZF1, and SALL4 after binding with ZE26-0001 compared to LEN. Detailed Description of the Invention

[0026] definition The term "H" refers to a single hydrogen atom. This radical can be attached to, for example, an oxygen atom to form a hydroxyl radical.

[0027]

number

[0028] The term "alkyl," when used alone or within other terms such as "haloalkyl" or "alkylamino," embraces straight- or branched-chain radicals having from 1 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The terms "alkylenyl" or "alkylene" embrace bridging divalent alkyl radicals such as methylenyl or ethylenyl. "R 2 The term "lower alkyl substituted with" does not include an acetal moiety. The term "alkyl" further includes alkyl radicals in which one or more carbon atoms in the chain is replaced with a heteroatom selected from oxygen, nitrogen, or sulfur.

[0029] The term "alkenyl" embraces straight- or branched-chain radicals having at least one carbon-carbon double bond of 2 to about 12 carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having 2 to about 6 carbon atoms. Most preferred lower alkenyl radicals are radicals having 2 to about 4 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

[0030] The term "alkynyl" refers to a straight- or branched-chain radical having at least one carbon-carbon triple bond and having from 2 to about 12 carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having from 2 to about 6 carbon atoms. Most preferred are lower alkynyl radicals having from 2 to about 4 carbon atoms. Examples of such radicals include propargyl and butynyl.

[0031] The alkyl, alkylenyl, alkenyl, and alkynyl radicals can be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

[0032] The term "halo" means halogens such as fluorine, chlorine, bromine, or iodine atoms.

[0033] The term "haloalkyl" embraces radicals in which any one or more of the alkyl carbon atoms is substituted with halo, as defined above. Specifically included are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals, including perfluorohaloalkyl. For example, monohaloalkyl radicals can have either iodo, bromo, chloro, or fluoro atoms within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having one to six carbon atoms. Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0034] The term "perfluoroalkyl" means an alkyl radical in which all hydrogen atoms have been replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

[0035] The term "hydroxyalkyl" embraces straight- or branched-chain alkyl radicals having 1 to about 10 carbon atoms, either of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having 1 to 6 carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having 1 to 3 carbon atoms.

[0036] The term "alkoxy" embraces straight- or branched-chain oxy-containing radicals, each having an alkyl portion of 1 to about 10 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy, and tert-butoxy. Even more preferred are lower alkoxy radicals having 1 to 3 carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having 1 to 3 carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropropoxy.

[0037] The term "aryl," alone or in combination, refers to a carbocyclic aromatic system containing one or two rings, which may be attached together in a fused manner. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. A more preferred aryl is phenyl. An "aryl" group may have one or more substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino. A phenyl substituted with -O-CH2-O- forms an arylbenzodioxolyl substituent.

[0038] The term "heterocyclyl" (or "heterocyclo") embraces saturated, partially saturated, and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur, and oxygen. It does not include rings containing -OO-, -OS-, or -SS- moieties. A "heterocyclyl" group may have 1 to 4 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, and lower alkylamino.

[0039] Examples of saturated heterocyclic radicals include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0040] Examples of unsaturated heterocyclic radicals, also called "heteroaryl" radicals, include 5- to 6-membered unsaturated heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; 5- to 6-membered unsaturated heteromonocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; and 5- to 6-membered unsaturated heteromonocyclic groups containing a sulfur atom. Examples of unsaturated heteromonocyclic groups include heteromonocyclic groups such as 2-thienyl and 3-thienyl; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, and oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, and 1,2,5-oxadiazolyl]; and unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl and thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, and 1,2,5-thiadiazolyl].

[0041] The term heterocyclyl (or heterocyclo) also includes radicals in which heterocyclic radicals are fused / condensed with aryl radicals: unsaturated fused heterocyclic groups containing 1-5 nitrogen atoms, e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated fused heterocyclic groups containing 1-2 oxygen atoms and 1-3 ... Unsaturated fused heterocyclic groups containing one or two sulfur atoms and one or three nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl); unsaturated fused heterocyclic groups containing one or two oxygen or sulfur atoms (e.g., benzothiazolyl, benzothiadiazolyl); saturated, partially unsaturated, and unsaturated fused heterocyclic groups containing one or two oxygen or sulfur atoms (e.g., benzofuryl, benzothienyl, 2,3-dihydrobenzo[1,4]dioxinyl, and dihydrobenzofuryl). Preferred heterocyclic radicals include 5- to 10-membered fused or non-fused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl containing one or two heteroatoms selected from sulfur, nitrogen, and oxygen and selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl, and pyrazinyl.

[0042] Particular examples of non-nitrogen-containing heteroaryls include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, and benzothienyl.

[0043] Specific examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-iso quinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0044] The term "heterocyclo" therefore encompasses the following ring systems: [ka] TIFF2026010047000014.tif197162, etc.

[0045] The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, refers to the respective divalent radical -SO2-.

[0046] The terms "sulfamyl," "aminosulfonyl," and "sulfonamidyl" refer to a sulfonyl radical that is substituted with an amine radical to form a sulfonamide (-SO2NH2).

[0047] The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" in which the sulfamyl radical is independently substituted with one or two alkyl radicals. More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl and N-ethylaminosulfonyl.

[0048] The terms "carboxy" or "carboxyl," whether used alone or with other terms such as "carboxyalkyl," mean -CO2H.

[0049] The term "carbonyl," whether used alone or with other terms, such as "aminocarbonyl," means --(C.dbd.O)--.

[0050] The term "aminocarbonyl" means an amide group of the formula C(=O)NH2.

[0051] The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" refer to aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are "lower alkylaminocarbonyls" having lower alkyl radicals as described above attached to the aminocarbonyl radical.

[0052] The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" refer to an aminocarbonyl radical substituted with one aryl radical, or one alkyl and one aryl radical, respectively.

[0053] The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" embrace heterocyclic-substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl" radicals having alkyl portions of 1 to 6 carbon atoms and 5- or 6-membered heteroaryl radicals. Even more preferred are lower heteroarylalkylenyl radicals having alkyl portions of 1 to 3 carbon atoms. Examples include radicals such as pyridylmethyl and thienylmethyl.

[0054] The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferred aralkyl radicals are "lower aralkyl" radicals having an aryl radical attached to an alkyl radical having 1 to 6 carbon atoms. Even more preferred are "phenylalkylenyl" radicals attached to alkyl moieties having 1 to 3 carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, and phenylethyl. The aryl in the aralkyl can be further substituted with halo, alkyl, alkoxy, halcoalkyl, and haloalkoxy.

[0055] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of an "alkylthio" is methylthio (CH3S-).

[0056] The term "haloalkylthio" embraces radicals containing a haloalkyl radical of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalkylthio radicals having one to three carbon atoms. An example of a "haloalkylthio" is trifluoromethylthio.

[0057] The term "alkylamino" encompasses "N-alkylamino" and "N,N-dialkylamino," in which an amino group is independently substituted with one alkyl radical and two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms attached to a nitrogen atom. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Suitable alkylamino radicals can be mono- or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino.

[0058] The term "arylamino" refers to an amino group substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals can be further substituted on the aryl ring portion of the radical.

[0059] The term "heteroarylamino" means an amino group substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals can be further substituted on the heteroaryl ring portion of the radical.

[0060] The term "aralkylamino" refers to an amino group substituted with one or two aralkyl radicals. More preferred are phenyl-C1-C3-alkylamino radicals, such as N-benzylamino. The aralkylamino radicals can be further substituted with aryl ring moieties.

[0061] The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" mean an amino group that is independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, on the amino group.

[0062] The term "aminoalkyl" embraces straight- or branched-chain alkyl radicals having 1 to about 10 carbon atoms, any of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having 1 to 6 carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl. Even more preferred are lower aminoalkyl radicals having 1 to 3 carbon atoms.

[0063] The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of 1 to 6 carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of 1 to 3 carbon atoms. Suitable alkylaminoalkyl radicals can be mono- or di-alkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, and N,N-diethylaminomethyl.

[0064] The term "alkylaminoalkyl" embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having an alkoxy radical of 1 to 6 carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having an alkyl radical of 1 to 3 carbon atoms. Suitable alkylaminoalkoxy radicals may be mono- or di-alkyl substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, and N,N-diethylaminoethoxy.

[0065] The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of 1 to 6 carbon atoms. Even more preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals of 1 to 3 carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono- or di-alkyl substituted, such as, for example, N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy, and N,N-diethylaminomethoxymethoxy.

[0066] The term "carboxyalkyl" embraces straight- or branched-chain alkyl radicals having 1 to about 10 carbon atoms, any one of which can be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having 1 to 6 carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having 1 to 3 CH groups.

[0067] The term "halosulfonyl" embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.

[0068] The term "arylthio" embraces aryl radicals of six to ten carbon atoms attached to a divalent sulfur atom. An example of an "arylthio" is phenylthio.

[0069] The term "aralkylthio" embraces aralkyl radicals as described above attached to a divalent sulfur atom. More preferred are phenyl-C1-C3-alkylthio radicals. An example of an "aralkylthio" is benzylthio.

[0070] The term "aryloxy" embraces optionally substituted aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.

[0071] The term "aralkoxy" embraces oxy-containing aralkyl radicals attached to other radicals through an oxygen atom. More preferred aralkoxy radicals are "lower aralkoxy" radicals having an optionally substituted phenyl radical attached to a lower alkoxy radical as described above.

[0072] The term "heteroaryloxy" embraces optionally substituted heteroaryl radicals, as defined above, attached to an oxygen atom.

[0073] The term "heteroarylalkoxy" embraces oxy-containing heteroarylalkyl radicals attached to other radicals through an oxygen atom. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having an optionally substituted heteroaryl radical attached to a lower alkoxy radical as described above.

[0074] The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups contain a C3-C6 ring. More preferred compounds include cyclopentyl, cyclopropyl, and cyclohexyl.

[0075] The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferred cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having a cycloalkyl radical attached to an alkyl radical having 1 to 6 carbon atoms. Even more preferred are "5- to 6-membered cycloalkylalkyl" radicals attached to an alkyl moiety having 1 to 3 carbon atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl in the radical can be further substituted with halo, alkyl, alkoxy, and hydroxy.

[0076] The term "cycloalkenyl" includes carbocyclic groups with one or more carbon-carbon double bonds, including "cycloalkyldienyl" compounds. Preferred cycloalkenyl groups contain C3-C6 rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cycloheptadienyl.

[0077] The term "comprising" is meant to be open-ended, including the indicated components, but not excluding other elements.

[0078] The group or atom that replaces the hydrogen atom is also called a substituent.

[0079] A particular molecule or group may have one or more substituents, depending on the number of hydrogen atoms that can be replaced.

[0080] The symbol "-" represents a covalent bond and may also be used on a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.

[0081] The term "therapeutically effective amount" means an amount of a compound that ameliorates, reduces, or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0082] The terms "patient" and "subject" may be used interchangeably and refer to animals such as dogs, cats, cows, horses, sheep, and humans. Particular patients are mammals. The term patient includes males and females.

[0083] The term "pharmaceutically acceptable" means that a compound of Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a reference substance such as a particular excipient, is suitable for administration to a patient.

[0084] Terms such as "treating," "treat," or "treatment" include preventative (eg, prophylactic) and palliative treatment.

[0085] The term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), that is typically included in a formulation and / or administration to a patient.

[0086] The term "cancer" refers to the physiological condition in mammals that is characterized by unregulated cell growth. General classes of cancer include carcinoma, lymphoma, sarcoma, and blastoma.

[0087] composition The compound of the present invention is administered to patients in a therapeutically effective amount.The compound can be administered alone or as part of a pharmaceutically acceptable composition or formulation.In addition, the compound or composition can be administered multiple times, for example, by bolus injection, all at once, by a series of tablets, etc., or can be delivered substantially uniformly over a period of time, for example, by transdermal delivery.It should also be noted that the dose of the compound can vary over time.

[0088] The compounds of the present invention can be administered to a patient either orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, topically (e.g., as a powder, ointment, or drops), or as a buccal or nasal spray, as appropriate. All methods used by those skilled in the art to administer pharmaceutically active agents are contemplated.

[0089] The composition suitable for parenteral injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.) and injectable organic esters, such as ethyl oleate.Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

[0090] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Microbial contamination can be prevented by adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical compositions can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin.

[0091] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) a filler or extender, such as starch, lactose, sucrose, mannitol, and silicic acid; (b) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) a humectant, such as glycerol; (d) a disintegrant, such as agar, calcium carbonate, potato or are mixed with tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retardants such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin and bentonite; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage form may also contain buffering agents.

[0092] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0093] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other well-known in the art.These can also contain opacifying agents, and can be of a composition that allows them to release active compound or active compounds in a delayed manner in a specific part of the intestinal tract.Examples of embedding compositions that can be used are polymeric substances and waxes.Active compound can also be in the form of microencapsulation, if appropriate, with one or more of the above-mentioned excipients.

[0094] The liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compound, liquid dosage form can contain the inert diluent commonly used in this field, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, or the mixture of these substances.

[0095] In addition to such inert diluents, compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar, and tragacanth, or mixtures of these substances.

[0096] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ordinary room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active ingredient.

[0097] The dosage form for topical administration of the compound of the present invention includes ointments, powders, sprays and inhalants.The active compound or compatible compound is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants that may be required.Ophthalmic preparations, eye ointments, powders and solutions are also contemplated within the scope of the present invention.

[0098] The compounds of the present invention can be administered to patients at dosage levels ranging from about 0.1 to about 3,000 mg per day. For a normal adult human weighing approximately 70 kg, a dosage ranging from about 0.01 mg to about 100 mg per kilogram of body weight is usually sufficient. The specific dosage and dosage range that can be used will depend on many factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determination of dosage ranges and optimal dosages for a particular patient is within the skill of one of ordinary skill in the art.

[0099] The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. Salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. Salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. See, e.g., S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977).

[0100] Examples of pharmaceutically acceptable esters of the compounds of the present invention include C1-C8 alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as aryl alkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of the compounds of the present invention can be prepared according to methods well known in the art.

[0101] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C1-C8 alkylamines, and secondary C1-C8 dialkylamines. In the case of secondary amines, the amines may also be in the form of 5- or 6-membered heterocycloalkyl groups containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkylamines, and C1-C2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

[0102] The term "prodrug" refers to a compound that is transformed in vivo to produce a compound of the invention. Transformation can occur by various mechanisms, such as hydrolysis in blood. A discussion of the use of prodrugs can be found in T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0103] For illustrative purposes, when the compounds of the invention contain a carboxylic acid functional group, prodrugs may include esters formed by replacing the hydrogen atom of the acid group with any of the following groups: (C1-C8 alkyl, (C2-C 12) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)amino having 3 to 9 carbon atoms Methyl, 1-(N-(alkoxycarbonyl)aminomethyl) having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidino-, pyrrolidino-, or morpholino(C2-C3)alkyl.

[0104] Similarly, if a compound of the invention contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with any group such as (C-C)alkanoyloxymethyl, 1-((C-C)alkanoyloxy)ethyl, 1-methyl-1-((C-C)alkanoyloxy)ethyl, (C-C)alkoxycarbonyloxymethyl, N—(C-C)alkoxycarbonylaminomethyl, succinoyl, (C-C)alkanoyl, α-amino(C-C)alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently a naturally occurring L-amino acid, —P(O)(OH), —P(O)(O(C-C)alkyl), or glycosyl (the radical resulting from removal of the hydroxyl group of a hemiacetal form of a carbohydrate).

[0105] The compounds of the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomeric forms.All stereoisomeric forms of the compounds and mixtures thereof, including racemic mixtures, are contemplated as part of the present invention.Furthermore, the present invention contemplates all geometric and positional isomers.For example, if a compound contains a double bond, both cis and trans forms (designated S and E, respectively), and mixtures thereof, are contemplated.

[0106] Mixtures of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Some compounds may also be atropisomers (e.g., substituted biaryls).

[0107] The compounds of the present invention can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water (hydrates), ethanol, etc. The present invention contemplates and encompasses both solvated and unsolvated forms.

[0108] It is also possible that the compounds of the present invention may exist in different tautomeric forms.All tautomeric forms of the compounds of the present invention are contemplated.For example, all tautomeric forms of the tetrazole moiety are included in the present invention.Also, for example, all keto-enol or imine-enamine forms of the compounds are included in the present invention.

[0109] Those skilled in the art will recognize that the compound names and structures contained herein may be based on particular tautomers of the compounds. While only the name or structure of a particular tautomer may be used, it is intended that all tautomers are included in the present invention unless otherwise specified.

[0110] It is also intended that the present invention encompasses compounds synthesized in vitro using laboratory techniques such as those familiar to synthetic chemists, or compounds synthesized using in vivo techniques such as via metabolism, fermentation, digestion, etc. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.

[0111] The present invention also includes isotopically labeled compounds, which are identical to those described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 16 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, and 36 In one aspect, the present invention relates to compounds in which one or more hydrogen atoms are replaced with deuterium (2H) atoms.

[0112] Compounds of the present invention that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g., 3 H and 14 Those in which a radioactive isotope, such as C, is incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. Additionally, heavier isotopes such as deuterium, i.e. 2Substitution with H can confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0113] The compounds of the present invention may exist in various solid states, including crystalline and amorphous states. The different crystalline states, also referred to as polymorphs, and amorphous states of the compounds of the present invention are contemplated as part of the present invention.

[0114] All patents, published patent applications and other publications cited herein are hereby incorporated by reference.

[0115] compound The present invention relates to novel compounds that can bind cereblon (CRBN) but have varying reduced abilities to recruit critical substrate proteins such as SALL4 and ASS1, and varying abilities to recruit more general substrates such as IKZF1 to CRBN. The distinct recruitment profiles among CRBN-binding molecules create new starting points for selective small molecule substrate degradation adhesives, either alone or as regulatory components of CRBN-binding heterobifunctional molecules (HBMs). The recruitment profiles of key liability substrates provide an objective means for prioritizing and selecting promising small molecules. In one embodiment, some CRBN-binding compounds described herein, upon binding to CRBN, reduce the ability of CRBN to recruit selected liability substrates, such as SALL4 and ASS1, and general substrates, such as IKZF1. These compounds are referred to as "silent" compounds. In one embodiment, some CRBN-binding compounds described herein, upon binding to CRBN, increase the ability of CRBN to recruit selected liability substrates.

[0116] CRBN acts as a substrate receptor protein within the E3 ligase complex to induce proteasome-mediated degradation of substrate proteins and forms functional interactions with E2 ligase proteins such as DNA damage-binding protein 1 (DDB1), Cullin4 (4A or 4B), and regulator of Culling1 (RoC1), as well as UBE2G1, for substrate ubiquitination and subsequent degradation.

[0117] Glutarimide-containing drugs (IMiDs), small molecules derived from thalidomide, have been shown to bind CRBN and, as a complex, recruit de novo nascent substrates to the E3 ligase complex.

[0118] The consequence of IMiD-induced recruitment of substrate proteins to CRBN is that such proteins are then degraded by the ubiquitin proteasome pathway (UPP).

[0119] Novel compounds that bind cereblon are provided, along with their uses and preparations. Binding of the disclosed compounds to cereblon is believed to increase or decrease cereblon's interaction with IKZF1, SALL4, and ASS1, leading to subsequent ubiquitination and degradation in the proteasome. Selected compounds have been found to be potent binders of cereblon and exhibit potential therapeutic uses.

[0120] The compounds disclosed herein, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof can be used to treat disorders mediated by one or more of cereblon, IKZF1, SALL4, and ASS1.

[0121] In one aspect, the compounds of the present invention have formula I: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 1 is aryl, -N(R 5 )-XR 6, -SO2R 5 , or -O(CH2) m R 5 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0122] In one embodiment, R 1 is one or more R as allowed by the valence w and phenyl optionally substituted with a group.

[0123] In one embodiment, R 1 is phenyl.

[0124] In one embodiment, R 1is phenyl optionally substituted with one or more (C1-C3) alkyl, (C1-C3) alkoxy, or OH.

[0125] In one aspect, the compounds of the present invention have formula II: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 2 is aryl, -NH-(C3-C 10 ) heteroaryl, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0126] In one embodiment, R 2 is one or more R as allowed by the valence wand phenyl optionally substituted with a group.

[0127] In one embodiment, R 2 is -NH-(C3-C 10 ) heteroaryl.

[0128] In one embodiment, R 2 is phenyl optionally substituted with one or more (C1-C3) alkyl, (C1-C3) alkoxy, or OH.

[0129] In one embodiment, R 2 is -N(R 5 )-(CH2)mX-(CH2)nR 6 and;R 5 is H;R 6 is OH, (C1-C3) alkyl, -(C1-C3) alkoxy, -NR5R5, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 ) heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl.

[0130] In one aspect, the compounds of the present invention have formula III: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 3 is cyano, aryl, -NH-(C3-C 10 ) heteroaryl, (C3-C 10 ) heterocyclo, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n-(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0131] In one embodiment, R 3 is -N(R 5 )-(CH2)mX-(CH2)nR 6 and;R 5 is H;R 6 is OH, (C1-C3) alkyl, -(C1-C3) alkoxy, -NR5R5, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 ) heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl.

[0132] In one aspect, the compounds of the present invention have formula IV: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 4 is halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2)n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0133] In one embodiment, R 4 is -N(R 5 )-(CH2)mX-(CH2)nR 6 and;R 5 is H;R 6 is OH, (C1-C3) alkyl, -(C1-C3) alkoxy, -NR5R5, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C10 ) heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl.

[0134] In one aspect, the compounds of the present invention have formula V: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 17 is cyano, heteroaryl, -(CH2) m -C(O)OR 6 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0135] In one embodiment, R 17is heteroaryl optionally substituted with OH, halo, (C1-C3)alkyl or (C1-C3)alkoxy.

[0136] In one aspect, the compounds of the present invention have formula VI: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 16 is NH2 or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 and any of these may contain one or more R as allowed by the valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0137] In one aspect, the compounds of the present invention have formula VII: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 18 , R 19 , R20 , R 21 are each independently H, halo, (C-C)alkyl, or -N(R 5 )-XR 6 where R 18 , R 19 , R 20 , R 21 wherein no more than two of the substituents are H; or R 18 , R 19 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) to form a heterocycle, or R 19 , R 20 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) to form a heterocycle, or R 20 , R 21 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) heterocycles, any of which may contain one or more R w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10)heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0138] In one aspect, the compounds of the present invention have formula VIII: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 8 , R 9 , R 10 , R 11 are each independently H, halo, OH, cyano, (C-C) alkyl, (C-C) alkoxy, aryl, or heteroaryl, any of which may be present in combination with one or more R as allowed by valence. w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; where n is 0, 1, 2, 3, or 4).

[0139] In one aspect, the compounds of the present invention have formula IX: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 12 , R 13 , R 14 , R 15 are each independently H, NH, (C-C) alkyl, -N(R 5 )-(CH2)mN(R 5 )-XR 6 where R 12 , R 13 , R 14 , and R 15 Not more than three substituents of R are H, and any of them may be substituted with one or more R as allowed by the valences. w may be optionally substituted with a group; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0140] In one aspect, the compounds of the present invention have the formula X: [ka] or a pharmaceutically acceptable salt thereof (Wherein, Y is —NHR 33 , -NHC(O)R33 , or -CHR 33 R 34 and; R 7 is H, (C1-C3) alkyl, or R 7 and R 34 together with the carbon to which they are attached to form a carbon-carbon double bond; R 33 is an aryl, heteroaryl, (C3-C 10 ) heterocyclo, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; where n is 0, 1, 2, 3, or 4).

[0141] In one aspect, the compounds of the invention have formula XI: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 22 is H, halo, OH, -NR5R5, (C1-C3) alkyl, (C1-C3) alkoxy, (hydroxy)(C1-C3) alkyl, cyano, -N(R 5 )-XR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR 6 , aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 23 H, halo, OH, -NR 5 R 5 , -(CH2) n -NR 5 R 5 , (C1-C3) alkyl, (C1-C3) alkoxy, -C(O)NR 5 R 6 , (hydroxy)(C1-C3) alkyl, cyano, -N(R 5 )-XR 6 , -N(R 5 )-(CHR 5 )mXR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR 6 , aryl, heteroaryl, or R 22 and R 23 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl ring or (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R 24 is H, halo, OH, -NR5R5, -(CH2)n-NR5R5, (C1-C3) alkyl, (C1-C3) alkoxy, (halo)(C1-C3) alkyl, (hydroxy)(C1-C3) alkyl, cyano, -NO2, -N(R 5 )-XR 6 , -N(R 5 )-(CH2)mN(R5 )-XR 6 , aryl, heteroaryl, or R 23 and R 24 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl ring or (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w may be optionally substituted with a group; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R wis, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0142] In one embodiment, R 22 is H;R 23 is H and R 24 is a halo.

[0143] In one aspect, the present invention provides a compound of formula XII, XIII, XIV, XV, XVI, XVII, or XVIII: [ka] or a pharmaceutically acceptable salt thereof (In the formula, R 28 , R 29 , R 30 , R 31 are independently H, halo, OH, -NR 5 R 5 , -(CH2)n-NR 5 R 5 , (C1-C3) alkyl, (C1-C3) alkoxy, (halo)(C1-C3) alkyl, (hydroxy)(C1-C3) alkyl, cyano, -NO2, -N(R 5 )-XR 6 , -N(R 5 )-(CH2)mN(R 5 )-XR 6 , aryl, heteroaryl, or R 28 , R 29 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) to form a heterocycle, or R 30 , R 31 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) to form a heterocycle, or R 29 , R 30 are taken together to form a linking group or R 29 , R 30 together with the carbon to which they are attached (C3-C 10 ) cycloalkyl or (C3-C 10 ) heterocyclo or aryl or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 5 is, at each occurrence, independently selected from H, (C1-C3) alkyl, (C3-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10) heterocyclo, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, any of which may contain one or more R as allowed by valence. w groups, which may be optionally substituted; R 6 is, at each occurrence, independently selected from OH, (C1-C3) alkyl, -(C1-C3) alkoxy, (C3-C 10 )heterocyclo, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 ) cycloalkyl, -(CH2)n-(C3-C 10 )heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atoms to which they are attached are a nitrogen-containing (C3-C 10 ) heterocyclic rings, any of which may contain one or more R w groups, which may be optionally substituted; R w is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo(C-C 10 ) heterocyclo, (C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) cycloalkyl, -(CH2) n -(C3-C 10 ) heterocyclo, -(CH2) n -aryl, -(CH2) n-can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n - and; m is 0, 1, 2, 3, or 4; where n is 0, 1, 2, 3, or 4).

[0144] In one aspect, the compound of the present invention is selected from the compounds listed in Table 1 of Example 4.

[0145] In one aspect, the compound of the present invention is selected from the group consisting of: 3-[1-oxo-5-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidin-2-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]acetamide; 3-[5-[(2-aminopyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetyl]amino]benzamide; 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindolin-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-methyl-acetamide; Acetic acid;3-[1-oxo-6-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxo-pyrazin-2-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxalin-2-ylamino)isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione 3-[6-(5,7-dihydrofuro[3,4-d]pyrimidin-2-ylamino)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-phenyl-acetamide; 3-[6-[[2-(2,4-dimethylpiperazin-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-[6-(dimethylamino)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindolin-2-yl)piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N,N-dimethylacetamide; 3-[6-[[2-(2-methylmorpholin-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-methyl-N-[(1-methylpyrazol-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]pyridazine-3-carbonitrile; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-(Dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; N-cyclopropyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 3-[1-oxo-6-(2-oxoimidazolidin-1-yl)isoindolin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]propanoic acid; 2-Acetamido-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 3-[6-[[2-(3-methyl-5-oxo-piperazin-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxo-piperazin-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetic acid; 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindolin-2-yl]piperidine-2,6-dione; 3-(1-oxo-7-phenyl-isoindolin-2-yl)piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-4-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-4-yl]amino]acetic acid; 3-(7-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione; 3-(5-amino-1-oxo-3,4-dihydroisoquinolin-2-yl)piperidine-2,6-dione; t-Butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-1-yl]acetate; 3-[1-(2H-indol-3-yl)-3-oxo-isoindolin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-carbonitrile; 3-[1-(dimethylamino)-3-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidin-1-yl)piperidine-2,6-dione; 3-(Quinazolin-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(quinoxalin-2-ylamino)piperidine-2,6-dione; 3-(pyrimidin-2-ylamino)piperidine-2,6-dione; N-(2,6-dioxo-3-piperidyl)-2-oxo-3H-pyridine-6-carboxamide; 3-(4-methyl-1,1,3-trioxo-1,2-benzothiazol-2-yl)piperidine-2,6-dione; 3-(8-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-amino-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(5-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; 3-(6-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione; and 3-(8-methyl-4-oxo-1,2,3-benzotriazin-3-yl)piperidine-2,6-dione.

[0146] In one aspect, the invention relates to a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0147] In one aspect, the present invention relates to a method of treating a disease, comprising administering to a subject in need thereof a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0148] In one aspect, the present invention relates to a method of treating cancer, comprising administering to a subject in need thereof a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, uterine cancer, leukemia, lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, e.g., Ewing's sarcoma, Selected from the group consisting of angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, schwannoma, testicular tumor, thyroid carcinoma, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

[0149] In another aspect, the present invention relates to a method of treating or preventing one or more autoimmune diseases or disorders, comprising administering to a subject in need thereof a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, the autoimmune disease or disorder is selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., allograft rejection prevention), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, and other autoimmune diseases or disorders, and the like.

[0150] In one embodiment, the subject is a human.

[0151] In another aspect, the present invention relates to a method of modulating cereblon, comprising administering to a subject in need thereof a composition comprising a compound of Formulas I-XVIII. In one embodiment, the present invention relates to a method of modulating cereblon, comprising administering to a subject in need thereof a composition comprising a compound selected from the compounds listed in Table 1 in Example 4.

[0152] In another aspect, the present invention relates to a method for modulating the proteasomal degradation of a protein, comprising administering to a subject in need thereof a composition comprising a compound of Formulas I-XVIII. In one embodiment, the present invention relates to a method for modulating the proteasomal degradation of a protein, comprising administering to a subject in need thereof a composition comprising a compound selected from the compounds listed in Table 1 of Example 4.

[0153] In another aspect, the present invention relates to a method for modulating sequestration of a protein in the proteasome, comprising administering to a subject in need thereof a composition comprising a compound of Formulas I-XVIII. In one embodiment, the present invention relates to a method for modulating sequestration of a protein in the proteasome, comprising administering to a subject in need thereof a composition comprising a compound selected from the compounds listed in Table 1 of Example 4.

[0154] Example General synthetic scheme The compounds of the present invention can generally be prepared starting from commercially available starting materials and using synthetic techniques known to those skilled in the art. Outlined below are some reaction schemes that are suitable for preparing the compounds of the present invention. Further examples can be found in the specific examples provided.

[0155] Example 1: Competitive Assay CRBN binding was assessed in a MAPPIT-like assay by determining the ability of test compounds to compete with a trimethoprim-lenalidomide hybrid ligand for intracellular CRBN binding. For example, the traditional MAPPIT assay described in Lemmens et al., "MAPPIT, a mammalian two-hybrid method for in-cell detection of protein-protein interactions," Methods Mol Biol. 2015;1278:447-55, has been used to monitor protein-protein interactions. A bait protein (protein A) was expressed as a fusion protein genetically fused to an engineered intracellular receptor domain of the leptin receptor, which itself was fused to the extracellular domain of the erythropoietin (Epo) receptor. Binding of the EpoR ligand to the EpoR component results in activation of the receptor-associated intracellular JAK2. However, activated JAK2 cannot activate the leptin receptor to bind and phosphorylate STAT3 because the tyrosine residue normally phosphorylated by activated JAK2 is mutated. Instead, the reconstitution of a JAK2-phosphorylatable STAT3 docking site is created by the interaction of protein B with protein A, whereby protein B is fused to the cytoplasmic domain of the gp130 receptor (which in turn possesses the appropriate tyrosine recognized by activated JAK2 kinase). Thus, the physical interaction of protein A with protein B is reconstituted, and Epo triggers activation of the JAK2-STAT3 signaling pathway. STAT3 activation can be monitored by introducing a STAT3-responsive reporter gene, such as a gene encoding luciferase or a fluorescent marker such as GFP or some other type of fluorescent protein (e.g., EGF). Thus, the MAPPIT assay provides a versatile assay for assessing such recombinant protein-protein interactions in intact cells, or compound- or hybrid-ligand-induced protein-protein interactions.

[0156] Here, we used a similar MAPPIT-like assay to determine the ability of test compounds to compete with trimethoprim-lenalidomide-induced binding between DHFR and CRBN. Therefore, HEK293 cells transfected with the appropriate cDNAs (encoding DHFR and CRBN fusion proteins) were used to express the DHFR fusion protein, trimethoprim (TMP)-lenalidomide hybrid ligand (TMP is the ligand for DHFR), and the CRBN-gp130 fusion protein (CRBN binds to the ligand lenalidomide)—thus generating a positive assay signal as a result of ternary protein / compound complex formation, including DHFR-TMP-LEN-CRBN complex formation. Complex formation resulted in activation of a STAT-responsive luciferase reporter gene. The signal was set to 100% luciferase activity. In another sample setup, cells were prepared in the same manner but were additionally co-cultured with test compounds to examine their interaction with CRBN. Binding to the CRBN fusion protein competes with binding of the hybrid ligand to the same CRBN protein, thus inhibiting the assay signal by preventing the formation of the ternary complex required to generate the assay signal. Increasing concentrations of test compounds were evaluated to determine the CRBN binding efficiency determined in this type of ligand competition experiment in live cells. The specificity of signal inhibition was assessed in a parallel experimental setup, in which the effect of the test compound was evaluated for inhibition of the signal generated by a control gp130 fusion protein (CTRL) that binds directly to the DHFR fusion protein (i.e., direct protein interaction) in the absence of the hybrid ligand.

[0157] More specifically, HEK293T cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum at 37°C and 8% CO2. Cells were transfected with a plasmid encoding Escherichia coli dihydrofolate reductase (DHFR) fused to the tail of the cytoplasmic domain of a mutant leptin receptor (pCLG-eDHFR), a plasmid encoding a CRBN prey fused to the gp130 cytoplasmic domain (pMG1-CRBN), or a plasmid encoding a REM2 control prey capable of directly interacting with the leptin receptor in a DHFR fusion protein (pMG1-REM2), and a STAT3-responsive pXP2d2-rPAPI-luciferase reporter plasmid, using standard transfection methods as described (Lievens, et al., "Array MAPPIT: high-throughput interactome analysis in mammalian cells," Journal of Proteome Research 8.2 (2009):877-886). Cells were treated with leptin to activate the leptin receptor fusion protein and supplemented with 300 nM trimethoprim-lenalidomide fusion compound (a hybrid ligand in which trimethoprim interacts with DHFR and lenalidomide interacts with CRBN) 24 hours after transfection, either without or with the indicated dose of test compound. Luciferase activity induced by the formation of a ternary complex containing DHFR, trimethoprim, lenalidomide, and CRBN, and the resulting activation of STAT3 signaling, was measured 24 hours after compound treatment using a luciferase assay system kit (Promega, Madison, Wisconsin) equipped with an Ensight plate reader (Perkin-Elmer Life Sciences, Waltham, Massachusetts).Data points represent the average luciferase activity of triplicate samples from cells treated with leptin + test compound or leptin + hybrid ligand + test compound (CRBN) for the REM2 control (CTRL), compared with leptin (CTRL) or leptin + hybrid ligand (CRBN) treated samples only (in both cases, the signal obtained without the addition of test compound is set to 100% of the luciferase activity on the y-axis). Error bars represent standard deviation. Curves were fitted using a four-parameter nonlinear regression with GRAPHPAD PRISM software.

[0158] Example 2: Recruitment Assay: In this Example 2, a MAPPIT-like assay similar to that described in Example 1 was applied to determine test compound-induced binding of a specific substrate protein of interest to CRBN. In this experimental setting, cells were transfected with a construct encoding a CRBN fusion protein and another construct encoding a substrate fusion protein. The activity of the test compound was assessed at increasing concentrations of the test compound (dose-response study) to monitor its ability to promote CRBN-ligand-induced protein interaction.

[0159] Specifically, HEK293T cells were transfected with a plasmid encoding a MAPPIT receptor fusion, in which the protein of interest (CRBN or a substrate protein) was genetically linked to the cytoplasmic domain of the leptin receptor, which itself was fused to the extracellular domain of the erythropoietin (Epo) receptor (pSEL-X, where X represents either CRBN or the substrate protein of interest to be tested), a plasmid encoding a MAPPIT gp130 fusion (pMG1-Y, where Y represents either the substrate protein of interest or CRBN), and a reporter plasmid encoding a STAT3-responsive luciferase (pXP2d2-rPAPI-luciferase reporter plasmid) (see Lievens, et al., "Array MAPPIT: high-throughput interactome analysis in mammalian cells," Journal of Proteome Research). 8.2(2009):877-886). Full-size proteins were fused to each of the tested target proteins, except for IKZF1, for which isoform 7 was used. In this study, the following were used: IKZF1 recruitment: pSEL-CRBN+pMG1-IKZF1 (isoform 7); ASS1 recruitment: pSEL-CRBN+pMG1-ASS1. SALL4 recruitment: pSEL-SALL4+pMG1-CRBN. Cells were treated with erythropoietin (Epo) 24 hours after transfection with or without the indicated doses of test compounds. Luciferase activity was measured using a Luciferase Assay System kit (PROMEGA, Madison, WI) and an Ensight plate reader (PERKIN ELMER LIFE Luciferase activity was measured 24 hours after test compound treatment using a fluorochrome-free fluorochrome analyzer (SCIENCES, Waltham, MA). Data points represent the fold induction of mean luciferase activity of triplicate samples from cells treated with EPO plus test compound and EPO alone. Error bars represent standard deviation. Curves were fitted using four-parameter nonlinear regression with GRAPHPAD PRISM software.

[0160] Example 3: Preparation of compounds The compounds of the present invention can be prepared by methods well known in the field of organic chemistry. See, for example, J. March, "Advanced Organic Chemistry," 4th Edition, John Wiley and Sons. During the synthetic sequence, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This is achieved using conventional protecting groups, such as those described in T.W. Greene and P.G.M. Hutts, "Protective Groups in Organic Synthesis," 3rd Edition, John Wiley and Sons, 1999. Protecting groups are optionally removed at a later appropriate stage using methods well known in the art. The products of the reaction are optionally isolated and purified, if necessary, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials are optionally characterized using conventional means, such as physical constants and spectral data.

[0161] In synthesizing the compounds of the present invention, it may be desirable to use a particular leaving group. The term "leaving group" ("LG") generally refers to a group displaceable by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), and the like.

[0162] HPLC purification Purification was carried out using HPLC (HO-MeOH; Agilent 1260 Infinity system equipped with DAD and mass detector). Waters Sunfire C18 OBD preparative column, 100 Å (Angstroms), 5 μm, 19 mm x 100 mm, SunFire C18 Prep Guard Cartridge, 100 Å (Angstroms), 10 μm, 19 mm x 10 mm) material was dissolved in 0.7 mL DMSO. Flow rate: 30 mL / min. The purity of the obtained fractions was confirmed via analytical LCMS. Spectra were recorded for each fraction immediately after it was chromatographed in solution form. The solvent was evaporated in a flow of N2 at 80 °C. Fractions were combined based on the LCMS analysis after chromatography. The solid was dissolved in 0.5 mL MeOH and transferred to a pre-weighed, marked vial. The resulting solution was again evaporated in a flow of N2 at 80 °C. After drying, the product was finally purified by LCMS and 1 The compound was characterized by HNMR. For clarity, in the synthetic schemes in this section, hydrogen atoms are not shown for simplicity. For example, "-NH" is shown as "-N" and "-OH" is shown as "-O".

[0163] Analysis method NMR Equipment specifications: Bruker AVANCE DRX 500 Varian UNITYplus 400 LC / MS Equipment specifications: Agilent 1100 series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD VL (G1956A), SL (G1956B) mass spectrometers. Agilent 1200 series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD SL(G6130A), SL(G6140A) mass spectrometer. All LC / MS data was acquired using positive / negative mode switching. Column: Zorbax SB-C18 1.8 μm 4.6 x 15 mm Rapid Resolution Cartridge (PN 821975-932) Mobile phase A - acetonitrile, 0.1% formic acid B-water (0.1% formic acid) Flow rate 3ml / min Gradient 0 min - 100%B 0.01 min-100%B 1.5 minutes-0%B 1.8 minutes-0%B 1.81 min-100%B Injection volume 1μl Ionization mode: atmospheric pressure chemical ionization (APCI) Scan range m / z 80-1000

[0164] C24031 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0165] General Procedure A: Compound 1 (20 mmol) and K2CO3 (24 mmol) were suspended in DMF (20 mL). Iodomethane (24 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then diluted with water (150 mL). The solution was extracted with ethyl acetate (2 x 200 mL), and the organic phase was washed with brine (3 x 150 ml), dried over CaCl2, and evaporated to give the methyl ester 2. Yield: 94%.

[0166] General Procedure B: To a solution of compound 2 (1.6 mmol) in CCl4 (3 ml) was added AIBN (0.1 mmol) and NBS (2 mmol) at 25°C for 15 min. The reaction was heated at 60°C for 12 h and cooled to room temperature. The solvent was then removed in vacuo. The crude residue was purified using LC. Yield: 64%.

[0167] General procedure C: Compound 1 (1 mmol), DIPEA (2.1 mmol), and compound 2 hydrochloride (1.3 mmol) were dissolved in 5 ml DMF, and the mixture was heated at 80° C. for 18 hours (TLC and LCMS control). The reaction mixture was cooled, filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 49%.

[0168] C74668 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0169] Step A: To a suspension of 1 (13.2 g, 86.8 mmol) in acetic acid (150 mL) at 0 °C, N-bromosuccinimide (17 g, 95.4 mmol) was added portionwise over 30 min. The mixture was warmed to 20 °C, stirred for 3 h, and then treated with 40% aqueous sodium hydrogen sulfate (100 mL). The acetonitrile was removed in vacuo, and the aqueous residue was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water and brine, dried, and concentrated to give 3-bromo-6-hydroxy-2-methylbenzoic acid as a white solid, 16 g. Yield: 82%.

[0170] Step B: This compound was prepared according to general procedure A for C24031. Yield: 87%. Step C: This compound was prepared according to general procedure B for C24031. Yield: 92%.

[0171] Step D: This compound was prepared according to general procedure C for C24031. Yield: 42%.

[0172] C07207 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0173] Step A: This compound was prepared according to general procedure B for C24031. Yield: 84%.

[0174] Step B: This compound was prepared according to general procedure C for C24031. Yield: 87%. Step C:

[0175] To a solution of compound 4 (0.5 mmol) in methanol (2 mL), palladium on carbon (5%, 10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and then purified by HPLC. Yield: 39%.

[0176] C89676 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0177] General Procedure A: Compound 1 (1 mmol), NaH(OAc)3 (5 mmol), HOAc (1 mmol), and compound 2 (1.3 mmol) were dissolved in 5 ml MeOH, and the mixture was heated at 80 °C for 12 h. TLC and LCMS control. The reaction mixture was cooled, then filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield 58%.

[0178] C28558 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0179] Step A: This compound was prepared according to general procedure A for C24031. Yield: 98%. Step B: This compound was prepared according to general procedure B for C24031. Yield: 56%. Step C:

[0180] This compound was prepared according to general procedure C for C24031. Yield: 67%.

[0181] C28577 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0182] Step A: This compound was prepared according to general procedure A for C24031. Yield: 98%.

[0183] Step B: This compound was prepared according to general procedure B for C24031. Yield: 59%. Step C:

[0184] This compound was prepared according to general procedure C for C24031. Yield: 81%.

[0185] C28620 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0186] Step A: This compound was prepared according to general procedure A for C24031. Yield: 95%.

[0187] Step B: This compound was prepared according to general procedure B for C24031. Yield: 59%.

[0188] Step C: This compound was prepared according to general procedure C for C24031. Yield: 72%.

[0189] C28661 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0190] Step A: This compound was prepared according to general procedure A for C24031. Yield: 95%.

[0191] Step B: This compound was prepared according to general procedure B for C24031. Yield: 49%.

[0192] Step C: This compound was prepared according to general procedure C for C24031. Yield: 64%.

[0193] C28891

[0194] The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0195] Step A: This compound was prepared according to general procedure B for C24031. Yield: 69%.

[0196] Step B: This compound was prepared according to general procedure C for C24031. Yield: 62%.

[0197] C28928 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0198] Step A: This compound was prepared according to general procedure B for C24031. Yield: 37%.

[0199] Step B: This compound was prepared according to general procedure C for C24031. Yield: 55%.

[0200] C28973 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0201] Step A: To a stirred solution of compound 1 (10 mmol) in acetone (10 mL) was added anhydrous powdered potassium carbonate (20 mmol). Dimethyl sulfate (12 mmol) was added portionwise at room temperature over approximately 10 minutes. After the addition was complete, the solution was heated to reflux on a water bath and maintained for 5 hours. The solution was cooled to room temperature and then concentrated under reduced pressure. Distilled water (20 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL). The organic layer was washed with distilled water (2 x 20 mL), dried over anhydrous sodium sulfate, and concentrated. Yield: 86%.

[0202] Step B: This compound was prepared according to general procedure B for C24031. Yield: 45%.

[0203] Step C: This compound was prepared according to general procedure C for C24031. Yield: 74%.

[0204] Step D: To a solution of compound 5 (0.5 mmol) in dichloromethane (2.0 ml) was added TFA (2 mmol). The reaction was stirred at room temperature for 0.5 hours. The reaction was poured into water and extracted with dichloromethane (twice). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by HPLC. Yield: 26%.

[0205] C47927 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0206] Step A: This compound was prepared according to general procedure C for C24031. Yield: 84%.

[0207] Step B: To a solution of compound 4 (0.5 mmol) in methanol (2 mL), palladium on carbon (5%, 10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and then purified using HPLC. Yield: 79%.

[0208] C47959 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0209] General Procedure A: Compound 1 (1 mmol), DIPEA (3.1 mmol) and compound 2 hydrochloride (1.3 mmol) were dissolved in 5 ml DMF, and the mixture was heated at 80° C. for 18 hours (TLC and LCMS control). The reaction mixture was cooled, filtered and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 29%.

[0210] C48003 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0211] General Procedure A: Compound 1 (27 mmol) was treated with 50 ml of dilute hydrochloric acid (1:3). The resulting suspension was cooled to 0-3°C, and 50 ml of an aqueous solution containing NaNO2 (108 mmol) was added over 20 min. The mixture was neutralized with NaHCO3, and a suspension of CuCN (30 mmol) in 20 ml of toluene was added. The mixture was kept at room temperature for 10-12 h, and 100 ml of toluene was added. The toluene was evaporated, washed with water, and recrystallized from a mixture of DMF / i-PrOH (1 / 3). Yield: 39%.

[0212] C80392 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0213] General Procedure A: Compounds 1 (1 mmol) and 2 (1 mmol) were dissolved in 7 ml of dry DMF, and DIPEA (3 mmol) and HATU (2 mmol) were added. The resulting mixture was stirred at 50 °C for 10-12 h (LCMS control), cooled to room temperature, and 15 ml of water and HOAc (5 mmol) were added. The mixture was extracted with EtOAc (3 x 25 ml), washed with brine (3 x 25 ml), and the EtOAc was evaporated. The crude residue was purified using HPLC. Yield: 49%.

[0214] C12584 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0215] General Procedure A: Compounds 1 (1 mmol) and 2 (1 mmol) were dissolved in 10 ml of dry DMF, and DIPEA (3 mmol) was added. The resulting mixture was stirred at 90°C for 3-5 hours (LCMS control), cooled to room temperature, and 20 ml of water was added. The precipitate was filtered and washed with water (3 x 25 ml). The crude residue was purified using HPLC. Yield: 24%.

[0216] C80370

[0217] The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0218] General Procedure A: Compounds 1 (1 mmol) and 2 (1 mmol) were dissolved in 10 ml of dry DMF, and DIPEA (2 mmol) was added. The resulting mixture was stirred at 80 °C for 10-12 h (LCMS control), cooled to room temperature, and 20 ml of water was added. The precipitate was filtered and washed with water (3 x 25 ml). The crude residue was purified using HPLC. Yield: 32%.

[0219] General Procedure B: Compounds 1 (1 mmol) and 2 (1 mmol) were dissolved in 10 ml of dry HOAc. The resulting mixture was heated at 80°C with stirring for 10-48 hours (LCMS control), cooled to room temperature, and 20 ml of water was added. The precipitate was filtered and washed with water (3 x 25 ml). The crude residue was purified using HPLC. Yield: 38%.

[0220] C48014 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0221] Step A: This compound was prepared according to general procedure A for C47959. Yield: 82%.

[0222] General Procedure B: Compound 2 (1 mmol), PhB(OH) (1.5 mmol), NaHCO (2 mmol), Pd(PPh) (0.1 mmol), and xPhOS (0.05 mmol) were dissolved in 10 ml of dry dioxane under Ar, and 10 ml of water was added. The resulting mixture was heated at 80 °C with stirring for 10-12 h (LCMS control), cooled to room temperature, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 24%.

[0223] C95330 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0224] General Procedure A: Compound 1 (1 mmol) was dissolved in 20 ml of CHCl, and water (20 ml) and NaHCO (2 mmol) were added. Chloroacetyl chloride (1.1 mmol) was added dropwise with stirring at 10-15°C for 15 min. The resulting mixture was stirred at room temperature for 3-5 h. The organic phase was removed, washed with brine (3 x 25 ml), dried, and the solvent was evaporated. The crude residue was purified using FC. Yield: 88%. Step B:

[0225] This compound was prepared according to general procedure A for C12584. Yield: 22%.

[0226] C95338 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0227] Step A: This compound was prepared according to general procedure A for C12584. Yield: 29%.

[0228] C80382 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0229] Step A: This compound was prepared according to general procedure A for C80370. Yield: 31%.

[0230] C80369 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0231] Step A: This compound was prepared according to general procedure A for C80370. Yield: 41%.

[0232] C47935 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0233] General Procedure A: Compound 1 (20 mmol) and K2CO3 (24 mmol) were suspended in DMF (20 mL). Iodomethane (24 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then diluted with water (150 mL). The solution was extracted with ethyl acetate (2 x 200 mL), and the organic phase was washed with brine (3 x 150 ml), dried over CaCl2, and evaporated to give the methyl ester 2. Yield: 94%.

[0234] General Procedure B: To a solution of compound 2 (1.6 mmol) in CCl4 (3 ml) was added AIBN (0.1 mmol) and NBS (2 mmol) at 25°C for 15 min. The reaction was heated at 60°C for 12 h and cooled to room temperature. The solvent was then removed in vacuo. The crude residue was purified using LC. Yield: 64%.

[0235] Step C: This compound was prepared according to general procedure A for C47959. Yield: 79%.

[0236] C12583 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0237] Step A: This compound was prepared according to general procedure A for C12584. Yield: 32%.

[0238] C80387 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0239] Step A: This compound was prepared according to general procedure A for C80370. Yield: 44%.

[0240] C80386 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0241] Step A: This compound was prepared according to general procedure B for C80370. Yield: 46%.

[0242] C67858 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0243] Step A: This compound was prepared according to general procedure A for C47935. Yield: 69%.

[0244] General Procedure B: Compound 1 (1 mmol), NaH(OAc)3 (5 mmol), HOAc (1 mmol), and compound 2 (1.3 mmol) were dissolved in 5 ml MeOH, and the mixture was heated at 80 °C for 12 h. TLC and LCMS control. The reaction mixture was cooled, then filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield 48%.

[0245] C98103 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0246] Step A: This compound was prepared according to general procedure A for C47935. Yield: 71%.

[0247] Step B: This compound was prepared according to general procedure B for C67858. Yield: 43%.

[0248] C80383 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0249] Step A: This compound was prepared according to general procedure A for C80370. Yield: 39%.

[0250] C80391 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0251] Step A: This compound was prepared according to general procedure A for C80370. Yield: 49%.

[0252] C48016 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0253] Step A: This compound was prepared according to general procedure A for C47935. Yield: 95%.

[0254] Step B: This compound was prepared according to general procedure B for C47935. Yield: 64%.

[0255] Step C: This compound was prepared according to general procedure A for C47959. Yield: 79%.

[0256] Step D: This compound was prepared according to general procedure A for C48014. Yield: 33%.

[0257] C05955 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0258] Step A: This compound was prepared according to general procedure A for C47959. Yield: 91%.

[0259] C80384 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0260] Step A: This compound was prepared according to general procedure A for C80370. Yield: 52%.

[0261] C51383 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0262] Step A: This compound was prepared according to general procedure A for C47935. Yield: 89%.

[0263] Step B: This compound was prepared according to general procedure B for C47935. Yield: 25%.

[0264] Step C: This compound was prepared according to general procedure A for C47959. Yield: 22%.

[0265] C84965 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0266] Step A: This compound was prepared according to general procedure A for C47935. Yield: 93%.

[0267] Step B: This compound was prepared according to general procedure B for C47935. Yield: 74%.

[0268] Step C: This compound was prepared according to general procedure A for C47959. Yield: 82%.

[0269] General Procedure D: To a solution of compound 5 (0.5 mmol) in methanol (2 mL), palladium on carbon (5%, 10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 10 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and then purified using HPLC. Yield: 39%.

[0270] Step E: This compound was prepared according to general procedure A for C12584. Yield: 34%.

[0271] C12595 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0272] Step A: This compound was prepared according to general procedure A for C95330. Yield: 82%.

[0273] Step B: This compound was prepared according to general procedure A for C12584. Yield: 22%.

[0274] C96622 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0275] Step A: This compound was prepared according to general procedure A for C47935. Yield: 88%.

[0276] Step B: This compound was prepared according to general procedure B for C67858. Yield: 57%.

[0277] C22622 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0278] Step A: This compound was prepared according to general procedure A for C95330. Yield: 53%.

[0279] C48018 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0280] Step A: This compound was prepared according to general procedure A for C47959. Yield: 79%.

[0281] Step B: This compound was prepared according to general procedure A for C48014. Yield: 28%.

[0282] C84964 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0283] Step A: This compound was prepared according to general procedure A for C12584. Yield: 39%.

[0284] C29137 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0285] Step A: This compound was prepared according to general procedure A for C47935. Yield: 97%.

[0286] Step B: This compound was prepared according to general procedure B for C47935. Yield: 64%.

[0287] Step C: This compound was prepared according to general procedure A for C47959. Yield: 62%.

[0288] C12586 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0289] Step A: This compound was prepared according to general procedure A for C12584. Yield: 42%.

[0290] C35856 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0291] Step A: This compound was prepared according to general procedure B for C47935. Yield: 91%.

[0292] Step B: This compound was prepared according to general procedure A for C47959. Yield: 82%.

[0293] Step C: This compound was prepared according to general procedure D for C84965. Yield: 81%.

[0294] Step D: This compound was prepared according to general procedure A for C12584. Yield: 22%.

[0295] C35751 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0296] General Procedure A: Compound 1 (20 mmol) and K2CO3 (24 mmol) were suspended in DMF (20 mL). Compound 2 hydrobromide (100 mmol) was added and the reaction mixture was heated at 90 °C with stirring for 10 h. The suspension was filtered, washed with DMF (3 x 10 ml), and the solvent was evaporated to give compound 3. The crude residue was purified using LC. Yield: 9%.

[0297] General Procedure B: Compound 3 (1 mmol) was dissolved in acetonitrile (10 mL). PhNCO (1.1 mmol) and 1 drop of NEt were added, and the reaction mixture was heated at 60-70 °C with stirring for 3-5 h. The suspension was cooled, filtered, washed with acetonitrile (3 x 10 mL), and the solvent was evaporated to give compound 3. The crude residue was purified using LC. Yield: 46%.

[0298] C48020 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0299] Step A: This compound was prepared according to general procedure A for C48014. Yield: 25%.

[0300] C68126 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0301] General Procedure A: Compound 1 (1 mmol) and K2CO3 (2 mmol) were mixed with water (20 mL). The reaction mixture was heated at 80 °C with stirring overnight, then the water was evaporated, and the Na salt of the product was treated with 50 ml of a mixture of EtOAc:THF (4:1), filtered, washed with a mixture of EtOAc:THF (4:1), and dried. Yield: 44%.

[0302] Step B: This compound was prepared according to general procedure A for C47935. Yield: 69%.

[0303] Step C: This compound was prepared according to general procedure B for C67858. Yield: 38%.

[0304] C95333 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0305] Step A: This compound was prepared according to general procedure A for C12584. Yield: 42%.

[0306] C84966 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0307] Step A: This compound was prepared according to general procedure A for C12584. Yield: 37%.

[0308] C66979 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0309] Step A: This compound was prepared according to general procedure A for C48003. Yield: 59%.

[0310] Step B: To a solution of compound 4 (0.5 mmol) in THF (2 mL), palladium on carbon (5%, 10 mg) was added, and the mixture was stirred under a hydrogen atmosphere at 80° C. for 20 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and then purified using HPLC. Yield: 14%.

[0311] C80389 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0312] Step A: This compound was prepared according to general procedure B for C80370. Yield: 25%.

[0313] C35833 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0314] Step A: This compound was prepared according to general procedure B for C47935. Yield: 96%.

[0315] General Procedure B: Compound 2 (1 mmol) was treated with 10 ml of dilute (1:3) hydrochloric acid and 10 ml of dioxane was added. The resulting suspension was cooled to 10 °C, and 10 ml of aqueous solution containing NaNO (2 mmol) was added over 2-3 min. The mixture was stirred at room temperature for 10 h, neutralized with NaHCO , and the precipitate was filtered, washed with water (3 x 25 ml), and recrystallized from the mixture DMF / i-PrOH (1 / 1). Yield: 29%.

[0316] Step C: This compound was prepared according to general procedure D for C84965. Yield: 32%.

[0317] C59904 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0318] Step A: This compound was prepared according to general procedure B for C47935. Yield: 95%.

[0319] Step A: This compound was prepared according to general procedure B for C35833. Yield: 23%.

[0320] Step C: This compound was prepared according to general procedure D for C84965. Yield: 37%.

[0321] C80390 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0322] Step A: This compound was prepared according to general procedure B for C80370. Yield: 21%.

[0323] C35754 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0324] Step A: This compound was prepared according to general procedure A for C35751. Yield: 9%.

[0325] Step B: This compound was prepared according to general procedure A for C95330. Yield: 51%.

[0326] C49708 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0327] Step A: This compound was prepared according to general procedure A for C80392. Yield: 57%.

[0328] C80380 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0329] Step A: This compound was prepared according to general procedure A for C80370. Yield: 36%.

[0330] C35797 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0331] Step A: This compound was prepared according to general procedure A for C12584. Yield: 39%. C80395 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0332] Step A: This compound was prepared according to general procedure A for C80392. Yield: 32%.

[0333] C80373 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0334] Step A: This compound was prepared according to general procedure A for C80370. Yield: 71%.

[0335] C45748 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0336] Step A: This compound was prepared according to general procedure B for C47935. Yield: 66%.

[0337] Step B: This compound was prepared according to general procedure A for C47959. Yield: 65%.

[0338] C80379 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0339] Step A: This compound was prepared according to general procedure B for C80370. Yield: 26%.

[0340] C47933 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0341] General Procedure A: Compound 1 (1 mmol) was dissolved in 10 ml of dry DMF, DMFDMA (1.2 mmol) was added, and the reaction mixture was stirred at 50 °C overnight and then diluted with water (50 mL). The solution was extracted with ethyl acetate (2 × 50 mL), and the organic phase was washed with brine (3 × 150 mL), dried over CaCl2, and evaporated to give the methyl ester 2. Yield: 88%.

[0342] General Procedure B: Compound 2 (1 mmol) was dissolved in 10 ml of dry DMF, glutarimide (1.2 mmol) was added, the reaction mixture was stirred at 90 °C for 10 h, and then the solvent was evaporated to give compound 3. The crude residue was recrystallized from the starting mixture DMF:iPrOH (1:2). Yield: 76%.

[0343] Step C: This compound was prepared according to general procedure D for C84965. Yield: 53%.

[0344] Step D: To a suspension of compound 4 (1 mmol) in dioxane (20 mL), palladium on carbon (5%, 15 mg) was added, and the mixture was stirred under a hydrogen atmosphere at 90° C. for 15 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and then purified using HPLC. Yield: 65%.

[0345] C22548 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0346] Step A: This compound was prepared according to general procedure A for C95330. Yield: 37%.

[0347] C84963 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0348] Step A: This compound was prepared according to general procedure A for C12584. Yield: 31%.

[0349] C22586 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0350] Step A: This compound was prepared according to general procedure A for C80392. Yield: 58%.

[0351] C84971 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0352] Step A: This compound was prepared according to general procedure B for C35751. Yield: 48%.

[0353] C48007 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0354] Step A: This compound was prepared according to general procedure A for C48003. Yield: 69%.

[0355] C99884 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0356] Step A: This compound was prepared according to general procedure B for C47935. Yield: 79%.

[0357] Step B: This compound was prepared according to general procedure A for C47959. Yield: 82%.

[0358] C29330 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0359] Step A: This compound was prepared according to general procedure A for C80392. Yield: 87%.

[0360] C84970 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0361] Step A: This compound was prepared according to general procedure A for C12584. Yield: 11%.

[0362] In this case, an additional amount of HOAc (3 eq) was used before isolating the product from the reaction mixture.

[0363] C29361 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0364] Step A: This compound was prepared according to general procedure A for C80392. Yield: 78%.

[0365] C22564 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0366] Step A: This compound was prepared according to general procedure A for C95330. Yield: 45%.

[0367] C48005 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0368] Step A: This compound was prepared according to general procedure A for C48003. Yield: 59%.

[0369] C80375 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0370] Step A: This compound was prepared according to general procedure A for C80370. Yield: 19%.

[0371] C48009 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0372] Step A: This compound was prepared according to general procedure A for C48003. Yield: 22%.

[0373] C80378 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0374] Step A: This compound was prepared according to general procedure A for C80370. Yield: 31%.

[0375] C21223 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0376] General Procedure A: Compound 1 (1.1 mmol) and glutarimide (1 mmol) were dissolved in dioxane (10 mL) and NEt (1.3 mmol) was added. The reaction mixture was heated at 80 °C with stirring overnight and then diluted with water (150 mL). The precipitate was filtered, washed with water (3 × 25 mL), and recrystallized from a mixture of iPrOH:water (4:1). Yield: 90%.

[0377] Step B: This compound was prepared according to general procedure B for C35833. Yield: 42%.

[0378] C13247 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0379] Step A: This compound was prepared according to general procedure A for C21223. Yield: 73%.

[0380] Step B: This compound was prepared according to general procedure B for C35833. Yield: 33%.

[0381] C35811 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0382] Step B: This compound was prepared according to general procedure A for C12584. Yield: 21%.

[0383] C80396 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0384] Step A: This compound was prepared according to general procedure A for C80392. Yield: 47%.

[0385] C64324 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0386] General Procedure A: Compound 1 (1 mmol), hydrochloride salt 2 (1 mmol), and dry NaOAc (5 mmol) were dissolved in 10 ml of dry HOAc, and the mixture was heated at 100 °C for 10-24 h (LCMS control). The reaction mixture was cooled, filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 29%.

[0387] C84967 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0388] Step A: This compound was prepared according to general procedure A for C80392. Yield: 34%.

[0389] C89940 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0390] Step A: This compound was prepared according to general procedure A for C64324. Yield: 34%.

[0391] General Procedure B: Compound 1 (1 mmol) was dissolved in 10 ml of HOAc, and NaBH4 (1 mmol) was added portionwise over 15 minutes at room temperature. The mixture was stirred at room temperature for 10 hours. TLC and LCMS control. The reaction mixture was mixed with water (25 ml), then filtered and washed with water (3 x 25 ml). The crude residue was purified using HPLC. Yield 58%.

[0392] C35830 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0393] Step A: This compound was prepared according to general procedure B for C35833. Yield: 36%.

[0394] Step B: This compound was prepared according to general procedure B for C35833. Yield: 30%.

[0395] C47995 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0396] Step A: This compound was prepared according to general procedure A for C12584. Yield: 8%.

[0397] In this case, an additional amount of HOAc (3 eq) was used before isolating the product from the reaction mixture.

[0398] C64376 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0399] Step A: This compound was prepared according to general procedure A for C64324. Yield: 31%.

[0400] C84961 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0401] Step A: This compound was prepared according to general procedure A for C12584. Yield: 11%.

[0402] C22594 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0403] Step A: This compound was prepared according to general procedure A for C95330. Yield: 34%.

[0404] C12598 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0405] Step A: This compound was prepared according to general procedure A for C95330. Yield: 81%.

[0406] Step B: This compound was prepared according to general procedure A for C12584. Yield: 19%.

[0407] C29408 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0408] Step A: This compound was prepared according to general procedure A for C80392. Yield: 68%.

[0409] C73349 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0410] Step A: This compound was prepared according to general procedure A for C95330. Yield: 86%.

[0411] Step B: Compound 2 (1 mmol), DIPEA (2 mmol) were dissolved in 10 ml of dioxane, and the mixture was heated at 90° C. for 20 hours (TLC and LCMS control). The reaction mixture was cooled, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 22%.

[0412] C12597 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0413] Step A: This compound was prepared according to general procedure A for C95330. Yield: 84%.

[0414] Step B: This compound was prepared according to general procedure A for C12584. Yield: 16%.

[0415] C98053 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0416] Step A: This compound was prepared according to general procedure B for C67858. Yield: 79%. Step B:

[0417] Compound 2 (1 mmol), Wittig reagent tertBu ester (1.1 mmol) were refluxed in 20 ml of toluene for 96 hours (TLC and LCMS control). The reaction mixture was cooled, filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 29%.

[0418] C51830 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0419] Step A: This compound was prepared according to general procedure A for C95330. Yield: 12%.

[0420] Step B: Compound 2 (1 mmol), K2CO3 (2 mmol) were dissolved in 10 ml of acetonitrile, and the mixture was heated at 80 °C for 12 h. The reaction mixture was cooled, filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 14%.

[0421] C97402 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0422] Step A: This compound was prepared according to general procedure A for C80370. Yield: 26%.

[0423] C68121 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0424] Step A: Compound 1 (1 mmol) and PPh3 (1.1 mmol) were heated in toluene (20 ml) at 80 °C for 10 h (TLC and LCMS control). The reaction mixture was cooled, filtered, and the precipitate was washed with toluene (3 x 25 ml). Yield: 94%.

[0425] Step B: Compound 2 (1 mmol) was dissolved in THF (20 ml), NaHCO (5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 50 ml of water was added, and the precipitate was filtered, washed with water, and dried. Yield: 54%.

[0426] Step C: Compounds 3 (1 mmol) and 4 (1.2 mmol) were dissolved in 10 ml of THF under Ar. NEt3 (0.1 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h and then at 50 °C for 10 h. HOAc (0.1 mol) was added and the solvent was evaporated. The residue was purified using LC. Yield: 42%.

[0427] Step D: Compound 5 (1 mmol), benzaldehyde (1.1 mmol) were refluxed in 20 ml of toluene for 96 hours (TLC and LCMS control). The reaction mixture was cooled, filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 22%.

[0428] C47998 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0429] Step A: This compound was prepared according to general procedure A for C12584. Yield: 14%.

[0430] In this case, an additional amount of HOAc (3 eq) was used before isolating the product from the reaction mixture.

[0431] C49713 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0432] Step A: This compound was prepared according to general procedure A for C80392. Yield: 39%.

[0433] Step B: Compound 2 (1 mmol) was dissolved in 10 ml of TFA and cooled to 10° C., and a solution of 3 in 5 ml of TFA was added under Ar. The reaction mixture was stirred at room temperature for 12 h, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 64%.

[0434] C36126 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0435] Step A: This compound was prepared according to general procedure A for C80392. Yield: 59%.

[0436] C39453 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0437] Step A: This compound was prepared according to general procedure A for C64324. Yield: 54%.

[0438] Step B: This compound was prepared according to general procedure B for C89940. Yield: 58%.

[0439] Step C: Compound 4 (1 mmol) was dissolved in 50 ml of methanol and refluxed for 12 hours. The solvent was evaporated. The crude residue was purified using HPLC. Yield: 83%.

[0440] Step D: Compound 5 (1 mmol) was dissolved in 10 ml of DMF and NaCN (0.5 mmol) was added. The reaction mixture was heated at 65° C. for 10 hours and refluxed for 12 hours. The mixture was filtered, washed with methanol (3×10 ml), and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 12%.

[0441] C10981 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0442] Step A: This compound was prepared according to general procedure A for C64324. Yield: 54%.

[0443] Step B: This compound was prepared according to general procedure B for C89940. Yield: 58%.

[0444] Step C: Compound 4 (1 mmol) and 40% aqueous dimethylamine (10 mmol) were dissolved in 50 ml of toluene, and 5 mg of TSA was added. The mixture was refluxed with Din-Stark 18, cooled, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 34%.

[0445] C80394 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0446] Step A: This compound was prepared according to general procedure A for C80392. Yield: 60%.

[0447] C11892 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0448] Step A: This compound was prepared according to general procedure A for C80392. Yield: 39%.

[0449] Step B: This compound was prepared according to general procedure B for C49713. Yield: 62%.

[0450] C44292 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0451] Step A: This compound was prepared according to general procedure B for C80370. Yield: 18%.

[0452] C12693 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0453] Step A: This compound was prepared according to general procedure A for C12584. Yield: 26%.

[0454] C56572 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0455] Step A: This compound was prepared according to general procedure B for C89940. Yield: 58%.

[0456] Step B: Compound 4 (1 mmol) was dissolved in 50 ml of methanol and refluxed for 12 hours. The solvent was evaporated. The crude residue was purified using HPLC. Yield: 83%.

[0457] C55468 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0458] Step A: This compound was prepared according to general procedure A for C80370. Yield: 38%.

[0459] C29490 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0460] C47997 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0461] Step A: This compound was prepared according to general procedure A for C12584. Yield: 14%.

[0462] In this case, an additional amount of HOAc (3 eq) was used before isolating the product from the reaction mixture.

[0463] C98696 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0464] Step A: This compound was prepared according to general procedure A for C80392. Yield: 72%.

[0465] Step B: Compound 2 (1 mmol) was dissolved in 10 ml of TFA, and the mixture was heated at 80° C. with stirring for 12 hours. The reaction mixture was cooled, filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield: 29%.

[0466] C12581 The synthesis of the target compound was carried out according to the scheme shown below: [ka]

[0467] Step A: This compound was prepared according to general procedure A for C12584. Yield: 22%.

[0468] Example 4: Test Results The following compounds were tested in the competition and / or recruitment assays described herein and the results are listed below. [Table 1] TIFF2026010047000139.tif242162 TIFF2026010047000140.tif242162TIFF2026010047000141.tif242162TIFF2026010047000142.tif242162TIFF2026010047000143.tif242162TIFF2026010047000144.tif242162TIFF2026010047000145.tif242162TIFF2026010047000146.tif242162TIFF2026010047000147.tif242161TIFF2026010047000148.tif242161TIFF2026010047000149.tif242161TIFF2026010047000150.tif242161TIFF2026010047000151.tif242162TIFF2026010047000152.tif242161TIFF2026010047000153.tif242161TIFF2026010047000154.tif242161TIFF2026010047000155.tif242161TIFF2026010047000156.tif242161TIFF2026010047000157.tif242161TIFF2026010047000158.tif242161TIFF2026010047000159.tif242162TIFF2026010047000160.tif242162TIFF2026010047000161.tif242161TIFF2026010047000162.tif242161TIFF2026010047000163.tif242162TIFF2026010047000164.tif242162TIFF2026010047000165.tif242162TIFF2026010047000166.tif242162TIFF2026010047000167.tif242162TIFF2026010047000168.tif242161TIFF2026010047000169.tif242161TIFF2026010047000170.tif242161TIFF2026010047000171.tif242161TIFF2026010047000172.tif242162TIFF2026010047000173.tif242162TIFF2026010047000174.tif242161TIFF2026010047000175.tif242162TIFF2026010047000176.tif242161TIFF2026010047000177.tif242161TIFF2026010047000178.tif242161TIFF2026010047000179.tif242161TIFF2026010047000180.tif242161TIFF2026010047000181.tif242161TIFF2026010047000182.tif242161TIFF2026010047000183.tif242161TIFF2026010047000184.tif242162TIFF2026010047000185.tif242161TIFF2026010047000186.tif242161TIFF2026010047000187.tif242161TIFF2026010047000188.tif242161TIFF2026010047000189.tif242161TIFF2026010047000190.tif242162TIFF2026010047000191.tif242161TIFF2026010047000192.tif242162TIFF2026010047000193.tif242162TIFF2026010047000194.tif242162. TIFF2026010047000195.tif242162TIFF2026010047000196.tif242162TIFF2026010047000197.tif242162TIFF2026010047000198.tif242162TIFF2026010047000199.tif242161TIFF2026010047000200.tif242161TIFF2026010047000201.tif242161TIFF2026010047000202.tif242162TIFF2026010047000203.tif242162TIFF2026010047000204.tif242161TIFF2026010047000205.tif242161TIFF2026010047000206.tif242161TIFF2026010047000207.tif242161TIFF2026010047000208.tif242161TIFF2026010047000209.tif242161TIFF2026010047000210.tif242162 TIFF2026010047000211.tif242162TIFF2026010047000212.tif242162TIFF2026010047000213.tif242161TIFF2026010047000214.tif242161TIFF2026010047000215.tif242161TIFF2026010047000216.tif242161TIFF2026010047000217.tif242162TIFF2026010047000218.tif242161TIFF2026010047000219.tif242161TIFF2026010047000220.tif242161TIFF2026010047000221.tif242162TIFF2026010047000222.tif242161TIFF2026010047000223.tif242162TIFF2026010047000224.tif242162TIFF2026010047000225.tif242162TIFF2026010047000226.tif242162TIFF2026010047000227.tif242162TIFF2026010047000228.tif242162TIFF2026010047000229.tif242161TIFF2026010047000230.tif242161TIFF2026010047000231.tif242161TIFF2026010047000232.tif242161

Claims

1. Compound of Formula II 【Chemistry 2】 or a pharmaceutically acceptable salt thereof (In the formula, R ２ is aryl, —NH—(C ３ -C １０ ) heteroaryl, or —N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ and any of which may contain one or more R ｗ may be optionally substituted with a group; R ５ is independently H, (C １ -C ３ ) alkyl, (C ３ -C １０ ) heterocyclo, (C ３ -C １０ ) cycloalkyl, —(CH ２ ) ｎ -(C ３ -C １０ ) cycloalkyl, —(CH ２ ) ｎ -(C ３ -C １０ ) heterocyclo, -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ -heteroaryl, aryl, or heteroaryl, any of which may be one or more R as allowed by valence. ｗ may be optionally substituted with a group; R ６ each occurrence independently represents OH, (C １ -C ３ ) alkyl, -(C １ -C ３ ) alkoxy, (C ３ -C １０ ) heterocyclo, (C ３ -C10) cycloalkyl, -(CH ２ )n-(C ３ -C １０ ) cycloalkyl, —(CH ２ )n-(C ３ -C １０ ) heterocyclo, -(CH ２ ) n-aryl, —(CH ２ ) n-heteroaryl, aryl, heteroaryl, or R ５ and R ６ together with the atoms to which they are attached form nitrogen-containing (C ３ -C １０ ) heterocyclic rings, any of which may contain one or more R ｗ may be optionally substituted with a group; R ｗ is, at each occurrence, independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are not limited to halo, cyano, oxo (C ３ -C １０ ) heterocyclo, (C ３ -C １０ ) cycloalkyl, —(CH ２ ) ｎ -(C ３ -C １０ ) cycloalkyl, —(CH ２ ) ｎ -(C ３ -C １０ ) heterocyclo, -(CH ２ ) ｎ -aryl, -(CH ２ ) ｎ -can be further independently substituted with one or more groups selected from the group consisting of heteroaryl, aryl, and heteroaryl; X is a bonding group, —SO ２ -, -(CH ２ ) ｎ C(O)(CH ２ ) ｍ -, -C(O)NH-, -C(O)N(R ｗ )-, -NHC(O)NH-, or -(CH ２ ) ｎ - and; m is 0, 1, 2, 3, or 4; and n is 0, 1, 2, 3, or 4.

2. R ２ is -N(R ５ )-(CH ２ )m-X-(CH ２ ) n-R ６ and R ５ is H; R ６ is OH, (C １ -C ３ ) alkyl, -(C １ -C ３ ) alkoxy, —NR ５ R ５ , (C ３ -C １０ ) heterocyclo, (C3-C １０ ) cycloalkyl, —(CH ２ )n-(C ３ -C １０ ) cycloalkyl, —(CH ２ )n-(C ３ -C １０ ) heterocyclo, -(CH ２ ) n-aryl, —(CH ２ ) n-heteroaryl, aryl, or heteroaryl; The compound of claim 1.

3. R ２ is one or more R as allowed by the valence ｗ phenyl optionally substituted with a group, and —NH—(C ３ -C １０ ) heteroaryl.

4. The compound is 3-[1-oxo-5-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2,6-dione.

5. The compound is 3-[5-[(4-aminothieno[2,3-d]pyrimidin-2-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione.

6. The compound is N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]acetamide.

7. The compound is 3-[5-[(2-aminopyrimidin-4-yl)amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione.

8. The compound is 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]pyridazine-3-carbonitrile.

9. The compound is 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetyl]amino]benzamide.

10. The compound is 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetic acid.

11. A composition comprising a pharmaceutically effective amount of a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. 12. The composition of claim 11 for use in treating a disease.

13. The composition for use according to claim 12, wherein the disease is cancer.

14. The cancer may be squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemia, lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, for example, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, adipose tissue cancer, or the like.

14. The composition for use of claim 13, wherein the tumor is selected from the group consisting of liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, schwannoma, testicular tumor, thyroid carcinoma, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

15. 15. The composition for use according to claim 14, wherein the cancer is multiple myeloma.

16. 13. The composition for use according to claim 12, wherein the disease is an autoimmune disease or disorder.

17. 17. The composition for use of claim 16, wherein the autoimmune disease or disorder is selected from multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barré syndrome, scleroderma, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary biliary sclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prophylaxis of allograft rejection), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, and other autoimmune diseases or disorders.

18. 12. The composition of claim 11 for use in modulating cereblon, modulating proteasomal degradation of proteins, or modulating sequestration of proteins in the proteasome.

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