Compounds that regulate protein recruitment and / or degradation

Abstract

The present invention provides cereblon-binding agents for the degradation of proteins by the ubiquitin-proteasome pathway for therapeutic use.

Description

[Technical Field]

[0001] The present invention provides, as further described herein, a cerebron conjugate for the degradation of proteins via the ubiquitin-proteasome pathway for therapeutic purposes.

[0002] Cross-reference with related applications This application claims the benefits of U.S. Provisional Application No. 62 / 949,027, filed on 17 December 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). UPP is essential for regulating almost all cellular processes.

[0004] The covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligase marks the protein for proteasomal degradation, where the protein is digested into small peptides, and finally into its constituent amino acids, which function as building blocks for new proteins.

[0005] Thalidomide and its analogs have been found to bind to the ubiquitin ligase cereblon and reorient 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 Cullin4 and the E2-binding protein ROC1 (known as RBX1), which functions as a substrate receptor for selecting 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] The object of the present invention is to provide novel compounds that bind to cereblon and their use for the treatment of various diseases and disorders, for example by modulating proteolysis.

Summary of the Invention

Problems to be Solved by the Invention

[0007] Novel compounds that bind to cereblon are provided, together with their uses and manufacture. Without wishing to be bound by theory, it is believed that binding of the disclosed compounds to cereblon results in an increase or decrease in the interaction of cereblon with one or more of IKZF1, SALL4, and ASS1, leading to their subsequent ubiquitination and proteasomal degradation. The selected compounds have been found to be potent binders of cereblon and to exhibit potential therapeutic uses. Thus, in various embodiments, the compounds are “molecular glues” and can therefore bind, for example, to protein surfaces or interfaces on cereblon, stabilize interactions (s) with another protein, and potentially lead to activation or inhibition of a cellular response (e.g., ubiquitination and degradation in the proteasome).

[0008] The compounds, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof disclosed herein can be used for treating 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 invention are of formula I:

Chemical formula

[0010] In one embodiment, the compound of the present invention is of formula II: [ka] or selected from its pharmaceutically acceptable salts. (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 allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0011] In one embodiment, the compound of the present invention is of formula III: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 3 This is cyano, aryl, -NH-(C3-C 10 ) Heteroaryl, (C3-C 10 ) Heterocyclo, or -N(R 5 )-(CH2) m-X-(CH2) n -R 6 where each of these is optionally substituted with one or more R w groups permitted by valence; R 5 is, independently at each occurrence, H, (C1-C3)alkyl, (C3-C 10 )heterocycle, (C3-C 10 )cycloalkyl, -(CH2) n -(C3-C 10 )cycloalkyl, -(CH2) n -(C3-C 10 )heterocycle, -(CH2) n -aryl, -(CH2) n -heteroaryl, aryl, or heteroaryl, where each of these is optionally substituted with one or more R w groups permitted by valence; R 6 is, independently at each occurrence, OH, (C1-C3)alkyl, -(C1-C3)alkoxy, (C3-C 10 )heterocycle, (C3-C10)cycloalkyl, -(CH2)n-(C3-C 10 )cycloalkyl, -(CH2)n-(C3-C 10 )heterocycle, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 together with the atom to which they are attached form a nitrogen-containing (C3-C 10 )heterocycle, where each of these is optionally substituted with one or more R w groups permitted by valence; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0012] In one embodiment, the compound of the present invention is of formula IV: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 4 These are halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2) n -R 6And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wis, each time it appears, independently, H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups are halo, cyano, oxo (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, and heteroaryl and can be further independently substituted with one or more groups selected from the group consisting of; X is a linking group, -SO2-, -(CH2) n C(O)(CH2) m -, -C(O)NH-, -C(O)N(R w )-, -NHC(O)NH-, or -(CH2) n -; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4).

[0013] In one aspect, the compound of the present invention is of formula V:

Chemical formula

[0014] In one embodiment, the compound of the present invention is of formula VI: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 16 is NH2, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence.w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0015] In one embodiment, the compound of the present invention is of formula VII: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 18 , R 19 , R 20 , R 21 These are, independently, H, halo, (C1-C3) alkyl, or -N(R) 5 )-XR 6 And, however, R 18 , R 19 , R 20 , R 21 Two or fewer substituents among them are H; or R 18 , R 19 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 19 , R 20 Together with the carbon to which they are attached, (C3-C10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 20 , R 21 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form heterocycloids, and each of these is allowed by one or more R atoms depending on their valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0016] In one embodiment, the compound of the present invention is of formula VIII: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 8 , R 9 , R 10 , R 11Each of these is independently H, halo, OH, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, aryl, or heteroaryl, and each of these is one or more R allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; n is 0, 1, 2, 3, or 4.

[0017] In one embodiment, the compound of the present invention is of formula IX: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 12 , R 13 , R 14 , R 15 These are, independently, H, NH2, (C1-C3) alkyl, and -N(R) 5 )-(CH2)mN(R 5 )-XR 6And, however, R 12 , R 13 , R 14 , and R 15 Three or fewer substituents are H, and each of them has one or more R atoms allowed by valence. w It can be arbitrarily substituted in the base; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0018] In one embodiment, the compound of the present invention is of formula X: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, 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 It combines with the carbon to which it is attached to form a carbon-carbon double bond; R 33 These are aryl, heteroaryl, (C3-C 10 ) are heterocycloidal, and each of these allows one or more R by valence w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; n is 0, 1, 2, 3, or 4.

[0019] In one embodiment, the compound of the present invention is selected from the group consisting of the following: 3-[1-oxo-5-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidine-2-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]acetamide; 3-[5-[(2-aminopyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]aminoacetyl]aminobenzamide; 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]aminoacetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindoline-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-methylacetamide; Acetic acid; 3-[1-oxo-6-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxopyrazine-2-yl)amino]-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxaline-2-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione 3-[6-(5,7-dihydrofl[3,4-d]pyrimidine-2-ylamino)-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-phenyl-acetamide; 3-[6-[[2-(2,4-dimethylpiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-(dimethylamino)-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N,N-dimethylacetamide; 3-[6-[[2-(2-methylmorpholine-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]-N-methyl-N-[(1-methylpyrazole-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; N-Cyclopropyl-2-[[2-(2,6-Dioxo-3-Piperidyl)-3-Oxo-Isoindorin-5-yl]aminoacetamide; 3-[1-oxo-6-(2-oxoimidazolidine-1-yl)isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino acid; 2-Acetamide-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 3-[6-[[2-(3-methyl-5-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetic acid; 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-7-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-4-carbonitrine; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-4-yl]aminoacetic acid; 3-(7-fluoro-1-oxo-isoindorin-2-yl)piperidine-2,6-dione; 3-(5-amino-1-oxo-3,4-dihydroisoquinoline-2-yl)piperidine-2,6-dione; t-butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-yl]acetate; 3-[1-(2H-indole-3-yl)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-carbonitrile; 3-[1-(dimethylamino)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidine-1-yl)piperidine-2,6-dione; 3-(Quinazoline-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(Quinoxaline-2-ylamino)piperidine-2,6-dione; 3-(pyrimidine-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-benzothiazole-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 embodiment, the present invention relates to a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0021] In one embodiment, the present invention relates to a method for treating a disease, comprising administering to a subject requiring such treatment a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier.

[0022] In one embodiment, the present invention relates to a method for treating or preventing cancer, comprising administering to a subject requiring such treatment a composition comprising a pharmaceutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. In one embodiment, cancer is 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, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, uterine cancer, leukemia, lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, e.g., Ewing's sarcoma. The group is selected from angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, testicular tumor, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratoma. In one embodiment, the subject is human.

[0023] In another aspect, the present invention relates to a method for 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, scleroderma, Goodpasture syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholangiosclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allograft rejection); pernicious anemia; rheumatoid arthritis; systemic lupus erythematosus; dermatomyositis; Sjögren's syndrome; lupus erythematosus; multiple sclerosis; myasthenia gravis; Reiter's syndrome; Graves' disease; and other autoimmune diseases or disorders.

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

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

[0027]

number

[0028] When the term "alkyl" is used alone or within other terms such as "haloalkyl" or "alkylamino," it encompasses linear or branched radicals having 1 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having 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, and hexyl. Even more preferred are lower alkyl radicals having 1 or 2 carbon atoms. The terms "alkylenyl" or "alkylene" encompass cross-linked divalent alkyl radicals such as methyleneyl or ethylene. 2 The term “lower alkyl substituted with” does not include the acetal moiety. The term “alkyl” further includes alkyl radicals in which one or more carbon atoms in the chain are substituted with heteroatoms selected from oxygen, nitrogen, or sulfur.

[0029] The term "alkenyl" encompasses linear or branched radicals having at least one carbon-carbon double bond between 2 and about 12 carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having 2 to about 6 carbon atoms. The 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" encompass radicals having "cis" and "trans" orientations, or "E" and "Z" orientations.

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

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

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

[0033] The term "haloalkyl" encompasses radicals in which one or more alkyl carbon atoms are substituted with a halo as defined above. Specifically, it includes polyhaloalkyl radicals, including monohaloalkyl, dihaloalkyl, and perfluorohaloalkyl. For example, a monohaloalkyl radical may have one of the following atoms within the radical: iodo, bromo, chloro, or fluoro. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or combinations of different halo radicals. "Lower haloalkyl" encompasses radicals having 1 to 6 carbon atoms. More preferably are lower haloalkyl radicals having 1 to 3 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" refers to an alkyl radical in which all hydrogen atoms are replaced by fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

[0035] The term "hydroxyalkyl" encompasses linear or branched alkyl radicals having 1 to about 10 carbon atoms, any 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" encompasses linear or branched oxy-containing radicals, each having an alkyl moiety of 1 to approximately 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 can be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide "haloalkoxy" radicals. Even more preferred are low 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. The "aryl" group may have one or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino. Phenyl substituted with -O-CH2-O- forms an arylbenzodioxolyl substituent.

[0038] The term “heterocyclyl” (or “heterocyclo”) encompasses saturated, partially saturated, and unsaturated heteroatom-containing ring radicals, where the heteroatom can be selected from nitrogen, sulfur, and oxygen. It does not contain a ring containing an -OO-, -OS-, or -SS- moiety. 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 1-4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, piperazinyl]; saturated 3- to 6-membered heteromonocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1-2 sulfur atoms and 1-3 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 5-6 member unsaturated heteromonocyclic groups containing 1-4 nitrogen atoms, e.g., pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; 5-6 member unsaturated heteromonocyclic groups containing an oxygen atom, e.g., pyranyl, 2-furyl, 3-furyl, etc.; and 5-6 member unsaturated heterocyclic groups containing a sulfur atom. Examples include telo-monocyclic groups such as 2-thienyl and 3-thienyl; 5-6 member unsaturated hetero-monocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, e.g., oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; and 5-6 member unsaturated hetero-monocyclic groups containing 1-2 sulfur atoms and 1-3 nitrogen atoms, e.g., thiazolyl and thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

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

[0042] Specific 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 heterocyclyls include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanil, chromanil, 1,2-dihydroquinolyl, and 1,2,3,4-tetrahydro-iso Examples include quinolyl, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 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]isothiazolyl-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.

[0044] The term "heterocycloidal" therefore encompasses the following ring systems: [ka] For example, TIFF0007871189000013.tif197162.

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

[0046] The terms "sulfamyl," "aminosulfonyl," and "sulfonamidyl" refer to sulfonyl radicals that are substituted with amine radicals to form sulfonamides (-SO2NH2).

[0047] The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" radicals in which a sulfamyl radical is independently substituted with one or two alkyl radicals. More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having 1 to 6 carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having 1 to 3 carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl and N-ethylaminosulfonyl.

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

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

[0050] The term "aminocarbonyl" refers to the 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 is the "lower alkylaminocarbonyl," which has the aforementioned lower alkyl radical attached to the aminocarbonyl radical.

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

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

[0054] The term "aralkyl" encompasses 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 an alkyl moiety 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" encompasses radicals including linear or branched alkyl radicals with 1 to 10 carbon atoms attached to a divalent sulfur atom. More preferably are lower alkylthio radicals having 1 to 3 carbon atoms. An example of "alkylthio" is methylthio(CH3S-).

[0056] The term "haloalkylthio" encompasses radicals containing 1 to 10 carbon atoms attached to a divalent sulfur atom, including haloalkyl radicals. More preferably, lower haloalkylthio radicals have 1 to 3 carbon atoms. An example of a "haloalkylthio" is trifluoromethylthio.

[0057] The term "alkylamino" encompasses "N-alkylamino" and "N,N-dialkylamino," where the 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 1 to 6 carbon atoms attached to the nitrogen atom. Even more preferred are lower alkylamino radicals having 1 to 3 carbon atoms. Preferred alkylamino radicals may be mono- or dialkylaminos such as N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino.

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

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

[0060] The term "aralkylamino" refers to an amino group that is substituted with one or two aralkyl radicals. More preferably, these are phenyl-C1-C3-alkylamino radicals, such as N-benzylamino. The aralkylamino radical can be further substituted at the aryl ring moiety.

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

[0062] The term "aminoalkyl" encompasses linear or branched 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" encompasses alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals with 1 to 6 carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals with 1 to 3 carbon atoms. Preferred alkylaminoalkyl radicals can be mono- or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethylaminoethyl, and N,N-diethylaminomethyl.

[0064] The term "alkylaminoalkyl" encompasses alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having 1 to 6 carbon atom alkoxy radicals. Even more preferred are lower alkylaminoalkoxy radicals having 1 to 3 carbon atom alkyl radicals. Preferred alkylaminoalkoxy radicals can be mono- or dialkyl-substituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy, and N,N-diethylaminoethoxy.

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

[0066] The term "carboxyalkyl" encompasses linear or branched alkyl radicals having 1 to about 10 carbon atoms, one of which may be substituted with one or more carboxyl radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having 1 to 6 carbon atoms and one carboxyl radical. Examples of such radicals include carboxymethyl and carboxypropyl. Even more preferred are lower carboxyalkyl radicals having 1 to 3 CH2 groups.

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

[0068] The term "arylthio" encompasses aryl radicals consisting of 6 to 10 carbon atoms attached to a divalent sulfur atom. An example of "arylthio" is phenylthio.

[0069] The term "aralkylthio" encompasses the above-mentioned aralkyl radicals attached to a divalent sulfur atom. More preferably, phenyl-C1-C3-alkylthio radicals are used. An example of "aralkylthio" is benzylthio.

[0070] The term "aryloxy" encompasses aryl radicals, as defined above, that are attached to an oxygen atom and optionally substituted. An example of such a radical is phenoxy.

[0071] The term "aralkoxy" encompasses oxy-containing aralkyl radicals attached to other radicals via an oxygen atom. A more preferred aralkoxy radical is a "lower aralkoxy" radical having an optionally substituted phenyl radical attached to a lower alkoxy radical as described above.

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

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

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

[0075] The term "cycloalkylalkyl" encompasses 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 "5-6 membered cycloalkylalkyls" attached to an alkyl moiety having 1 to 3 carbon atoms. An example of such a radical is cyclohexylmethyl. The cycloalkyl in the radical can be further substituted with halo, alkyl, alkoxy, and hydroxyl.

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

[0077] The term "comprising" means that it includes the listed components but does not exclude other elements; it is open-ended.

[0078] A group or atom that substitutes for a 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 substituted.

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

[0081] The term "therapeutic dose" means the amount of a compound that improves, 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” can be used interchangeably and refer to animals such as dogs, cats, cows, horses, sheep, and humans. A specific patient is a mammal. The term patient includes both males and females.

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

[0084] Terms such as "to treat," "to treat," or "treatment" include preventative (e.g., prophylactic) and palliative treatments.

[0085] The term "excipients" refers to any pharmaceutically acceptable additives, carriers, diluents, adjuvants, or other components other than the active pharmaceutical ingredient (API), which are typically included in formulations and / or administration to patients.

[0086] The term "cancer" refers to a physiological condition in mammals characterized by unregulated cell growth. Common classes of cancer include carcinomas, lymphomas, sarcomas, and blastomas.

[0087] composition The compounds of the present invention are administered to patients in therapeutically effective doses. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds or compositions can be administered, for example, by bolus injection, in a single dose, by a series of tablets, or by transdermal delivery, for example, substantially uniformly over a period of time. It should also be noted that the dose of the compound may vary over time.

[0088] The compounds of the present invention may be administered to a patient, as needed, orally, rectally, parenterally (e.g., intravenously, intramuscularly, or subcutaneously), intracisional, intravaginally, intraperitoneally, intravesically, topically (e.g., as a powder, ointment, or drop), or as a buccal or nasal spray. All methods used by those skilled in the art for administering pharmaceutically active agents are intended.

[0089] Compositions suitable for parenteral injection may 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 (such as propylene glycol, polyethylene glycol, and glycerol), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0090] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Microbial contamination can be prevented by adding various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. The inclusion of isotonic agents, such as sugars and sodium chloride, may also be desirable. Long-term absorption of injectable pharmaceutical compositions can be achieved by using absorption-delaying agents, 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 composed of at least one inert common excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or bulking agents, e.g., starch, lactose, sucrose, mannitol, and silicic acid; (b) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, e.g., glycerol; (d) disintegrants, e.g., agar, calcium carbonate, potato or It is mixed with tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, e.g., paraffin; (f) absorption enhancers, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin and bentonite; (i) lubricants, e.g., 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 buffers.

[0092] Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0093] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and others well known in the art. These may also contain opacifying agents, and their composition may be such that they release one or more active compounds in a delayed manner in a specific part of the intestinal tract. Examples of usable embedding compositions are polymers and waxes. The active compounds may also be in microencapsulated form, together with one or more of the above excipients, where appropriate.

[0094] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, or mixtures of these substances.

[0095] In addition to such inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances. The suspension 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 thereof.

[0096] The compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at normal room temperature but liquid at body temperature, and thus dissolve in the rectum or vaginal cavity, releasing the active ingredient.

[0097] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active or compatible compound is mixed under sterile conditions with a physiologically acceptable carrier and any necessary preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be 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 being weighing about 70 kg, a dosage ranging from about 0.01 mg to about 100 mg per kilogram of body weight is usually sufficient. The specific dosages and dosage ranges that can be used depend on many factors, including the patient's requirements, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. Determining the dosage range and optimal dosage for a particular patient is within the scope of those skilled 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 or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Typical 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, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. See, for example, SMBerge, 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. Other acceptable esters include C5-C7 cycloalkyl esters and arylalkyl 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 amine may also be in the form of a 5 or 6-membered heterocycloalkyl group containing at least one nitrogen atom. Ammonia-derived amides, 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 the compound of the present invention. Transformation can occur through various mechanisms, such as hydrolysis in the blood. Discussions regarding the use of prodrugs are published in T. Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14, the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0103] For illustrative purposes, if the compound of the present invention contains a carboxylic acid functional group, the prodrug may include an ester formed by substituting a hydrogen atom of the acid group with any of the following groups: (C1-C8 alkyl, (C2-C 12Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl with 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl with 5-10 carbon atoms, alkoxycarbonyloxymethyl with 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl with 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl with 5-8 carbon atoms, N-(alkoxycarbonyl)amino with 3-9 carbon atoms Methyl, 1-(N-(alkoxycarbonyl)aminomethyl) having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-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 the compounds of the present invention contain an alcohol functional group, the prodrug may be formed by substituting the hydrogen atoms of the alcohol group with any group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)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)2, -P(O)(O(C1-C6)alkyl)2, or glycosyl (a radical resulting from the removal of a hydroxyl group from the 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, including racemic mixtures, and mixtures thereof, are intended to form part of the present invention. Furthermore, the present invention intends all geometric and positional isomers. For example, if the compound contains a double bond, both cis and trans forms (designated S and E, respectively), and mixtures thereof are intended.

[0106] Mixtures of stereoisomers, such as diastereomer mixtures, can be separated into their individual stereochemical components based on their physicochemical differences by known methods such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomer mixture into a diastereomer mixture through reaction with a suitable optically active compound (e.g., an alcohol), separating the diastereomers, and converting the individual diastereomers back into their corresponding pure enantiomers (e.g., by hydrolysis). In addition, some compounds may be atropisomers (e.g., substituted biaryls).

[0107] The compounds of the present invention can exist in both solvated and solvated forms using pharmaceutically acceptable solvents such as water (hydrate) and ethanol. The present invention intends to encompass both solvated and solvated forms.

[0108] The compounds of the present invention may also exist in different tautomer forms. All tautomers of the compounds of the present invention are intended. For example, all tautomer forms of the tetrazole moiety are included in the present invention. Also, for example, all ketoenol or imine enamine forms of the compounds are included in the present invention.

[0109] Those skilled in the art will recognize that the names and structures of compounds included herein may be based on specific tautomers of the compounds. While only the names or structures of specific tautomers may be used, all tautomers are intended to be included in the present invention unless otherwise specified.

[0110] It is also intended that the present invention may encompass compounds synthesized in vitro using experimental techniques such as those well known to synthetic chemists, or compounds synthesized using in vivo techniques such as metabolism, fermentation, or digestion. It is also intended 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 isotope-labeled compounds, which are identical to those described herein, but in which one or more atoms are substituted with atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 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 Cl is an example. In one embodiment, the present invention relates to a compound in which one or more hydrogen atoms are substituted with deuterium (2H) atoms.

[0112] Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Specific isotope-labeled compounds of the present invention, for example, 3 H and 14 The incorporation of radioactive isotopes such as 13C is useful in drug and / or substrate tissue distribution assays. Tritiation, i.e. 3 H, and carbon 14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, heavier isotopes such as deuterium, i.e. 2Substitution with H can result in greater metabolic stability, for example, certain therapeutic benefits arising from an increased in vivo half-life or a reduction in the required dosage, and is therefore preferable in some situations. The isotope-labeled compounds of the present invention can generally be prepared by replacing the non-isotopically labeled reagent with a readily available isotope-labeled reagent.

[0113] The compounds of the present invention can exist in various solid states, including crystalline states, and in amorphous states. Different crystalline states, also called polymorphs, and amorphous states of the compounds of the present invention are intended as part of the present invention.

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

[0115] compound The present invention relates to novel compounds that can bind cereblon (CRBN) but have varying degrees of ability to recruit responsible substrate proteins such as SALL4 and ASS1, and varying degrees of ability to recruit more common substrates such as IKZF1 to CRBN. The different recruitment profiles among CRBN-binding molecules create a new starting point for selective small molecule substrate degradation adhesives, either alone or as regulatory components of CRBN-binding heterobifunctional molecules (HBMs). The recruitment profiles of important susceptibility substrates provide an objective means for prioritizing and selecting promising small molecules. In one embodiment, some CRBN-binding compounds described herein reduce CRBN's ability to recruit selected susceptibility substrates such as SALL4 and ASS1, and common substrates such as IKZF1, after binding to CRBN. These compounds are referred to as “silent” compounds. In one embodiment, some CRBN-binding compounds described herein increase CRBN's ability to recruit selected susceptibility substrates after binding to CRBN.

[0116] CRBN acts as a substrate receptor protein within the E3 ligase complex, inducing proteasome-mediated degradation of substrate proteins and forming functional interactions with DNA damage-binding protein 1 (DDB1), Cullin4 (4A or 4B), Cullin1 regulator (RoC1), and E2 ligase proteins such as UBE2G1 for substrate ubiquitination and subsequent degradation.

[0117] Small molecules derived from glutarimide-containing drugs (IMiDs) and thalidomide have been shown to bind to CRBN and, as a complex, recruit novel substrates to the E3 ligase complex.

[0118] The result of IMiD-induced recruitment of substrate proteins to CRBNs is that these proteins are subsequently degraded via the ubiquitin-proteasome pathway (UPP).

[0119] Novel compounds for conjugating cereblon are provided, along with their applications and manufacturing methods. The binding of the disclosed compounds to cereblon is thought to result in increased or decreased interactions of cereblon with IKZF1, SALL4, and ASS1, leading to subsequent ubiquitination and degradation in the proteasome. The selected compounds have been found to be potent conjugates of cereblon while also exhibiting potential therapeutic applications.

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

[0121] In one embodiment, the compound of the present invention is of formula I: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 1 is aryl, -N(R 5 )-XR 6, -SO2R 5 , or -O(CH2) m R 5 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0122] In one embodiment, R 1 This is one or more R allowed by valence. w It is a phenyl compound that is optionally substituted with a group.

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

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

[0125] In one embodiment, the compound of the present invention is of formula II: [ka] or selected from its pharmaceutically acceptable salts. (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 allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0126] In one embodiment, R 2 This is one or more R allowed by valence. wIt is a phenyl compound that is optionally substituted with a group.

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

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

[0129] In one embodiment, R 2 is -N(R 5 )-(CH2)mX-(CH2)nR 6 And; R 5 H is; 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 ) are heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl.

[0130] In one embodiment, the compound of the present invention is of formula III: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 3 This 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 allows one or more R by valence. w The base, which can be optionally replaced; R 5Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; 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 H is; 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 ) are heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl.

[0132] In one embodiment, the compound of the present invention is of formula IV: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 4 These are halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2) m -X-(CH2)n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; 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 H is; 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 ) are heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl.

[0134] In one embodiment, the compound of the present invention is of formula V: [ka] or selected from its pharmaceutically acceptable salts. (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 allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

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

[0136] In one embodiment, the compound of the present invention is of formula VI: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 16 is NH2, or -N(R 5 )-(CH2) m -X-(CH2) n -R 6 And any of these allows one or more R by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0137] In one embodiment, the compound of the present invention is of formula VII: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 18 , R 19 , R20 , R 21 These are, independently, H, halo, (C1-C3) alkyl, or -N(R) 5 )-XR 6 And, however, R 18 , R 19 , R 20 , R 21 Two or fewer substituents among them are H; or R 18 , R 19 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 19 , R 20 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 20 , R 21 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form heterocycloids, and each of these is allowed by one or more R atoms depending on their valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0138] In one embodiment, the compound of the present invention is of formula VIII: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 8 , R 9 , R 10 , R 11 Each of these is independently H, halo, OH, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, aryl, or heteroaryl, and each of these is one or more R allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; n is 0, 1, 2, 3, or 4.

[0139] In one embodiment, the compound of the present invention is of formula IX: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, R 12 , R 13 , R 14 , R 15 These are, independently, H, NH2, (C1-C3) alkyl, and -N(R) 5 )-(CH2)mN(R 5 )-XR 6 And, however, R 12 , R 13 , R 14 , and R 15 Three or fewer substituents are H, and each of them has one or more R atoms allowed by valence. w It can be arbitrarily substituted in the base; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

[0140] In one embodiment, the compound of the present invention is of formula X: [ka] or selected from its pharmaceutically acceptable salts. (In the formula, 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 These, together with the carbon to which they are attached, form a carbon double bond; R 33 These are aryl, heteroaryl, (C3-C 10 ) are heterocycloidal, and each of these allows one or more R by valence w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; n is 0, 1, 2, 3, or 4.

[0141] In one embodiment, the compound of the present invention is of formula XI: [ka] or a pharmaceutically acceptable salt thereof. (In the formula, R 22 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, and any of these is allowed by valence to contain one or more R w The base, which can be optionally replaced; 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 ) Forms a heterocyclic ring, and each of these rings contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 24 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 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w It can be optionally substituted by the base; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R wEach instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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 -Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

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

[0143] In one embodiment, the present invention relates to compounds of formula XII, XIII, XIV, XV, XVI, XVII, or XVIII. [ka] or relating to its pharmaceutically acceptable salts (In the formula, R 28 , R 29 , R 30 , R 31 These are independently H, Halogen, OH, and -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 ) form a heterocycloid, or R 30 , R 31 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) form a heterocycloid, or R 29 , R 30 They either combine to form a bonding group, or R 29 , R 30 Together with the carbon to which they are attached, (C3-C 10 )Cycloalkyl or (C3-C 10 ) Forming heterocyclo, aryl, or heteroaryl atoms, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 5 Each instance independently produces H, (C1-C3) alkyl, and (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 -A heteroaryl, aryl, or heteroaryl, each of which contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R 6 Each instance independently produces OH, (C1-C3)alkyl, -(C1-C3)alkoxy, and (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 atom to which they are attached, nitrogen-containing (C3-C 10 ) form a heterocycle, and each of these contains one or more R atoms allowed by valence. w The base, which can be optionally replaced; R w Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are halo, cyano, oxo (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-Can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; 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; n is 0, 1, 2, 3, or 4.

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

[0145] In one embodiment, the compound of the present invention is selected from the group consisting of the following: 3-[1-oxo-5-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidine-2-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]acetamide; 3-[5-[(2-aminopyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-yl]aminoacetyl]aminobenzamide; 2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindorin-5-yl]aminoacetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindoline-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-methylacetamide; Acetic acid; 3-[1-oxo-6-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxopyrazine-2-yl)amino]-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxaline-2-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione 3-[6-(5,7-dihydrofl[3,4-d]pyrimidine-2-ylamino)-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-phenyl-acetamide; 3-[6-[[2-(2,4-dimethylpiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-(dimethylamino)-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N,N-dimethylacetamide; 3-[6-[[2-(2-methylmorpholine-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]-N-methyl-N-[(1-methylpyrazole-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitrile; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidine-4-yl)amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; N-Cyclopropyl-2-[[2-(2,6-Dioxo-3-Piperidyl)-3-Oxo-Isoindorin-5-yl]aminoacetamide; 3-[1-oxo-6-(2-oxoimidazolidine-1-yl)isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino acid; 2-Acetamide-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetamide; 3-[6-[[2-(3-methyl-5-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]aminoacetic acid; 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindorin-2-yl]piperidine-2,6-dione; 3-(1-oxo-7-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorine-4-carbonitrine; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-4-yl]aminoacetic acid; 3-(7-fluoro-1-oxo-isoindorin-2-yl)piperidine-2,6-dione; 3-(5-amino-1-oxo-3,4-dihydroisoquinoline-2-yl)piperidine-2,6-dione; t-butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-yl]acetate; 3-[1-(2H-indole-3-yl)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-1-carbonitrile; 3-[1-(dimethylamino)-3-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidine-1-yl)piperidine-2,6-dione; 3-(Quinazoline-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(Quinoxaline-2-ylamino)piperidine-2,6-dione; 3-(pyrimidine-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-benzothiazole-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 embodiment, the present invention relates to a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0147] In one embodiment, the present invention relates to a method for treating a disease, comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject requiring such treatment.

[0148] In one embodiment, the present invention relates to a method for treating cancer, comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject requiring it. In one embodiment, the cancer is 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, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, uterine cancer, leukemia, lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcoma, e.g., Ewing's sarcoma. The group is selected from angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, testicular tumor, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratoma.

[0149] In another embodiment, the present invention relates to a method for treating or preventing one or more autoimmune diseases or disorders, comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject in need thereof. 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, scleroderma, Goodpasture syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholangiosclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allograft rejection); pernicious anemia; rheumatoid arthritis; systemic lupus erythematosus; dermatomyositis; Sjögren's syndrome; lupus erythematosus; multiple sclerosis; myasthenia gravis; Reiter's syndrome; Graves' disease; and other autoimmune diseases or disorders.

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

[0151] In another embodiment, the present invention relates to a method for preparing cereblon, comprising administering a composition comprising compounds of formulas I to XVIII to a subject requiring it. In one embodiment, the present invention relates to a method for preparing cereblon, comprising administering a composition comprising compounds selected from those listed in Table 1 of Example 4 to a subject requiring it.

[0152] In another embodiment, the present invention relates to a method for regulating proteasomal degradation of proteins, comprising administering a composition comprising compounds of formulas I to XVIII to a subject requiring such composition. In one embodiment, the present invention relates to a method for regulating proteasomal degradation of proteins, comprising administering a composition comprising compounds selected from those listed in Table 1 of Example 4 to a subject requiring such composition.

[0153] In another embodiment, the present invention relates to a method for regulating protein sequestration to the proteasome, comprising administering a composition comprising compounds of formulas I to XVIII to a subject requiring such composition. In one embodiment, the present invention relates to a method for regulating protein sequestration to the proteasome, comprising administering a composition comprising compounds selected from those listed in Table 1 of Example 4 to a subject requiring such composition.

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

[0155] Example 1: Competitive Assay CRBN binding was evaluated using a MAPPIT-like assay that determines the ability of test compounds to compete with trimethoprim-lenalidomide hybrid ligands for binding to intracellular CRBN. For example, the conventional 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, is used to monitor protein-protein interactions. Bait protein (protein A) is expressed as a fusion protein in which it is gene-fused to an engineered intracellular receptor domain of the leptin receptor, and the leptin receptor itself is fused to the extracellular domain of the erythropoietin (Epo) receptor. Binding of the Epo ligand to the EpoR component results in activation of receptor-associated intracellular JAK2. However, the activated JAK2 cannot activate the leptin receptor to cause STAT3 binding and its phosphorylation because the tyrosine residue that is normally phosphorylated by activated JAK2 is mutated. The reconfiguration of the JAK2 phosphorylation-enabled STAT3 docking site is instead created by the interaction of protein B and protein A, thereby fusing protein B to the cytoplasmic domain of the gp130 receptor (which now possesses the appropriate tyrosine, which is recognized by activated JAK2 kinase). Thus, the physical interaction of protein A with protein B is reconfigured, 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 gene encoding a fluorescent marker such as GFP or several other types of fluorescent proteins (e.g., EGF). Thus, the MAPPIT assay provides a versatile assay for evaluating such recombinant protein-protein interactions, or compound or hybrid ligand-induced protein-protein interactions, in intact cells.

[0156] Here, a similar MAPPIT-like assay was used to determine the ability of test compounds to compete with trimethoprim-lenalidomide-induced binding between DHFR and CRBN. Therefore, using HEK293 cells transfected with appropriate cDNA encoding the transgene (encoding the DHFR and CRBN fusion proteins), a positive assay signal was generated as a result of ternary protein / compound complex formation, including the formation of a DHFR-TMP-LEN-CRBN complex, which involves the DHFR fusion protein trimethoprim (TMP)-lenalidomide hybrid ligand (TMP being the ligand for DHFR) and the CRBN-gp130 fusion protein (CRBN binding to the ligand lenalidomide). Complex formation resulted in activation of a STAT-responsive luciferase reporter gene, setting its signal to 100% luciferase activity. In a different sample setup, cells were prepared in the same manner but co-cultured with the test compound, further examining its interaction with CRBN. Binding to the CRBN fusion protein competes with the binding of the hybrid ligand to the same CRBN protein, and therefore inhibits the assay signal by preventing the formation of the ternary complex required to generate the assay signal. The CRBN binding efficiency determined in this type of ligand competition experiment in live cells was determined by evaluating the increasing concentration of the test compound. The specificity of signal inhibition was evaluated by parallel experimental settings, where the effect of the test compound was assessed for inhibition of the signal (i.e., direct protein interaction) generated by the control gp130 fusion protein (CTRL) that directly binds to the DHFR fusion protein in the absence of the hybrid ligand.

[0157] More specifically, HEK293T cells were cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum at 37°C and 8% CO2. The cells were transfected with plasmids encoding *E. coli* dihydrofolate reductase (DHFR) fused to the tail of the cytoplasmic domain of the mutant leptin receptor (pCLG-eDHFR), plasmids encoding a CRBN prey fused to the gp130 cytoplasmic domain (pMG1-CRBN), plasmids encoding a REM2 control prey capable of directly interacting with the leptin receptor (pMG1-REM2) of the DHFR fusion protein, and a STAT3-responsive pXP2d2-rPAPI-luciferase reporter plasmid. These were transfected 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 24 hours after transfection, cells were supplemented with 300 nM of the trimethoprim-lenalidomide fusion compound (a hybrid ligand in which trimethoprim interacts with DHFR and lenalidomide interacts with CRBN), either without the test compound or with the indicated dose of the test compound. Luciferase activity induced by the formation of a ternary complex containing DHFR-trimethoprim-lenalidomide-CRBN and the resulting activation of STAT3 signaling was measured 24 hours after compound treatment using a luciferase assay system kit (PROMEGA, Madison, WI) equipped with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA).The data points represent the mean luciferase activity of three samples, compared to leptin (CTRL) or leptin + hybrid ligand (CRBN) treated with the REM2 control (CTRL), for which the cells were treated with either leptin + test compound or leptin + hybrid ligand + test compound (CRBN). (In both cases, the signal obtained without the test compound is set to 100% of luciferase activity on the y-axis.) Error bars represent the standard deviation. The curves were fitted using GRAPHPAD PRISM software with 4-parameter nonlinear regression.

[0158] Example 2: Mobilization Assay: In this Example 2, a MAPPIT-like assay similar to that described in Example 1 was applied to determine the inducible binding of the test compound to the specific substrate protein of interest to CRBN. In this experimental setup, 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 evaluated by increasing the concentration of the test compound to monitor its ability to promote CRBN-ligand-induced protein interactions (dose-response study).

[0159] Specifically, HEK293T cells were transfected with plasmids encoding MAPPIT receptor fusion. Here, the target protein (CRBN or substrate protein) is genetically linked to the cytoplasmic domain of the leptin receptor, which in turn is fused to the extracellular domain of the erythropoietin (Epo) receptor (pSEL-X (where X represents either CRBN or the target substrate protein of interest)), a plasmid encoding MAPPIT gp130 fusion (pMG1-Y (where Y is either the target substrate protein or CRBN)), and a reporter plasmid encoding STAT3-responsive luciferase (pXP2d2-rPAPI-luciferase reporter plasmid). These plasmids are described in Lievens, et al. "Array MAPPIT: high-throughput interactome analysis in mammalian cells," Journal of Proteome Research. (As described in 8.2(2009):877-886). Full-size proteins were fused to each of the target proteins tested, except for IKZF1, which used isoform 7. In this study, the following were used: Recruitment of IKZF1: pSEL-CRBN+pMG1-IKZF1 (isoform 7); Recruitment of ASS1: pSEL-CRBN+pMG1-ASS1; Recruitment of SALL4: pSEL-SALL4+pMG1-CRBN. Cells were treated with erythropoietin (Epo) 24 hours after transfection, with or without the indicated dose of the test compound. Luciferase activity was measured using the Luciferase Assay System kit (PROMEGA, Madison, WI) and the Ensight plate reader (PERKIN ELMER LIFE). Measurements were taken 24 hours after treatment with the test compound using SCIENCES, Waltham, MA. The data points represent the induction ratio of mean luciferase activity from three samples: cells treated with EPO+ and cells treated with EPO alone. Error bars represent the standard deviation. Curves were fitted using 4-parameter nonlinear regression in GRAPHPAD PRISM software.

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

[0161] When synthesizing the compounds of the present invention, it may be desirable to use specific leaving groups. The term "leaving group" ("LG") generally refers to a group that can be substituted by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups, but not limited to these, include halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylates, tosylates), sulfides (e.g., SCH3), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles, but not limited to these, include amines, thiols, alcohols, Grignard reagents, and anionic species (e.g., alkoxides, amides, carbanions).

[0162] HPLC purification Purification was performed using HPLC (H2O-MeOH; Agilent 1260 Infinity system with DAD and mass detector). The material was dissolved in 0.7 mL DMSO using a Waters Sunfire C18 OBD preparative column, 100 A (angstrom), 5 μm, 19 mm x 100 mm, and a SunFire C18 Prep Guard Cartridge, 100 A (angstrom), 10 μm, 19 mm x 10 mm. Flow rate: 30 mL / min. The purity of the obtained fractions was confirmed by analytical LC-MS. Spectra were recorded for each fraction as soon as they were obtained after chromatography in solution form. The solvent was evaporated in an N2 flow at 80°C. The fractions were combined based on LC-MS analysis after chromatography. The solids were dissolved in 0.5 mL MeOH and transferred to pre-weighed marked vials. The resulting solutions were again evaporated in an N2 flow at 80°C. After drying, the product is finally subjected to LC-MS and 1 The compounds were characterized by 1H NMR. For clarity, hydrogen atoms are not shown in the synthesis scheme in this section for simplification. For example, "-NH2" 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) and SL (G1956B) mass spectrometers. Agilent 1200 series LC / MSD system equipped with DAD\ELSD and Agilent LC\MSD SL (G6130A) and SL (G6140A) mass spectrometers. All LC / MS data were obtained using positive / negative mode switching. Zorbax SB-C18 1.8μm 4.6x15mm Rapid Resolution Column 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 target compound was synthesized 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 mixture was stirred overnight at room temperature, then diluted with water (150 mL). The solution was extracted with ethyl acetate (2 x 200 mL), the organic phase was washed with brine (3 x 150 mL), dried over CaCl2, and evaporated to obtain methyl ester 2. Yield: 94%.

[0166] General procedure B: To a solution of compound 2 (1.6 mmol) in CCl4 (3 ml), AIBN (0.1 mmol) and NBS (2 mmol) were added and incubated at 25°C for 15 minutes. The reaction mixture was heated at 60°C for 12 hours and then cooled to room temperature. The solvent was then removed by vacuum. The crude residue was purified by 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 of 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 target compound was synthesized 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), N-bromosuccinimide (17 g, 95.4 mmol) was gradually added over 30 minutes at 0°C. The mixture was heated to 20°C and stirred for 3 hours, then treated with 40% sodium bisulfate aqueous solution (100 mL). Acetonitrile was removed by vacuum, and the aqueous residue was extracted with toluene (3 x 40 mL). The combined organic layers were washed with water and brine, dried, and concentrated to obtain 16 g of 3-bromo-6-hydroxy-2-methylbenzoic acid as a white solid. 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 the general procedure C of C24031. Yield: 42%.

[0172] C07207 The target compound was synthesized 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 the general procedure C of C24031. Yield: 87%. Step C:

[0175] To a solution of compound 4 (0.5 mmol) in methanol (2 mL), palladium-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 target compound was synthesized 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 of MeOH, and the mixture was heated at 80°C for 12 hours. TLC and LCMS control were performed. The reaction mixture was cooled, then filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield 58%.

[0178] C28558 The target compound was synthesized according to the scheme shown below: [ka]

[0179] Step A: This compound was prepared according to general procedure A of 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 the general procedure C of C24031. Yield: 67%.

[0181] C28577 The target compound was synthesized according to the scheme shown below: [ka]

[0182] Step A: This compound was prepared according to general procedure A of 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 the general procedure C of C24031. Yield: 81%.

[0185] C28620 The target compound was synthesized according to the scheme shown below: [ka]

[0186] Step A: This compound was prepared according to general procedure A of 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 the general procedure C of C24031. Yield: 72%.

[0189] C28661 The target compound was synthesized according to the scheme shown below: [ka]

[0190] Step A: This compound was prepared according to general procedure A of 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 the general procedure C of C24031. Yield: 64%.

[0193] C28891

[0194] The target compound was synthesized 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 the general procedure C of C24031. Yield: 62%.

[0197] C28928 The target compound was synthesized 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 the general procedure C of C24031. Yield: 55%.

[0200] C28973 The target compound was synthesized according to the scheme shown below: [ka]

[0201] Step A: To a stirred solution of compound 1 (10 mmol) in acetone (10 mL), anhydrous potassium carbonate powder (20 mmol) was added. Dimethyl sulfate (12 mmol) was gradually added at room temperature over approximately 10 minutes. After the addition was complete, the solution was heated to reflux temperature 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 the general procedure C of C24031. Yield: 74%.

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

[0205] C47927 The target compound was synthesized according to the scheme shown below: [ka]

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

[0207] Step B: To a solution of compound 4 (0.5 mmol) in methanol (2 mL), palladium-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: 79%.

[0208] C47959 The target compound was synthesized 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 of 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 target compound was synthesized 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 an aqueous solution containing 50 ml of NaNO2 (108 mmol) was added for 20 minutes. 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 hours, and 100 ml of toluene was added. The toluene was evaporated, washed with water, and the mixture was recrystallized from DMF / i-PrOH (1 / 3). Yield: 39%.

[0212] C80392 The target compound was synthesized 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 hours (LC-MS control), cooled to room temperature, and 15 ml of water and HOAc (5 mmol) were added. The mixture was extracted with SiO (3 x 25 ml), washed with brine (3 x 25 ml), and the SiO was evaporated. The crude residue was purified by HPLC. Yield: 49%.

[0214] C12584 The target compound was synthesized 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 (LC-MS 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 by HPLC. Yield: 24%.

[0216] C80370

[0217] The target compound was synthesized 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 hours (LC-MS 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 by 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 for 10–48 hours with stirring (LC-MS 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 by HPLC. Yield: 38%.

[0220] C48014 The target compound was synthesized according to the scheme shown below: [ka]

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

[0222] General procedure B: Compound 2 (1 mmol), PhB(OH)2 (1.5 mmol), NaHCO3 (2 mmol), Pd(PPh3)4 (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 for 10-12 hours with stirring (LC-MS control), cooled to room temperature, and the solvent was evaporated. The crude residue was purified by HPLC. Yield: 24%.

[0223] C95330 The target compound was synthesized according to the scheme shown below: [ka]

[0224] General procedure A: Compound 1 (1 mmol) was dissolved in 20 ml of CH2Cl2, and water (20 ml) and NaHCO3 (2 mmol) were added. Chloroacetyl chloride (1.1 mmol) was added dropwise with stirring at 10-15°C for 15 minutes. The resulting mixture was stirred at room temperature for 3-5 hours. 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 of C12584. Yield: 22%.

[0226] C95338 The target compound was synthesized 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 target compound was synthesized according to the scheme shown below: [ka]

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

[0230] C80369 The target compound was synthesized according to the scheme shown below: [ka]

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

[0232] C47935 The target compound was synthesized 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 mixture was stirred overnight at room temperature, then diluted with water (150 mL). The solution was extracted with ethyl acetate (2 x 200 mL), the organic phase was washed with brine (3 x 150 mL), dried over CaCl2, and evaporated to obtain methyl ester 2. Yield: 94%.

[0234] General procedure B: To a solution of compound 2 (1.6 mmol) in CCl4 (3 ml), AIBN (0.1 mmol) and NBS (2 mmol) were added and incubated at 25°C for 15 minutes. The reaction mixture was heated at 60°C for 12 hours and then cooled to room temperature. The solvent was then removed by vacuum. The crude residue was purified by LC. Yield: 64%.

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

[0236] C12583 The target compound was synthesized according to the scheme shown below: [ka]

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

[0238] C80387 The target compound was synthesized according to the scheme shown below: [ka]

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

[0240] C80386 The target compound was synthesized according to the scheme shown below: [ka]

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

[0242] C67858 The target compound was synthesized according to the scheme shown below: [ka]

[0243] Step A: This compound was prepared according to general procedure A of 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 of MeOH, and the mixture was heated at 80°C for 12 hours. TLC and LCMS control were performed. The reaction mixture was cooled, then filtered, and the solvent was evaporated. The crude residue was purified using HPLC. Yield 48%.

[0245] C98103 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0248] C80383 The target compound was synthesized according to the scheme shown below: [ka]

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

[0250] C80391 The target compound was synthesized according to the scheme shown below: [ka]

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

[0252] C48016 The target compound was synthesized according to the scheme shown below: [ka]

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

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

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

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

[0257] C05955 The target compound was synthesized according to the scheme shown below: [ka]

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

[0259] C80384 The target compound was synthesized according to the scheme shown below: [ka]

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

[0261] C51383 The target compound was synthesized according to the scheme shown below: [ka]

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

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

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

[0265] C84965 The target compound was synthesized according to the scheme shown below: [ka]

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

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

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

[0269] General Procedure D: To a solution of compound 5 (0.5 mmol) in methanol (2 mL), palladium-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%.

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

[0271] C12595 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0274] C96622 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0277] C22622 The target compound was synthesized according to the scheme shown below: [ka]

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

[0279] C48018 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0282] C84964 The target compound was synthesized according to the scheme shown below: [ka]

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

[0284] C29137 The target compound was synthesized according to the scheme shown below: [ka]

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

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

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

[0288] C12586 The target compound was synthesized according to the scheme shown below: [ka]

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

[0290] C35856 The target compound was synthesized according to the scheme shown below: [ka]

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

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

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

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

[0295] C35751 The target compound was synthesized 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 hours. The suspension was filtered, washed with DMF (3 x 10 ml), and the solvent was evaporated to obtain compound 3. The crude residue was purified by LC. Yield: 9%.

[0297] General procedure B: Compound 3 (1 mmol) was dissolved in acetonitrile (10 mL). PhNCO (1.1 mmol) and one drop of NET3 were added, and the reaction mixture was heated at 60–70°C with stirring for 3–5 hours. The suspension was cooled, filtered, washed with acetonitrile (3 x 10 mL), and the solvent was evaporated to obtain compound 3. The crude residue was purified by LC. Yield: 46%.

[0298] C48020 The target compound was synthesized according to the scheme shown below: [ka]

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

[0300] C68126 The target compound was synthesized 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 overnight with stirring, then the water was evaporated, the Na salt of the product was treated with 50 mL of a mixture of siRNA:THF (4:1), filtered, washed with a mixture of siRNA:THF (4:1), and dried. Yield: 44%.

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

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

[0304] C95333 The target compound was synthesized according to the scheme shown below: [ka]

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

[0306] C84966 The target compound was synthesized according to the scheme shown below: [ka]

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

[0308] C66979 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0311] C80389 The target compound was synthesized according to the scheme shown below: [ka]

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

[0313] C35833 The target compound was synthesized according to the scheme shown below: [ka]

[0314] Step A: This compound was prepared according to general procedure B of 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 NaNO2 (2 mmol) was added for 2-3 minutes. The mixture was stirred at room temperature for 10 hours, neutralized with NaHCO3, 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 of C84965. Yield: 32%.

[0317] C59904 The target compound was synthesized according to the scheme shown below: [ka]

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

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

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

[0321] C80390 The target compound was synthesized according to the scheme shown below: [ka]

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

[0323] C35754 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0326] C49708 The target compound was synthesized according to the scheme shown below: [ka]

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

[0328] C80380 The target compound was synthesized according to the scheme shown below: [ka]

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

[0330] C35797 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0333] C80373 The target compound was synthesized according to the scheme shown below: [ka]

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

[0335] C45748 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0338] C80379 The target compound was synthesized according to the scheme shown below: [ka]

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

[0340] C47933 The target compound was synthesized 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 overnight at 50°C. Then it was diluted with water (50 mL). The solution was extracted with ethyl acetate (2 x 50 mL), the organic phase was washed with brine (3 x 150 ml), dried over CaCl2, and evaporated to obtain 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, and the reaction mixture was stirred at 90°C for 10 hours. Then the solvent was evaporated to obtain compound 3. The crude residue was recrystallized in the used mixture DMF:iPrOH (1:2). Yield: 76%.

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

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

[0345] C22548 The target compound was synthesized according to the scheme shown below: [ka]

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

[0347] C84963 The target compound was synthesized according to the scheme shown below: [ka]

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

[0349] C22586 The target compound was synthesized according to the scheme shown below: [ka]

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

[0351] C84971 The target compound was synthesized according to the scheme shown below: [ka]

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

[0353] C48007 The target compound was synthesized according to the scheme shown below: [ka]

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

[0355] C99884 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0358] C29330 The target compound was synthesized according to the scheme shown below: [ka]

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

[0360] C84970 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0363] C29361 The target compound was synthesized according to the scheme shown below: [ka]

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

[0365] C22564 The target compound was synthesized according to the scheme shown below: [ka]

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

[0367] C48005 The target compound was synthesized according to the scheme shown below: [ka]

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

[0369] C80375 The target compound was synthesized according to the scheme shown below: [ka]

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

[0371] C48009 The target compound was synthesized according to the scheme shown below: [ka]

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

[0373] C80378 The target compound was synthesized according to the scheme shown below: [ka]

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

[0375] C21223 The target compound was synthesized 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 NEt3 (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 x 25 mL), and recrystallized from the mixture iPrOH:water (4:1). Yield: 90%.

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

[0378] C13247 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0381] C35811 The target compound was synthesized according to the scheme shown below: [ka]

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

[0383] C80396 The target compound was synthesized according to the scheme shown below: [ka]

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

[0385] C64324 The target compound was synthesized according to the scheme shown below: [ka]

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

[0387] C84967 The target compound was synthesized according to the scheme shown below: [ka]

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

[0389] C89940 The target compound was synthesized 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 gradually added at room temperature for 15 minutes. The mixture was stirred at room temperature for 10 hours. TLC and LCMS control were performed. 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 target compound was synthesized according to the scheme shown below: [ka]

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

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

[0395] C47995 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0398] C64376 The target compound was synthesized according to the scheme shown below: [ka]

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

[0400] C84961 The target compound was synthesized according to the scheme shown below: [ka]

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

[0402] C22594 The target compound was synthesized according to the scheme shown below: [ka]

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

[0404] C12598 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0407] C29408 The target compound was synthesized according to the scheme shown below: [ka]

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

[0409] C73349 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0412] C12597 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0415] C98053 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0418] C51830 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0421] C97402 The target compound was synthesized according to the scheme shown below: [ka]

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

[0423] C68121 The target compound was synthesized 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 hours (TLC and LC-MS 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), NaHCO3 (5 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Then, 50 ml of water was added, 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 hour, then at 50°C for 10 hours. HOAc (0.1 mol) was added, and the solvent was evaporated. The residue was purified by LC. Yield: 42%.

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

[0428] C47998 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0431] C49713 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0434] C36126 The target compound was synthesized according to the scheme shown below: [ka]

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

[0436] C39453 The target compound was synthesized 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 of 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 x 10 ml), and the solvent was evaporated. The crude residue was purified by HPLC. Yield: 12%.

[0441] C10981 The target compound was synthesized 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 of C89940. Yield: 58%.

[0444] Step C: Compound 4 (1 mmol) and a 40% aqueous solution of 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 by HPLC. Yield: 34%.

[0445] C80394 The target compound was synthesized according to the scheme shown below: [ka]

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

[0447] C11892 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0450] C44292 The target compound was synthesized according to the scheme shown below: [ka]

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

[0452] C12693 The target compound was synthesized 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 target compound was synthesized according to the scheme shown below: [ka]

[0455] Step A: This compound was prepared according to general procedure B of 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 target compound was synthesized according to the scheme shown below: [ka]

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

[0459] C29490 The target compound was synthesized according to the scheme shown below: [ka]

[0460] C47997 The target compound was synthesized according to the scheme shown below: [ka]

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

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

[0463] C98696 The target compound was synthesized according to the scheme shown below: [ka]

[0464] Step A: This compound was prepared according to general procedure A of 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 target compound was synthesized according to the scheme shown below: [ka]

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

[0468] Example 4: Test Results The following compounds were tested in the competitive and / or recruitment assays described herein, and the results are listed below. [Table 1] TIFF0007871189000138.tif242162TIFF0007871189000139.tif242162TIFF0007871189000140.tif242162TIFF0007871189000141.tif242162TIFF0007871189000142.tif242162TIFF0007871189000143.tif242162TIFF0007871189000144.tif242162TIFF0007871189000145.tif242162TIFF0007871189000146.tif242161TIFF0007871189000147.tif242161TIFF0007871189000148.tif242161TIFF0007871189000149.tif242161TIFF0007871189000150.tif242162TIFF0007871189000151.tif242161TIFF0007871189000152.tif242161TIFF0007871189000153.tif242161TIFF0007871189000154.tif242161TIFF0007871189000155.tif242161TIFF0007871189000156.tif242161TIFF0007871189000157.tif242161TIFF0007871189000158.tif242162TIFF0007871189000159.tif242162TIFF0007871189000160.tif242161TIFF0007871189000161.tif242161TIFF0007871189000162.tif242162TIFF0007871189000163.tif242162TIFF0007871189000164.tif242162TIFF0007871189000165.tif242162TIFF0007871189000166.tif242162TIFF0007871189000167.tif242161TIFF0007871189000168.tif242161TIFF0007871189000169.tif242161TIFF0007871189000170.tif242161TIFF0007871189000171.tif242162TIFF0007871189000172.tif242162TIFF0007871189000173.tif242161TIFF0007871189000174.tif242162TIFF0007871189000175.tif242161TIFF0007871189000176.tif242161TIFF0007871189000177.tif242161TIFF0007871189000178.tif242161TIFF0007871189000179.tif242161TIFF0007871189000180.tif242161TIFF0007871189000181.tif242161TIFF0007871189000182.tif242161TIFF0007871189000183.tif242162TIFF0007871189000184.tif242161TIFF0007871189000185.tif242161TIFF0007871189000186.tif242161TIFF0007871189000187.tif242161TIFF0007871189000188.tif242161TIFF0007871189000189.tif242162TIFF0007871189000190.tif242161TIFF0007871189000191.tif242162TIFF0007871189000192.tif242162TIFF0007871189000193.tif242162TIFF0007871189000194.tif242162TIFF0007871189000195.tif242162TIFF0007871189000196.tif242162TIFF0007871189000197.tif242162TIFF0007871189000198.tif242161TIFF0007871189000199.tif242161TIFF0007871189000200.tif242161TIFF0007871189000201.tif242162TIFF0007871189000202.tif242162TIFF0007871189000203.tif242161TIFF0007871189000204.tif242161TIFF0007871189000205.tif242161TIFF0007871189000206.tif242161TIFF0007871189000207.tif242161TIFF0007871189000208.tif242161TIFF0007871189000209.tif242162TIFF0007871189000210.tif242162TIFF0007871189000211.tif242162TIFF0007871189000212.tif242161TIFF0007871189000213.tif242161TIFF0007871189000214.tif242161TIFF0007871189000215.tif242161TIFF0007871189000216.tif242162TIFF0007871189000217.tif242161TIFF0007871189000218.tif242161TIFF0007871189000219.tif242161TIFF0007871189000220.tif242162TIFF0007871189000221.tif242161TIFF0007871189000222.tif242162TIFF0007871189000223.tif242162TIFF0007871189000224.tif242162TIFF0007871189000225.tif242162TIFF0007871189000226.tif242162TIFF0007871189000227.tif242162TIFF0007871189000228.tif242161TIFF0007871189000229.tif242161TIFF0007871189000230.tif242161TIFF0007871189000231.tif242161.

Claims

1. Compounds of formula III: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (wherein R ｗ is -N(R ５ )-(CH ２ ) ｍ -X-(CH ２ ) ｎ -R ６ , aryl, or -NH-(C ３ -C １０ ) heteroaryl, and any of these may optionally be substituted with one or more R ｗ groups permitted by valence; R ５ Each occurrence independently determines H and (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 - A heteroaryl, aryl, or heteroaryl, each of which is allowed by valence to contain one or more R ｗ It can be optionally substituted by the base; R ６ Each occurrence is independently (C ３ -C １０ ) heterocyclo, (C １ -C ３ ) alkyl, -(C １ -C ３ ) Alkoxy, (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, or heteroaryl, any of which is one or more R allowed by valence ｗ It can be optionally substituted by the base; R ｗ Each instance independently consists of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, and heterocycloalkyl, while alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl are 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 - It can be further independently substituted with one or more groups selected from the group consisting of heteroaryls, aryls, and heteroaryls; X is -(CH ２ ) ｎ C(O)(CH ２ ) ｍ -, bonding group, -SO ２ -, -NHC(O)NH-, or -(CH ２ ) ｎ - and; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4).

2. In equation III, R ３ is -N(R ５ )-(CH ２ )m-X-(CH ２ )n-R ６ And; R ５ H is; R ６ is (C ３ -C １０ ) heterocycle, (C １ -C ３ ) alkyl, -(C １ -C ３ ) alkoxy, (C3-C １０ ) cycloalkyl, -(CH ２ ) n-(C ３ -C １０ ) cycloalkyl, -(CH ２ ) n-(C ３ -C １０ ) heterocycle, -(CH ２ ) n-aryl, -(CH ２ ) n-heteroaryl, aryl, or heteroaryl, The compound according to claim 1.

3. Compounds selected from the following group: N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]quinoline-2-carboxamide; 3-[6-[[2-(2-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(2-isoindoline-2-yl-2-oxo-ethyl)amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinazoline-4-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[[2-(3-methyl-1-piperidyl)-2-oxo-ethyl]amino]-1-oxo-isoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(4-methyl-3-oxopyrazine-2-yl)amino]-1-oxoisoindoline-2-yl]piperidine-2,6-dione; 3-[1-oxo-6-(quinoxaline-2-ylamino)isoindoline-2-yl]piperidine-2,6-dione; 3-[6-[(1-methylpyrazolo[3,4-d]pyrimidine-4-yl)amino]-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[6-(5,7-dihydrofl[3,4-d]pyrimidine-2-ylamino)-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 3-[6-[(6-methylpyrimidine-4-yl)amino]-1-oxoisoindoline-2-yl]piperidine-2,6-dione; 3-[6-[[2-(2,4-dimethylpiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 3-(1-oxo-6-phenyl-isoindoline-2-yl)piperidine-2,6-dione; 3-[6-[[2-(2-methylmorpholine-4-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]-N-methyl-N-[(1-methylpyrazole-4-yl)methyl]acetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]pyridazine-3-carbonitride; 3-[6-[(6-methylpyrrolo[3,2-d]pyrimidine-4-yl)amino]-1-oxoisoindorin-2-yl]piperidine-2,6-dione; 2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-5H-pyrrolo[2,3-b]pyridine-4-carboxamide; 3-[1-oxo-6-(2-oxoimidazolidine-1-yl)isoindorin-2-yl]piperidine-2,6-dione; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]propanoic acid; 2-Acetamide-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 3-[6-[[2-(3-methyl-5-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindorin-5-yl]acetamide; 3-[6-[[2-(4-methyl-3-oxopiperazine-1-yl)-2-oxo-ethyl]amino]-1-oxo-isoindoline-2-yl]piperidine-2,6-dione; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]-3H-imidazo[4,5-b]pyridine-6-carboxamide; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-yl]amino]-N-tetrahydropyran-4-yl-acetamide; and 3-[1-oxo-6-[[2-oxo-2-(1-piperidyl)ethyl]amino]isoindorin-2-yl]piperidine-2,6-dione.

4. A composition comprising a pharmaceutically effective amount of the compound described in any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

5. The composition according to claim 4, for use in treating cancer.

6. The aforementioned cancers include 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, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemia, lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, melanoma, myeloproliferative disorders, multiple myeloma, sarcomas, such as Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and lipid sarcoma. A composition for use according to claim 5, selected from the group consisting of liposarcoma, myasarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglionectomy, ganglionectomy, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, testicular tumor, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratoma.

7. The composition for use according to claim 6, wherein the cancer is multiple myeloma.

8. The composition according to claim 4, for use in treating an autoimmune disease or disorder.

9. The composition for use according to claim 8, 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 syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, primary cholangiosclerosis, sclerosing cholangitis, autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, fibromyalgia, Meniere's syndrome; transplant rejection (e.g., prevention of allograft rejection), pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, and other autoimmune diseases or disorders.

10. The composition according to claim 4, for use in regulating cerebron, regulating proteasomal degradation of proteins, or regulating the sequestration of proteins into proteasomes.

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