3-(5-Methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

Abstract

The present disclosure relates to compounds and pharmaceutical compositions of formula (I') and their use in reducing widely interpaced zinc finger motif (WIZ) expression levels or inducing fetal hemoglobin (HbF) expression, and in treating inherited blood disorders (e.g., hemoglobinopathies, e.g., β-hemoglobinopathies), such as sickle cell disease and β-thalassemia.

Description

[Technical field]

[0001] Priority claim This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 950,048, filed December 18, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to 3-(5-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds and pharmaceutical compositions and their use in reducing Widely Interspaced Zinc Finger Motif (WIZ) protein expression levels and / or inducing fetal hemoglobin (HbF) protein expression levels and in the treatment of inherited blood disorders (hemoglobinopathies, e.g., β-hemoglobinopathies), such as sickle cell disease and β-thalassemia. [Background technology]

[0003] Sickle cell disease (SCD) is a group of severe inherited blood disorders in which red blood cells become distorted into a sickle shape. These cells cause blockage of blood flow, which can lead to severe pain, organ damage, and premature death. β-thalassemia is a group of inherited blood disorders that result in anemia caused by reduced or absent synthesis of β-globin.

[0004] Fetal hemoglobin (HbF) induction is known to improve symptoms in patients with SCD and β-thalassemia and has been clinically validated both genetically (single nucleotide polymorphisms in the globin regulatory locus and BCL11A) and pharmacologically (hydroxyurea) (Vinjamur, DS, et al. (2018), The British Journal of Haematology, 180(5), 630-643). Hydroxyurea is the current standard of care for SCD and is thought to provide benefit through induction of HbF, but is genotoxic, causes dose-limiting neutropenia, and has a response rate of less than 40%. Other mechanisms targeted in clinical and preclinical studies include HDAC1 / 2 (Shearstone et al., 2016, PLoS One, 11(4), e0153767), LSD1 (Rivers et al., 2018, Experimental Hematology, 67, 60-64), DNMT1, PDE9a (McArthur et al., 2019, Haematologica.doi:10.3324 / haematol.2018.213462), HRI kinase (Grevet et al., 2018, Science, 361(6399), 285-290) and G9a / GLP (Krivega et al., 2015, Blood, 126(5), 665-672; Renneville et al., 2016, Physiology, 11(1), 113-114). al.,2015,Blood,126(16),1930-1939). In addition, the immunomodulatory drugs pomalidomide and lenalidomide induce HbF in human primary erythroid cells ex vivo (Moutouh-de Parseval,LA et al.(2008),The Journal of Clinical Investigation,118(1),248-258) and in vivo (Meiler,SE et al.(2011),Blood,118(4),1109-1112). WIZ is ubiquitously expressed and plays a role in regulating chromatin structure and transcription by targeting G9a / GLP histone methyltransferase to genomic loci (Bian,Chen,et al.(2015),eLife 2015;4:e05606). Summary of the Invention

[0005] The present disclosure relates to therapeutic agents effective for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression. In some embodiments, the therapeutic agents are small molecules, siRNAs, shRNAs, ASOs, miRNAs, AMOs. The present disclosure further relates to 3-(5-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds, pharma- ceutically acceptable salts thereof, compositions thereof, and uses thereof in therapy for the conditions and purposes detailed above.

[0006] The present disclosure relates to a compound of formula (I') or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, [ka] [In the formula, Y is O, CH 2 , C.F. 2 and CHF; z is an integer from 0 to 2; R X1 and R X2 are each independently hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 are each independently hydrogen and C 1 ~C 6 alkyl; R Z1 and R Z2 are both hydrogen or or R Z1 and R Z2 One of and R Y1 and R Y2 Together with one of 1 ~C 2Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 the other two are both hydrogen; R 1 is hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl, and -O-(R 2a ) is substituted with 0 to 1 substituents independently selected from wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 2a is C 1 ~C 6 alkyl, where alkyl is C 6 ~C 10 substituted with 0 to 1 substituents independently selected from aryl; R 3 is -CH=CR 3a R 3b , C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3a and R 3b together with the carbon atoms to which they are attached, C 3 ~C 8 forming a cycloalkyl ring; Each R 3c For each occurrence, -C(=O)-R 3d , N.R. 3e R 3f , C 1 ~C 6 Alkoxyl, -OR 3d , Hydroxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3d is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 3e and R 3fare each independently hydrogen and C 1 ~C 6 alkyl; Each R 4 For each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 Alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Here, cycloalkyl is -CN, C1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl and C 1 ~C 6 substituted with 0 to 3 substituents, each independently selected from haloalkyl; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, C 1 ~C 6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 6 cycloalkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 For each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 haloalkyl; R 4b is -CN, halogen, -C(=O)NR 6a R 6b , N.R. 6a R 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH;1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c is C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 is C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b are each independently hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c For each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C6 alkyl), oxo, and C 1 ~C 6 alkyl, where alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S.

[0007] In one embodiment, z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 One of them is C 1 ~C 2 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 The other two are both hydrogen.

[0008] In one embodiment, z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 One of them is C 1 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 The other two are both hydrogen.

[0009] In one embodiment, z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 One of them is C 2 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 The other two are both hydrogen.

[0010] The disclosure provides in a first aspect a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, [ka] [In the formula, Y is O, CH 2 , and C.F. 2 Selected from; z is an integer from 0 to 2; R X1 and R X2 are each independently hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 are each independently hydrogen and C 1 ~C 6 alkyl; R 1 is hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 substituted with 0 to 1 substituents independently selected from cycloalkyl; wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3 is -CH=CR 3a R 3b , C 6 ~C 10aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3a and R 3b together with the carbon atoms to which they are attached, C 3 ~C 8 forming a cycloalkyl ring; Each R 3c For each occurrence, -C(=O)-R 3d , N.R. 3e R 3f , C 1 ~C 6 Alkoxyl, -OR 3d , Hydroxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3d is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 3e and R 3f are each independently hydrogen and C 1 ~C 6 alkyl; Each R 4 For each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 Alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Here, cycloalkyl is -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 substituted with 0 to 3 substituents each independently selected from alkoxyl, and hydroxyl; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 For each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 independently selected from haloalkyl; R 4b is -CN, -C(=O)NR for each occurrence. 6a R 6b , N.R. 6aR 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; 1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c is C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 is C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b are each independently hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c For each occurrence, C 6 ~C 10 Aryl C 1 ~C 6Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 alkyl, where alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S.

[0011] In a second aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier or excipient.

[0012] In a third aspect, the present disclosure provides a compound of formula (I'), (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), Provided is a compound of formula (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), or (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0013] In a fourth aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... and administering to a subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0014] In a fifth aspect, the disclosure provides a method of treating or preventing a disorder affected by decreased levels of a WIZ protein in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), The present invention provides a method of treating a subject comprising administering to the subject a compound of Formula Ia-ii), Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0015] In a sixth aspect, the disclosure provides a method of inhibiting WIZ protein expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i), formula (I ... and administering to a subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0016] In a seventh aspect, the disclosure provides a method of degrading a WIZ protein in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i), formula (I ... The present invention provides a method for treating a subject comprising administering to the subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0017] In an eighth aspect, the disclosure provides a method of inhibiting, reducing, or eliminating a WIZ protein activity or WIZ protein expression, comprising administering to a patient a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), or (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided.

[0018] In a ninth aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), The present invention provides a method of administering to a subject a compound of Formula (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), or (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0019] In a tenth aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii ... (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), or (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided.

[0020] In an eleventh aspect, the disclosure provides a method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii ... The present invention provides a method for treating a subject comprising administering to the subject a compound of formula (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), or (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0021] In a twelfth aspect, the disclosure provides a method of treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ib-i), (Ic-i), (Id ... and administering to a subject a compound of Formula (Ia-ii), Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0022] In a thirteenth aspect, the disclosure provides a method of treating sickle cell disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi ... The present invention provides a method of treating a subject comprising administering to the subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0023] In a fourteenth aspect, the present disclosure provides a method of treating β-thalassemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The present invention provides a method for treating a subject comprising administering to the subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), or Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0024] In a fifteenth aspect, the disclosure provides a compound of formula (I'), (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-ii-c), formula (Ia-ii-d), formula (Ia-ii-e), formula (Ia ... or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0025] In a sixteenth aspect, the present disclosure provides a method for the treatment of a disease or disorder selected from sickle cell disease and β-thalassemia, comprising administering to said patient a therapeutically effective amount of a medicament for the treatment of said disease or disorder selected from sickle cell disease and β-thalassemia. or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0026] In a seventeenth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ib, formula (Ic), formula (Id), formula (Ia-i), formula Ib, formula (Ic), formula (Id), formula (Ia-i), formula Ib, formula (Ic), formula (Id), formula (Ic ... or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0027] In an eighteenth aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i-i), formula (Ia-ii ... or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0028] In a nineteenth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-i-i, ... or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0029] In a twentieth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-i, ... and a medicament comprising a compound of formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), or formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0030] In a twenty-first aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia- In one embodiment, the present invention provides a compound of formula Ia-i), formula Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), or formula (Ih-ii), or a pharma-ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0031] In a twenty-second aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii ... (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), or formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0032] In a twenty-third aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii) for use in reactivating fetal hemoglobin production or expression. or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0033] In a twenty-fourth aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii ... or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0034] In a twenty-fifth aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i-i), formula (I ... and m is an integer from 1 to 3. In one embodiment, the present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), or formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0035] In a twenty-sixth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-ii-a), formula (Ia-ii-b), formula (Ia-ii-c), formula (Ia-ii-d), formula (Ia-ii-e), formula (Ia ...b), formula (Ia-ii-c), formula (Ia-ii-c), formula (Ia-ii-d), formula (Ia-ii-e), formula (Ia-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-ii-c), formula (Ia-ii-c or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0036] In a twenty-seventh aspect, the present disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i ... and a medicament comprising a compound of formula (Ia-ii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), or formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0037] In a twenty-eighth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i ... or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0038] In a twenty-ninth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ig), formula (Iih), formula (Iij ... The present invention provides a compound of formula Ia-i), Ia-ii), Ia-iii), Ia-iv), Ia-v), Ia-vi), Ia-vii), Ia-viii), Ia-ix), Ia-x), Ia-xi), Ia-xii), Ia-xiii), Ia-xiv), Ie), (If), Ig), Ih), Ih-i), or Ih-ii; or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0039] In a thirtieth aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-i-ii, ... and a medicament comprising a compound of formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), or formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0040] In a thirty-first aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ib, formula (Ic), formula (Id), formula (Ia-i), formula Ic, formula (Id), formula (Ia-i), formula Id, formula (Ib), formula (Ic ... or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0041] Various aspects of the disclosure are set forth in the specification and claims.

[0042] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and claims, the singular form includes the plural form unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein may be used to practice or test this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes. References cited herein are not admitted to be prior art to the claimed disclosure. In case of conflict, the present specification, including definitions, shall control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0043] Other features and advantages of the compounds, compositions, and methods disclosed herein will become apparent from the following detailed description and claims. [Brief description of the drawings]

[0044] [Figure 1A] Volcano plot of differentially expressed genes from WIZ KO cells compared to scrambled gRNA control. Each point represents a gene. HBG1 / 2 genes are differentially upregulated by WIZ_6 and WIZ_18 gRNAs targeting WIZ KO. [Figure 1B] 1 depicts a bar graph showing HbF+ cell frequency due to shRNA-mediated WIZ deficiency in human mobilized peripheral blood CD34+ derived erythroid cells. [Figure 1C] 1 depicts a bar graph showing HbF+ cell frequency due to CRISPR / Cas9-mediated WIZ deletion in human mobilized peripheral blood CD34+ derived erythroid cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The compounds disclosed herein are effective in reducing WIZ protein expression levels or inducing fetal hemoglobin (HbF) expression. Without wishing to be bound by any theory, it is believed that the disclosed compounds can treat blood disorders, such as inherited blood disorders, for example, sickle cell disease and β-thalassemia, by inducing fetal hemoglobin HbF expression.

[0046] definition Unless otherwise specified, the terms "compounds of the present disclosure," "compounds of the disclosure," or "compounds of the disclosure" may be used interchangeably. "disclosure") means any of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii ... ii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i) and Formula (Ih-ii), exemplified compounds, salts thereof, particularly pharma- ceutically acceptable salts thereof, hydrates, solvates, prodrugs, and all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties.

[0047] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C 1 ~C 10Alkyl means an alkyl group or radical having 1 to 10 carbon atoms. In general, for groups containing two or more subgroups, the last named group is the point of attachment of the group; for example, "alkylaryl" means a monovalent group of the formula alkyl-aryl-, while "arylalkyl" means a monovalent group of the formula aryl-alkyl-. Thus, the term C 6 ~C 10 Aryl C 1 ~C 6 Alkyl is a group that has C in the base molecule. 1 ~C 6 Formula C, which is bonded via an alkyl moiety 6 ~C 10 Aryl C 1 ~C 6 It means a monovalent radical of alkyl-.

[0048] R 3c or R 4 In embodiments where is arylalkyl-O-, it refers to a monovalent O group of formula aryl-alkyl-O- or -O-alkyl-aryl.

[0049] Additionally, the use of terms designating monovalent radicals where divalent radicals are appropriate shall be construed as designating the respective divalent radical, and vice versa. Unless otherwise specified, conventional definitions of terms shall prevail and conventional stable valences are assumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or to more than one (e.g., at least one) of the grammatical referent of the article.

[0050] The term "and / or" means either "and" or "or" unless otherwise indicated.

[0051] The term "substituted" means that the specified group or moiety bears one or more suitable substituents, where the substituents may be linked to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is linked to an atom of the aryl by a bond or by sharing two or more common atoms by being fused with the aryl.

[0052] Any R group, e.g. R 4 The bond to may be, for example, a heteroaryl group as shown below: [ka] In embodiments of the formula (I) that is not bound to any specified atom, it is R 4 It means that the group may be attached via any atom on the ring.

[0053] As used herein, the term "C 1 ~C 10 "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, free of unsaturation, having from 1 to 10 carbon atoms, attached to the remainder of the molecule by a single bond. 1 ~C 3 Alkyl, C 1 ~C 4 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 8 "Alkyl" should be construed accordingly. 1 ~C 10 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (t-butyl), n-pentyl, n-hexyl, n-heptyl, 4-heptyl, n-octyl, 2-isopropyl-3-methylbutyl, n-nonyl, and n-decyl.

[0054] As used herein, the term "C 1 ~C 6 "Alkoxy" is a group represented by the formula -OR a (wherein R a is C as broadly defined above 1 ~C 6 C refers to an alkyl group. 1 ~C 6 Examples of alkoxyl include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, and hexoxy.

[0055] "Alkynyl" means a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkynyl" group contains at least one triple bond in the chain. The term "C 2 ~C 4 "Alkynyl" should be construed accordingly. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0056] "C 2 ~C 4 Preferred examples of "alkynyl" include, without limitation, ethynyl, prop-1-ynyl, prop-2-ynyl and but-2-ynyl.

[0057] As used herein, the term "C 1 ~C 6 "Haloalkyl" refers to a C alkyl group, as defined above, substituted with one or more halo groups, as defined herein. 1 ~C 6 Refers to an alkyl group. 1 ~C 6Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0058] As used herein, the term "C 1 ~C 6 haloalkoxyl" means a C 1 ~C 6 alkoxyl group as defined herein substituted with one or more halo groups. C 1 ~C 6 Examples of C 1 ~C 6 haloalkoxyl include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3,3-difluoropropoxy, and 3-dibromopropoxy. Preferably, one or more halo groups of the C 1 ~C 6 haloalkoxyl are fluorine. Preferably, the C

[0059] haloalkoxyl is selected from trifluoromethoxy, difluoromethoxy, fluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, and pentafluoroethoxy.

[0059] The term "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

[0060] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms and lacking delocalized π-electrons shared between ring carbons (aromaticity). 3 ~C 8 Cycloalkyl" and "C 3 ~C 6 Cycloalkyl" should be construed accordingly. The term polycyclic includes bridged (e.g., norbornane), fused (e.g., decalin) and spirocyclic cycloalkyls. Preferably, cycloalkyls, e.g., C 3 ~C 8 Cycloalkyl is a monocyclic or bridged hydrocarbon group of 3 to 8 carbon atoms.

[0061] Examples of cycloalkyl groups include, without limitation, cyclopropenyl, cyclopropyl cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[1.1.1]pentanyl, and derivatives thereof.

[0062] C 3 ~C 8 Preferred examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[2.2.2]octyl, and bicyclo[1.1.1]pentanyl.

[0063] "Heterocyclyl" means a saturated or partially saturated monocyclic or polycyclic ring containing at least one heteroatom selected from carbon as well as oxygen, nitrogen, and sulfur (O, N, and S), and having no delocalized π electrons (aromaticity) shared between ring carbons or heteroatoms. The terms "4- to 6-membered heterocyclyl" and "4- to 11-membered heterocyclyl" should be construed accordingly. The heterocyclyl ring structure may be substituted by one or more substituents. The substituents themselves may also be optionally substituted. Heterocyclyl may be bonded via a carbon atom or a heteroatom. The term polycyclic includes bridged, fused, and spiro ring heterocyclyl.

[0064] Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), and the like.

[0065] Preferred examples of heterocyclyl include, without limitation, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0066] As used herein, the term "aryl" refers to a monocyclic, bicyclic or polycyclic carbocyclic aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl (e.g., naphth-1-yl, naphth-2-yl), anthryl (e.g., anthryl-1-yl, anthryl-9-yl), phenanthryl (e.g., phenanthr-1-yl, phenanthr-9-yl), and the like. Aryl is also intended to include a monocyclic, bicyclic or polycyclic carbocyclic aromatic ring substituted with a carbocyclic aromatic ring. Representative examples are biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl), phenylnaphthyl (e.g., 1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings having at least one unsaturated moiety (e.g., benzo moiety).Representative examples are indanyl (e.g., indan-1-yl, indan-5-yl), indenyl (e.g., inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-6-yl), 1,2-dihydronaphthyl (e.g., 1,2-dihydronaphth-1-yl, 1,2-dihydronaphth-4-yl, 1,2-dihydronaphth-6-yl), fluorenyl (e.g., fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are benzonorbornyl (e.g., benzonorborn-3-yl, benzonorborn-6-yl), 1,4-ethano-1,2,3,4-tetrahydronapthyl (e.g., 1,4-ethano-1,2,3,4-tetrahydronaphth-2-yl, 1,4-ethano-1,2,3,4-tetrahydronaphth-10-yl), and the like. The term "C 6 ~C 10"Aryl" should be construed accordingly.

[0067] Preferred examples of aryl include, but are not limited to, indenyl, (e.g., inden-1-yl, inden-5-yl)phenyl (C 6 H 5 ), naphthyl (C 10 H 7 ) (e.g., naphth-1-yl, naphth-2-yl), indanyl (e.g., indan-1-yl, indan-5-yl), and tetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalenyl).

[0068] Preferably, C 6 ~C 10 Aryl refers to mono- or bicyclic carbocyclic aromatic rings.

[0069] C 6 ~C 10 Preferred examples of aryl include, but are not limited to, phenyl and naphthyl. 6 ~C 10 Aryl is phenyl.

[0070] The term "heteroaryl," as used herein, is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, and the like.

[0071] Heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, imidazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

[0072] Heteroaryl is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, phenanthrolinyl, and the like.

[0073] Heteroaryl is also intended to include partially saturated monocyclic, bicyclic, or polycyclic heterocyclyls containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are imidazolinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and the like.

[0074] The heteroaryl ring structure may be substituted by one or more substituents, which may themselves be optionally substituted. The heteroaryl ring may be attached via a carbon atom or a heteroatom.

[0075] The term "5- to 10-membered heteroaryl" should be construed accordingly.

[0076] Examples of 5-10 membered heteroaryls include, but are not limited to, indolyl, imidazopyridyl, isoquinolinyl, benzoxazolonyl, pyridinyl, pyrimidinyl, pyridinonyl, benzotriazolyl, pyridazinyl, pyrazolotriazinyl, indazolyl, benzimidazolyl, quinolinyl, triazolyl (e.g., 1,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), imidazolyl, pyrrolopyridinyl, tetrahydroindazolyl, Zolyl, quinoxalinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, oxazolopyridinyl, pyrazolopyrimidinyl, benzoxazolyl, indolinyl, isoxazolopyridinyl, dihydropyridoxazinyl, tetrazolyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), and dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine).

[0077] As used herein, the term "C 6 ~C 10 Aryl C 1 ~C 6 "Alkyl" is a group of the formula -R a -C 6 ~C 10 Aryl (wherein R a is C as broadly defined above 1 ~C 6 C refers to a monovalent group of alkyl groups. 6 ~C 10 Aryl C 1 ~C 6 Examples of alkyl include, but are not limited to, C alkyl-C 6 H 5 (Benzyl), C1 alkyl-C 10 H 7, -CH(CH 3 )-C 6 H 5 , -C(CH 3 ) 2 -C 6 H 5 , and -(CH 2 ) 2-6 -C 6 H 5 Examples include:

[0078] As used herein, the term "oxo" refers to the group ═O.

[0079] As used herein, the term “di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 "Alkyl" is a group of the formula -R a1 -N(R a2 )-R a2 (wherein R a1 is C as defined above 1 ~C 6 is an alkyl group, and each R a2 are C as defined above, which may be the same or different; 1 ~C 6 The nitrogen atom may be attached to any carbon atom of any alkyl group. Examples include, but are not limited to, (C alkyl-NR 6a R 6b ), (C1 alkyl-CH 2 -NR 6a R 6b ), (-(CH 2 ) 3 -NR 6a R 6b ), (-(CH 2 ) 4 -NR 6a R 6b ), (-(CH 2 ) 5 -NR 6a R 6b ), and (-(CH 2 ) 6 -NR 6a R 6b )(wherein, R 6aand R 6b are as defined herein.

[0080] As used herein, the term “di(C 1 ~C 6 "N(R alkyl)amino" refers to a group represented by the formula -N(R a1 )-R a1 (wherein each R a1 are C as defined above, which may be the same or different; 1 ~C 6 It refers to an alkyl group.

[0081] "Cyano" or "-CN" refers to a substituent having a carbon atom connected to a nitrogen atom with a triple bond, e.g., C≡N.

[0082] As used herein, the term "C 1 ~C 2 "Alkylene" refers to a straight or branched hydrocarbon chain divalent radical, containing only carbon and hydrogen atoms, free of unsaturation, having from 1 to 2 carbon atoms. 1 ~C 2 Alkylene" should be construed accordingly.

[0083] R Z1 and R Z2 One of and R Y1 and R Y2 For embodiments in which one of the groups forms a bridging group, this is 1 ~C 2 Alkylene linkers, e.g., C 1 Or C 2 It should be understood as the ring formed by two non-adjacent carbon atoms of an N-containing heterocycloalkyl linked to form an alkylene group. Examples of bridging groups included in the compounds of formula (I') include, but are not limited to: [ka] Examples include:

[0084] As used herein, the term "optionally substituted" includes unsubstituted or substituted.

[0085] As used herein,

Chemical formula

[0086] As used herein, the term nitrogen protecting group (PG) of a compound of formula (X) or any intermediate in any of General Schemes 1-4 and its sub-formulas refers to a group that should protect the functional groups of concern, such as acylation, etherification, esterification, oxidation, solvolysis, and similar reactions, from unwanted side reactions. This can be removed under deprotection conditions. One of ordinary skill in the art will know how to remove the protecting group to obtain the free amine NH 2It will be known by reference to known procedures whether the groups are accessible. These include references to organic chemistry textbooks and literature procedures, such as JFW MacOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PG M Huts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; PJ Kocienski, "Protecting Groups", Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0087] Preferred nitrogen protecting groups are generally trialkylsilyl-C 1 ~C 7 C which is mono-, di- or tri-substituted by alkoxy (e.g. trimethylsilyethoxy), aryl, preferably phenyl, or heterocyclic groups (e.g. benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene). 1 ~C 6 Alkyl (e.g., tert-butyl), preferably C 1 ~C 4 Alkyl, more preferably C 1 ~C 2 Alkyl, more preferably C1 alkyl, where the aryl or heterocyclic group is unsubstituted or 1 ~C 7 Alkyl, Hydroxy, C 1 ~C 7 Alkoxy (e.g., paramethoxybenzyl (PMB)), C 2 ~C 8 -alkanoyl-oxy, halogen, nitro, cyano, and CF 3 , Aryl-C 1 ~C 2 -alkoxycarbonyl (preferably phenyl-C 1 ~C 2 -alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM)), C 1 ~C 10 -Alkenyloxycarbonyl, C 1 ~C 6 Alkylcarbonyl (e.g., acetyl or pivaloyl), C 6 ~C 10 -Arylcarbonyl; C 1 ~C 6 -alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C 6 ~C 10 -Aryl C 1 ~C 6 -substituted by one or more, for example two or three, residues selected for example from the group consisting of alkoxycarbonyl (e.g. 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, silyl group (e.g. triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tertbutyldimethylsilyl).

[0088] According to the present disclosure, the preferred protecting group (PG) may be selected from the group including tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), paramethoxybenzyl (PMB), methyloxycarbonyl, trimethylsilylethoxymethyl (SEM) and benzyl. The protecting group (PG) is preferably tert-butyloxycarbonyl (Boc).

[0089] In some embodiments, the compounds of the present disclosure are selective over other proteins.

[0090] As used herein, the term "therapeutic agent" in the context of a method for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression refers to a substance that results in detectably lower expression of a WIZ gene or WIZ protein or a lower activity level of a WIZ protein compared to the level in the absence of the substance. In some embodiments, the substance is a small molecule compound that can target WIZ for degradation (e.g., via the E3 ubiquitin pathway, also known as a "WIZ degrader", e.g., a compound as described herein). In some embodiments, the substance is an anti-WIZ shRNA. In some embodiments, the substance is an anti-WIZ siRNA. In some embodiments, the substance is an anti-WIZ ASO. In some embodiments, the substance is an anti-WIZ AMO (anti-miRNA oligonucleotide). In some embodiments, the substance is an anti-WIZ antisense nucleic acid. In some embodiments, the substance is a composition or a cell or cell population described herein (including a gRNA molecule described herein).

[0091] As used herein, the term "small molecule" refers to an agent with a molecular weight of less than 900 daltons. Small molecules according to the present disclosure can target WIZ protein for degradation, for example, via the E3 ubiquitin pathway, and / or induce fetal hemoglobin (HbF) expression. In some embodiments, small molecules refer to compounds as disclosed herein, for example, compounds of formula (I').

[0092] As used herein, "siRNA" refers to a nucleic acid that forms a double-stranded RNA and that has the ability to reduce or inhibit expression of a gene or target gene when the siRNA is present (e.g., expressed) in the same cell as the gene or target gene. siRNAs are typically about 5 to about 100 nucleotides in length, more typically about 10 to about 50 nucleotides in length, more typically about 15 to about 30 nucleotides in length, and most typically about 20 to 30 base nucleotides, or about 20 to 25 or about 24 to 29 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. siRNA molecules and methods for making them are described, for example, in Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; WO 00 / 44895; WO 01 / 36646; WO 99 / 32619; WO 00 / 01846; WO 01 / 29058; WO 99 / 07409; and WO 00 / 44914. DNA molecules that transcribe dsRNA or siRNA (e.g., as hairpin duplexes) also provide RNAi. DNA molecules that transcribe dsRNA are disclosed in U.S. Patent No. 6,573,099, and U.S. Patent Application Publication Nos. 2002 / 0160393 and 2003 / 0027783, as well as Tuschl and Borkhardt, Molecular Interventions, 2:158 (2002).

[0093] As used herein, an antisense oligonucleotide (ASO) is a single strand of DNA or RNA that is complementary to a selected sequence. In the case of antisense RNA, it prevents protein translation of a certain messenger RNA strand by binding to it in a process called hybridization. Antisense oligonucleotides can be used to target specific complementary (coding or non-coding) RNA. When binding occurs, the hybrid is susceptible to degradation by the enzyme RNase H.

[0094] As used herein, "modulator" or "degrader" refers to a compound of the present disclosure that, for example, effectively regulates, reduces, or decreases the level of a specific protein (e.g., WIZ) or degrades a specific protein (e.g., WIZ). The amount of specific protein (e.g., WIZ) that is degraded can be measured by comparing the amount of specific protein (e.g., WIZ) remaining after treatment with a compound of the present disclosure compared to the initial amount or initial level of specific protein (e.g., WIZ) present when measured before treatment with a compound of the present disclosure.

[0095] As used herein, a "selective modulator," "selective degrader," or "selective compound" refers to a compound of the present disclosure that effectively modulates, reduces, or decreases the level of a specific protein (e.g., WIZ) or degrades a specific protein (e.g., WIZ) to a greater extent than any other protein. A "selective modulator," "selective degrader," or "selective compound" may be identified, for example, by comparing the ability of a compound to modulate, reduce, or decrease the level of or degrade a specific protein (e.g., WIZ) to its ability to modulate, reduce, or decrease the level of or degrade other proteins. In some embodiments, selectivity is measured by the EC 50 or IC 50 Degradation may be achieved through the mediation of an E3 ligase, for example an E3-ligase complex that includes the protein cereblon.

[0096] In one embodiment, the specific protein degraded is a WIZ protein. In some embodiments, at least about 30% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 40% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 50% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 60% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 70% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 75% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 80% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 85% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 90% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 95% of the WIZ is degraded compared to the initial level. In some embodiments, more than 95% of the WIZ is degraded compared to the initial level. In some embodiments, at least about 99% of the WIZ is degraded compared to the initial level.

[0097] In some embodiments, the WIZ is degraded at about 30% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 40% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 50% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 60% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 70% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 80% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 90% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 95% to about 99% of the initial level. In some embodiments, the WIZ is degraded at about 90% to about 95% of the initial level.

[0098] As used herein, the terms "inducing fetal hemoglobin," "fetal hemoglobin induction," or "increasing fetal hemoglobin expression" refer to increasing the proportion of HbF in the blood of a subject. In some embodiments, the amount of total HbF in the blood of a subject is increased. In some embodiments, the amount of total hemoglobin in the blood of a subject is increased. In some embodiments, the amount of HbF is increased by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 100%, or more than 100%, e.g., at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold, or at least about 9-fold, or at least about 10-fold, or more than 10-fold, compared to the amount in the absence of any of the compounds disclosed herein.

[0099] In certain embodiments, total hemoglobin in the blood, e.g., in the blood of a subject, is increased by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 100%, or more than 100%, e.g., at least about 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about 6-fold, or at least about 7-fold, or at least about 8-fold, or at least about 9-fold, or at least about 10-fold, or more than 10-fold, compared to either case in the absence of a compound disclosed herein.

[0100] The term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that will elicit a biological or medical response in a subject, such as reducing or inhibiting an enzyme or protein activity, or ameliorate symptoms, alleviate a pathology, slow or delay progression of a disease, or prevent a disease, etc. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, upon administration to a subject, is effective to at least partially alleviate, prevent, and / or ameliorate a condition, or disorder or disease that is (i) mediated by WIZ, or (ii) associated with WIZ activity, or (iii) characterized by activity (normal or abnormal) of WIZ; (2) is effective in reducing or inhibiting the activity of WIZ; or (3) is effective in reducing or inhibiting the expression of WIZ. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, upon administration to a cell, or tissue, or non-cellular biological material, or medium, is effective to at least partially reduce or inhibit the activity of WIZ; or to at least partially reduce or inhibit the expression of WIZ.

[0101] By "HBF-dependent disease or disorder" is meant any disease or disorder that is directly or indirectly affected by the regulation of HbF protein levels.

[0102] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0103] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0104] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the onset of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0105] As used herein, the terms "prevent", "preventing" or "prevention" of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or the delay in the onset or progression of the disease or disorder.

[0106] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0107] As used herein, the terms "a," "an," "the," and similar terms as used in the context of this disclosure (particularly in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0108] Various enumerated embodiments of the present disclosure are described herein. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0109] Enumerated Embodiments Embodiment 1. A compound of formula (I') or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, [ka] [In the formula, Y is O, CH 2 , C.F.2 and CHF; z is an integer from 0 to 2; R X1 and R X2 are each independently hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 are each independently hydrogen and C 1 ~C 6 alkyl; R Z1 and R Z2 are both hydrogen or or R Z1 and R Z2 One of and R Y1 and R Y2 Together with one of 1 ~C 2 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 the other two are both hydrogen; R 1 is hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and -O-(R 2a ) is substituted with 0 to 1 substituents independently selected from wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 2a is C 1 ~C 6 alkyl, where alkyl is C 6 ~C 10 substituted with 0 to 1 substituents independently selected from aryl; R 3 is -CH=CR 3a R 3b , C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3a and R 3b together with the carbon atoms to which they are attached, C 3 ~C 8 forming a cycloalkyl ring; Each R 3c For each occurrence, -C(=O)-R 3d , N.R. 3e R 3f , C 1 ~C 6 Alkoxyl, -OR 3d , Hydroxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3d is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 3e and R 3f are each independently hydrogen and C 1 ~C 6 alkyl; Each R 4 For each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 Alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c, halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Here, cycloalkyl is -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl and C 1 ~C 6 substituted with 0 to 3 substituents, each independently selected from haloalkyl; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, C 1 ~C 6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C6 cycloalkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 For each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 independently selected from haloalkyl; R 4b is -CN, halogen, -C(=O)NR 6a R 6b , N.R. 6a R 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; 1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c is C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 is C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b are each independently hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c For each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 alkyl, where alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S.

[0110] Embodiment 2. Wherein z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 Together with one of them, C 1 ~C 2 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 and the other of both are hydrogen, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0111] Embodiment 3. Wherein z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 Together with one of them, C 1 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 and the other of both are hydrogen.

[0112] Embodiment 4. Formula (I) [ka] [In the formula, Y is O, CH 2 , and C.F. 2 Selected from; z is an integer from 0 to 2; R X1 and R X2 are each independently hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 are each independently hydrogen and C 1 ~C 6 alkyl; R 1 is hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 substituted with 0 to 1 substituents independently selected from cycloalkyl; wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3 is -CH=CR 3a R 3b , C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3a and R 3b together with the carbon atoms to which they are attached, C 3 ~C 8 forming a cycloalkyl ring; Each R 3c For each occurrence, -C(=O)-R 3d , N.R. 3e R 3f , C 1 ~C 6 Alkoxyl, -OR 3d , Hydroxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3d is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 3e and R 3f are each independently hydrogen and C 1 ~C 6 alkyl; Each R 4 For each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 Alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Here, cycloalkyl is -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 substituted with 0 to 3 substituents each independently selected from alkoxyl, and hydroxyl; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 For each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 independently selected from haloalkyl; R 4b is -CN, -C(=O)NR for each occurrence. 6a R 6b , N.R. 6a R 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; 1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c is C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 is C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R6b are each independently hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c For each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0113] Embodiment 5. Formula (Ii) [ka] [In the formula, R X1 , R X2 , R Y1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt thereof.

[0114] Embodiment 6. Formula (Iia) or Formula (Iib) [ka] [In the formula, R X1 , R X2 , R Y1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt thereof.

[0115] Embodiment 7. Formula (Iic) or (Iid) [ka] [In the formula, R X1 , R X2 , R Y1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0116] Embodiment 8. Formula (Iie) or (Iif) [ka] [In the formula, R X1 , R X2 , R Y1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0117] Embodiment 9. Formula (I-ii) [ka] [In the formula, R X1 , R X2 , RY1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0118] Embodiment 10. Formula (I-ii-a) or (I-ii-b) [ka] [In the formula, R X1 , R X2 , R Y1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0119] Embodiment 11. Formula (I-ii-c) or (I-ii-d) [ka] [In the formula, R X1 , R X2 , R Y1 , R Y2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0120] Embodiment 12. Formula (I-ii-e) or (I-ii-f) [ka] [In the formula, R X1 , R X2 , R Y1 , RY2 , R 1 , R 2 and z is defined according to any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0121] Embodiment 13. The compound of formula Y is O, CH 2 , and C.F. 2 Selected from; z is an integer from 0 to 2; R X1 and R X2 each independently represents hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 each independently represents hydrogen and C 1 ~C 6 alkyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 substituted with 0 to 1 substituents independently selected from cycloalkyl; and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3 But, C 6 ~C 10aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3c However, for each occurrence, NR 3e R 3f , C 1 ~C 6 Alkoxyl, -OR 3d , Hydroxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3d is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 3eand R 3f wherein each of them is independently hydrogen and C 1 ~C 6 alkyl selected from; R 4 wherein each occurrence is C 6 ~C 10 aryl, -O-C 6 ~C 10 aryl, C 1 ~C 6 aryl C 6 ~C 10 alkyl -O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 alkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkyl, -SO 2 R 4c 、halogen, hydroxyl, -CN, -O-4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, oxo, C 1 ~C 6 haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b 、NR 6a R 6b 、-NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl independently selected from, wherein aryl, -O-aryl, arylalkyl -O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently substituted with 0 to 3 R 4a ; wherein alkyl and alkoxyl are each independently substituted with 0 to 1 R 4b ; and Wherein cycloalkyl is -CN, C 1 ~C 6 Alkyl, and C 1 ~C 6 substituted by 0 to 2 substituents each independently selected from alkoxyl; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 However, for each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 independently selected from haloalkyl; R 4b For each occurrence, -CN, -C(=O)NR 6a R 6b , N.R. 6a R 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; 1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c But, C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 But, C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b each independently represents hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c However, for each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6alkyl, where the alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0122] Embodiment 14. The compound of formula Y is O and CH 2 Selected from ; z is an integer from 0 to 2; R X1 and R X2 each independently represents hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 each independently represents hydrogen and C 1 ~C 6 alkyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 substituted with 0 to 1 substituents independently selected from cycloalkyl; and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3But, C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3c However, each time it appears, 1 ~C 6 Alkyl)amino, C 1 ~C 6 Alkoxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 4 However, for each occurrence, C 6 ~C 10 Aryl, -OC 6~C 10 Aryl C 1 ~C 6 Aryl C 6 ~C 10 Alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and where cycloalkyl is -CN 1 ~C 6 substituted with 0 to 2 substituents each independently selected from alkyl, methoxy, and ethoxy; R 4a For each occurrence, -CN, C 1 ~C 6Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 However, for each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 haloalkyl; R 4b For each occurrence, -CN, -C(=O)NR 6a R 6b , N.R. 6a R 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; 1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6substituted with 0 to 1 substituents each independently selected from alkyl; R 4c But, C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 But, C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b each independently represents hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c However, for each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 alkyl, where the alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0123] Embodiment 15. The compound of formula Y is O and CH 2 Selected from ; z is an integer from 0 to 2; R X1 and R X2 each independently represents hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 each independently represents hydrogen and C 1 ~C 6 alkyl; Here, R X1 and R X2 and are both C 1 ~C 6 If it is alkyl, then R Y1 and R Y2 are both hydrogen, and where R X1 and R X2 If and are both hydrogen, then R Y1 and R Y2 Both are C 1 ~C 6 is alkyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 is hydrogen, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 substituted with 0 to 1 substituents independently selected from cycloalkyl; and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4Replaced with; R 3 But, C 6 ~C 10 aryl, a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 Cycloalkyl and C 1 ~C 3 alkyl, where alkyl is selected from 0 to 2 R 3c is replaced by, and wherein aryl, heteroaryl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3c However, for each occurrence, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein aryl, heteroaryl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 4 However, for each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, oxo, C1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and wherein cycloalkyl is substituted with 0 to 1 substituents independently selected from: —CN; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; R 4a-1 However, for each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C1 ~C 6 haloalkyl; R 4b For each occurrence, -CN, -C(=O)NR 6a R 6b , a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH, a 4-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c But, C 6 ~C 10 Aryl, NH 2 and halogen; R 5 But, C 1 ~C 6 Alkyl, and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b each independently represents hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N and O, where the heterocyclyl is selected from 0-2 R 6c Replaced with; R 6c However, for each occurrence, C 6 ~C 10 Aryl C 1~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 alkyl, where alkyl is substituted with 0-1 substituents independently selected from 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0124] Embodiment 16. The compound of formula Y is O and CH 2 Selected from ; z is an integer from 0 to 2; R X1 and R X2 each independently represents hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 each independently represents hydrogen and C 1 ~C 6 alkyl; Here, R X1 and R X2 and are both C 1 ~C 6 If it is alkyl, then R Y1 and R Y2 are both hydrogen, and where R X1 and R X2 If and are both hydrogen, then R Y1 and R Y2 Both are C 1 ~C 6 is alkyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 But, C3 ~C 8 Cycloalkyl, C 1 ~C 6 Alkyl, -(CH 2 ) 1~2 -C 6 ~C 10 -(CH) containing 1 to 4 heteroatoms independently selected from aryl, N, O, and S 2 ) 1~2 - 5-10 membered heteroaryl, containing 1-2 heteroatoms independently selected from N and O -(CH 2 ) 1~2 -4-6 membered heterocyclyl, and -(CH 2 ) 1~2 -C 3 ~C 8 cycloalkyl; and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 4 R 4 Replaced with; R 4 However, for each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and wherein cycloalkyl is substituted with 0 to 1 substituents independently selected from: —CN; R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 2 R 4a-1 Replaced with; R 4a-1 However, for each occurrence, C 1 ~C 6 Alkyl and di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 independently selected from alkyl; R 4b For each occurrence, -C(=O)NR 6a R 6b , a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N and O, -C(=O)-OH, a 4-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S, and C 6 ~C 10 aryl, where aryl is selected from -CN, and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from haloalkyl; R 4c But, C 6 ~C 10 Aryl and NH 2 Selected from; R 5 But, C 1 ~C 6 Alkyl, and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b each independently represents hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N and O, where the heterocyclyl is selected from 0-1 R 6c Replaced with; R 6c However, for each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 alkyl, where alkyl is substituted with 0-1 substituents independently selected from 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0125] Embodiment 17. The compound of formula Y is O and CH 2 Selected from ; z is an integer from 0 to 2; R X1 and R X2each independently represents hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 each independently represents hydrogen and C 1 ~C 6 alkyl; Here, R X1 and R X2 and are both C 1 ~C 6 If it is alkyl, then R Y1 and R Y2 are both hydrogen, and where R X1 and R X2 are both hydrogen, then R Y1 and R Y2 Both are C 1 ~C 6 is alkyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 But, C 1 ~C 6 Alkyl, -(CH 2 )-phenyl, -(CH 2 )-5 to 10-membered heteroaryl, containing one heteroatom independently selected from N and O, -(CH 2 )-6-membered heterocyclyl, and -(CH 2 )-C 3 ~C 8 cycloalkyl; and wherein phenyl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 3 R 4 Replaced with; R 4each occurrence of is selected from phenyl, -O-phenyl, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Fluoroalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, oxo, C 1 ~C 6 Fluoroalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where phenyl, -O-phenyl, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and wherein cycloalkyl is substituted with 0 to 1 substituents independently selected from: —CN; R 4a However, for each occurrence, C 1 ~C 6 Fluoroalkyl, fluoro, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 2 R 4a-1 Replaced with; R 4a-1 However, for each occurrence, C 1 ~C 6 Alkyl and di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 independently selected from alkyl; R 4b For each occurrence, -C(=O)NR 6a R 6b , a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, -C(=O)-OH, a 4-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, and phenyl, wherein the phenyl is substituted with 0-1 substituents each independently selected from -CN; R 4c phenyl, and NH 2 Selected from; R 5 But, C 1 ~C 6 alkyl, and benzyl; R 6a and R 6b each independently represents hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6b together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N and O, where the heterocyclyl is selected from 0-1 R 6c Replaced with; R 6c Each occurrence of benzyl, -C(=O)-O-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0126] Embodiment 18. In the formula, R 3 is a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from phenyl, N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O; 3 ~C 6 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein phenyl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 4 R 4 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with

[0127] Embodiment 19. In the formula, R 3 is a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from phenyl, N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O; 3 ~C 6 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 1 R 3c is replaced by wherein phenyl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 4 R 4 is replaced by, and where R for each occurrence 3cis selected from phenyl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, and C 3 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, independently selected from: cycloalkyl.

[0128] Embodiment 20. In the formula, R 3 is a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from phenyl, N, O, and S; a 4-, 5-, or 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl, -(CH 2 ) 1~2 -phenyl, -(CH 2 ) 1~2 - 5-10 membered heteroaryl, containing 1-2 heteroatoms independently selected from N, O, and S -(CH 2 ) 1~2 -4- to 6-membered heterocyclyl and -(CH 2 ) 1~2 -C 3 ~C 8 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from cycloalkyl.

[0129] Embodiment 21. In the formula, each R 4 However, for each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 2 R 4a wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl are each independently substituted with 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Wherein cycloalkyl is -CN, C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0-2 substituents each independently selected from alkyl, methoxy, and ethoxy.

[0130] Embodiment 22. In the formula, each R4 each occurrence of each of these is selected from the group consisting of phenyl, -O-phenyl, benzyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl; wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by Wherein cycloalkyl is -CN, C 1 ~C 6 substituted with 0 to 2 substituents each independently selected from alkyl, methoxy and ethoxy; wherein phenyl and heteroaryl are each independently -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 substituted with 0 to 2 substituents each independently selected from haloalkyl and halogen; wherein heterocyclyl is independently -C(=O)-O-(R 5 ), and C1 ~C 6 substituted with 0 to 2 substituents each independently selected from alkyl, wherein alkyl is independently selected from 6 ~C 10 substituted by 0 to 1 substituents independently selected from aryl, and a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O; and wherein -O-phenyl, benzyl-O-, and -O-heteroaryl are each independently selected from hydroxyl, -C(=O)-O-(R 5 ), halogen, C 1 ~C 6 substituted with 0 to 3 substituents each independently selected from alkyl, wherein alkyl is independently selected from -C(=O)-NR 6a R 6b , and N.R. 6a R 6b , and 0 to 1 substituents independently selected from a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is 1 ~C 6 Alkyl and di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0-2 substituents each independently selected from alkyl.

[0131] Embodiment 23. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R3 is a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, or a C substituted with a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S 1 ~C 6 alkyl, wherein the heteroaryl is, each occurrence, independently selected from indolyl, imidazopyridyl, isoquinolinyl, benzoxazolonyl, pyridinyl, pyrimidinyl, pyridinonyl, benzotriazolyl, pyridazinyl, pyrazolotriazinyl, indazolyl, benzimidazolyl, quinolinyl, triazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, oxadiazolyl, imidazolyl, pyrrolopyridinyl, tetrahydroindazolyl, quinoxalinyl, thiadiazolyl, pyrazinyl, oxazolopyridinyl, pyrazolopyrimidinyl, benzoxazolyl, indolinyl, isoxazolopyridinyl, dihydropyridooxazinyl, and tetrazolyl, and wherein said heteroaryl is, each occurrence, independently substituted with 0 to 4 R 4 and, wherein R 4 is as defined in any of the preceding embodiments, a compound of any of the preceding embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0132] Embodiment 24. Wherein R 2 is unsubstituted C 1 ~C 6 alkyl or C substituted with a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S 1 ~C 10 alkyl (e.g., C 1 ~C 6 alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and, wherein R 3is substituted with a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heteroaryl is [ka] are independently selected from and wherein said heteroaryl, at each occurrence, independently represents 0 to 4 R 4 is replaced by In the formula, R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0133] Embodiment 25. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 is substituted with a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heteroaryl is [ka] Independently selected from, and wherein said heteroaryl is, each occurrence, independently, 0 to 3 R 4 substituted with, wherein R 4 is as defined by any of the previous embodiments, a compound of any of the previous embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0134] Embodiment 26. Wherein R 2 is unsubstituted C 1 ~C 6 alkyl or C substituted with 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S 1 ~C 10 alkyl (e.g., C 1 ~C 6 alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 wherein R is 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, or C substituted with 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S 3 ~C 1 ~C 6 alkyl, wherein heteroaryl is, each occurrence,

Chemical formula

Chemical formula

[0135] Embodiment 27. Wherein R 2But non-substituted C 1 ~C 6 C substituted with alkyl or a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 is substituted with a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heteroaryl is [ka] wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0136] Embodiment 28. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or a 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3is substituted with a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S, or a 5- to 10-membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heteroaryl is [ka] wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0137] Embodiment 29. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 is substituted with a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heterocyclyl is independently selected from piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, dihydroisoxazolyl, tetrahydropyran, pyrrolidinyl, and 2-oxaspiro[3.3]heptanyl; and wherein each occurrence of said heterocyclyl independently represents 0 to 4 R 4 wherein R4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0138] Embodiment 30. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 is substituted with a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heterocyclyl is [ka] are independently selected from and each occurrence of said heterocyclyl independently represents 0 to 3 R 4 wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0139] Embodiment 31. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 is substituted with a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heterocyclyl is [ka] wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0140] Embodiment 32. In the formula, R 2 But non-substituted C 1 ~C 6 C substituted with alkyl or 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 is substituted with a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 1 ~C 6 is alkyl, wherein each occurrence of heterocyclyl is [Chemistry] independently selected from, wherein R 4 is as defined by any of the previous embodiments, a compound of any of the previous embodiments, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0141] Embodiment 33. In the formula, each R 4 is, each time it appears, phenyl, -O-phenyl, benzyloxy-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 8 alkyl, C 1 ~C 6 alkoxyl, C 1 ~C 6 haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, -O-4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, oxo, C 1 ~C 6 haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-NR 6a R 6b , NR 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 6 cycloalkyl, independently selected, where phenyl, -O-phenyl, benzyloxy-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently substituted with 0 to 3 R 4a s, wherein alkyl and alkoxyl are each independently substituted with 0 to 1 R 4b s, and Wherein cycloalkyl is -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0-3 substituents each independently selected from alkoxyl, and hydroxyl.

[0142] Embodiment 34. In the formula, each R 4 each occurrence of is selected from phenyl, -O-phenyl, benzyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N and O, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 6 cycloalkyl, where phenyl, -O-phenyl, benzyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Wherein cycloalkyl is -CN, C 1 ~C 8 Alkyl, C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0-3 substituents each independently selected from alkoxyl, and hydroxyl.

[0143] Embodiment 35. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 6 ~C 10 Aryl-substituted C 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 6 ~C 10 Aryl or C 6 ~C 10 Aryl-substituted C 1 ~C 6 is alkyl, wherein each occurrence of aryl independently represents 0 to 3 R 4 is replaced by In the formula, each R 4 each occurrence of is selected from phenyl, -O-phenyl, benzyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from the group consisting of 1-2 heteroatoms, -O-4- to 6-membered heterocyclyl, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b , -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 6 cycloalkyl, where phenyl, -O-phenyl, benzyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0144] Embodiment 36. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 6 ~C 10 Aryl-substituted C 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 6 ~C 10 Aryl or C 6 ~C 10 Aryl-substituted C 1 ~C6 is alkyl, wherein each occurrence of aryl independently represents 0 to 3 R 4 is replaced by In the formula, each R 4 each occurrence of is selected from the group consisting of -O-phenyl, benzyl-O-, -O-(5- to 10-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing one heteroatom independently selected from N and O, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from the group consisting of 1-2 heteroatoms, -O-4- to 6-membered heterocyclyl, C 1 ~C 6 Haloalkoxyl, -C(=O)-NR 6a R 6b , and NR 6a R 6b are independently selected from wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by wherein -O-phenyl, benzyl-O-, and -O-heteroaryl are each independently selected from hydroxyl, -C(=O)-O-(R 5 ), halogens, and C 1 ~C 6 substituted with 0 to 2 substituents each independently selected from alkyl; wherein heterocyclyl is independently selected from C 1 ~C 6 substituted with 0 to 1 substituents independently selected from alkyl, wherein heteroaryl is independently -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl and C 1 ~C6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0-1 substituents independently selected from haloalkyl.

[0145] Embodiment 37. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 6 ~C 10 Aryl-substituted C 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 6 ~C 10 Aryl or C 6 ~C 10 Aryl-substituted C 1 ~C 6 is alkyl, wherein each occurrence of aryl independently represents 0 to 3 R 4 is replaced by In the formula, each R 4 Each occurrence of oxadiazolyl, pyrazolyl, tetrazolyl, 4-membered heterocyclyl containing one O heteroatom, C 1 ~C 8 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 haloalkyl, fluoro, chloro, iodo, hydroxyl, -CN, -O-4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, -C(=O)-NR 6a R 6b , and NR 6a R 6b are independently selected from wherein alkyl is a 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S; 1 ~C6 substituted with 0 to 1 substituents independently selected from alkoxyl, and phenyl; wherein each of the alkoxyl groups is independently -C(=O)-N(CH 2 ) 4~5 and morpholinyl, wherein the point of attachment to said morpholinyl is through the N atom; wherein heterocyclyl is independently selected from C 1 ~C 6 substituted with 0 to 1 substituents independently selected from alkyl, wherein oxadiazolyl, pyrazolyl, and tetrazolyl are each independently -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl and C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with 0-1 substituents independently selected from haloalkyl.

[0146] Embodiment 38. In the formula, R 2 But, C 1 ~C 6 Alkyl, [ka] [In the formula, [ka] represents an optional C=C double bond, which when present, A is O; A is NR 4d , O and CH 2 Selected from; R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6selected from haloalkyl, fluoro, chloro, iodo, hydroxyl, and -CN; R 4d is hydrogen, -C(=O)-O-(C 1 ~C 6 alkyl), 4-6 membered heterocyclyl containing one heteroatom selected from N and O, C 3 ~C 6 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 6 alkyl, wherein alkyl is selected from C 3 ~C 6 substituted by 0-1 substituents selected from cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O; Sub is C 1 ~C 6 Alkyl, halogen and C 1 ~C 6 haloalkyl], or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0147] Embodiment 39. In the formula, R 2 But, C 1 ~C 6 Alkyl, [ka] [In the formula, A is NR 4d , O and CH 2 Selected from; R 4 is C 1 ~C 6 is alkyl; R 4d is hydrogen, -C(=O)-O-(C 1 ~C 6 alkyl), 4-6 membered heterocyclyl containing one heteroatom selected from N and O, C 3 ~C 6Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 6 alkyl, wherein alkyl is selected from C 3 ~C 6 cycloalkyl, 4-6 membered heterocyclyl containing 1 O heteroatom; Sub is C 1 ~C 6 Haloalkyl, e.g., CF 3 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein

[0148] Embodiment 40. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C 6 is alkyl, where cycloalkyl, at each occurrence, is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bridging C 5 ~C 8 cycloalkyl; and wherein each occurrence of said cycloalkyl independently represents 0 to 3 R 4 wherein R 4is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0149] Embodiment 41. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C 6 is alkyl, wherein each occurrence of cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[2.2.2]octyl, and bicyclo[1.1.1]pentanyl; and wherein each occurrence of said cycloalkyl independently represents 0 to 3 R 4 wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0150] Embodiment 42. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 3 ~C 8 Cycloalkyl-substituted C1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C 6 is alkyl, where cycloalkyl at each occurrence is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and [ka] are independently selected from and wherein each occurrence of said cycloalkyl independently represents 0 to 3 R 4 wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0151] Embodiment 43. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C 10 Alkyl (e.g., C 1 ~C 6 Alkyl, e.g., C 1 alkyl), or -C(=O)-R 3 and In the formula, R 3 But, C 3 ~C 8 Cycloalkyl, or C 3 ~C 8 Cycloalkyl-substituted C 1 ~C6 is alkyl, where cycloalkyl at each occurrence is cyclobutyl, cyclopentyl, cyclohexyl, and [ka] wherein said cycloalkyl is independently selected from 0 to 2 occurrences of R 4 wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0152] Embodiment 44. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or [ka] One C to be selected 3 ~C 8 Cycloalkyl-substituted C 1 ~C 6 Alkyl (e.g., C 1 alkyl), wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0153] Embodiment 45. In the formula, R 2 But non-substituted C 1 ~C 6 Alkyl or [ka] One C to be selected 3 ~C 8 Cycloalkyl-substituted C 1 ~C 6Alkyl (e.g., C 1 alkyl), wherein R 4 is as defined by any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0154] Embodiment 46. In the formula, each R 4 However, for each occurrence, C 1 ~C 6 Alkoxyl, -NH-C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-O-(C 1 ~C 6 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0155] Embodiment 47. In the formula, each R 4 However, for each occurrence, C 1 ~C 6 Alkoxyl, -NH-C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-O-(C 1 ~C 3 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0156] Embodiment 48. Formula (Ia) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 is defined according to any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0157] Embodiment 49. Formula (Ib) [ka] (In the formula, R X1 , R X2 , R 1 and R 2 is defined according to any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0158] Embodiment 50. Formula (Ic) [ka] (In the formula, R 1 and R 2 is defined according to any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0159] Embodiment 51. Formula (Id) [ka] (In the formula, R 1 and R 2 is defined according to any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0160] Embodiment 52. Formula (Ia-i) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2is as defined in any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0161] Embodiment 53. Formula (Ia-ii) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 is as defined in any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0162] Embodiment 54. Formula (Ia-iii) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0163] Embodiment 55. Formula (Ia-iv) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0164] Embodiment 56. Formula (Ia-v) or (Ia-vi) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0165] Embodiment 57. Formula (Ia-vii) or (Ia-viii) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0166] Embodiment 58. Formula (Ia-ix) or (Ia-x) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0167] Embodiment 59. Formula (Ia-xi) or (Ia-xii) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0168] Embodiment 60. Formula (Ia-xiii) or (Ia-xiv) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0169] Embodiment 61. Formula (Ie) [ka] (In the formula, R Y1 , R Y2 , R 1 and R 2 is as defined in any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0170] Embodiment 62. Formula (If) [ka] (In the formula, R Y1 , R Y2 , R1 and R 2 is as defined in any of the preceding embodiments), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0171] Embodiment 63. In the formula: R Y1 and R Y2 each independently represents hydrogen and C 1 ~C 6 alkyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 But hydrogen, C 1 ~C 6 Alkyl, -C(=O)-CH 2 -(CH 2 ) 0~1 -R 3c , C 3 ~C 8 Cycloalkyl, -(CH 2 ) 1~2 -phenyl, -(CH 2 ) 1~2 - 5-10 membered heteroaryl, containing 1-2 heteroatoms independently selected from N, O, and S -(CH 2 ) 1~2 -4- to 6-membered heterocyclyl and -(CH 2 ) 1~2 -C 3 ~C 8 cycloalkyl, and wherein phenyl, heteroaryl, heterocyclyl, and cycloalkyl are each independently selected from 0 to 5 R 4 is replaced by, A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0172] Embodiment 64. In the formula: R Y1and R Y2 are each independently selected from hydrogen and methyl; R 1 But hydrogen and C 1 ~C 6 alkyl; R 2 But, C 1 ~C 6 Alkyl, C 3 ~C 8 Cycloalkyl, -(CH 2 ) 1~2 -phenyl, -(CH 2 ) 1~2 - 5-10 membered heteroaryl, containing 1-2 heteroatoms independently selected from N, O, and S -(CH 2 ) 1~2 -4- to 6-membered heterocyclyl and -(CH 2 ) 1~2 -C 3 ~C 8 cycloalkyl, and wherein phenyl, heteroaryl, heterocyclyl, and cycloalkyl are each independently selected from 0 to 5 R 4 is replaced by A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0173] Embodiment 65. In the formula, R Y1 and R Y2 and hydrogen and C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R is selected from alkyl, R is 0, R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is 11, R is 12, R is 13, R is 14, R is 15, R is 16, R is 17, R is 18, R is 19 ...

[0174] Embodiment 66. In the formula, R X1 and R X2 and hydrogen and C 1 ~C 6The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R is selected from alkyl.

[0175] Embodiment 67. In the formula, R 1 is hydrogen, and C 1 ~C 4 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R is selected from alkyl.

[0176] Embodiment 68. In the formula, R 1 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein is hydrogen.

[0177] Embodiment 69. In the formula, R 1 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein is methyl.

[0178] Embodiment 70. In the formula, R 2 But hydrogen, C 1 ~C 6 Alkyl, -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl, -(CH 2 ) 1~2 -phenyl, -(CH 2 ) 1~2 - 5-10 membered heteroaryl, containing 1-2 heteroatoms independently selected from N, O, and S -(CH 2 ) 1~2 -4- to 6-membered heterocyclyl and -(CH 2 ) 1~2 -C 3 ~C 8 cycloalkyl, where phenyl, heteroaryl, and heterocyclyl are each independently selected from 0 to 4 R 4and wherein cycloalkyl is independently substituted with 0 to 3 R 4 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with

[0179] Embodiment 71. In the formula, R 2 But, C 1 ~C 6 Alkyl, and -(CH 2 )-phenyl, where 0 to 4 occurrences of phenyl are selected from R 4 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with

[0180] Embodiment 72. In the formula, R 2 C 1 ~C 6 The compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R is alkyl.

[0181] Embodiment 73. In the formula, R 2 Ga-(CH 2 )-phenyl, where 0 to 3 occurrences of phenyl are R 4 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, substituted with

[0182] Embodiment 74. Formula (Ig) [ka] {where, R 1 and R 2 is as defined in any of the previous embodiments; For example, R 1 is hydrogen and C 1 ~C 6 alkyl, and R 2 is C1 ~C 6 Alkyl, e.g., unsubstituted C 1 ~C 6 Alkyl, [ka] [In the formula, [ka] represents an optional C=C double bond, which when present, A is O; A is NR 4d , O and CH 2 Selected from; R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 selected from haloalkyl, fluoro, chloro, iodo, hydroxyl, and -CN; R 4d is hydrogen, -C(=O)-O-(C 1 ~C 6 alkyl), 4-6 membered heterocyclyl containing one heteroatom selected from N and O, C 3 ~C 6 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 6 alkyl, wherein alkyl is selected from C 3 ~C 6 substituted by 0-1 substituents selected from cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O; Sub is C 1 ~C 6 Alkyl, halogen and C 1 ~C 6or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0183] Embodiment 75. Formula (Ih) [ka] {where, R 2 is as defined in any of the previous embodiments; For example, R 2 is C 1 ~C 6 Alkyl, e.g., unsubstituted C 1 ~C 6 Alkyl, [ka] [In the formula, A is NR 4d , O and CH 2 Selected from; R 4 is C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 selected from haloalkyl, fluoro, chloro, iodo, hydroxyl, and -CN; R 4d is hydrogen, -C(=O)-O-(C 1 ~C 6 alkyl), 4-6 membered heterocyclyl containing one heteroatom selected from N and O, C 3 ~C 6 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 6 alkyl, wherein alkyl is selected from C 3 ~C 6substituted by 0-1 substituents selected from cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N and O; Sub is C 1 ~C 6 Alkyl, halogen and C 1 ~C 6 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0184] Embodiment 76. Formula (Ih-i) [ka] [In the formula, R 2 is as defined in any of the preceding embodiments, for example, R 2 is as defined in embodiment 75], or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0185] Embodiment 77. Formula (Ih-ii) [ka] [In the formula, R 2 is as defined in any of the preceding embodiments, for example, R 2 is as defined in embodiment 75], or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0186] Embodiment 78. The glutarimide portion of the molecule is [ka] 2. The compound according to the preceding claim,

[0187] Embodiment 79. The glutarimide portion of the molecule is [ka] 2. The compound according to the preceding claim,

[0188] Embodiment 80. 3-(5-(((R)-1-((1-cyclohexyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-5-phenyl-1H-pyrazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenoxy)benzoate methyl; 3-(5-(((R)-1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(3-(pyrrolidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-((1H-pyrazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((3-(m-tolyl)-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(2H-1,2,3-triazol-2-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-methoxy-4-methylbenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(2-methyl-1H-imidazol-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-((1H-imidazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-isobutyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((2S)-1-((1-(cyclohex-3-en-1-ylmethyl)piperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((6-(diethylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-chloro-6-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((5-(benzyloxy)-6-methoxy-1H-indazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-benzylpiperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-morpholinobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((R)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperazine-1-carboxylate; 3-(5-(((R)-1-(3-((1H-imidazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(3-(pyrrolidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-Oxo-5-(((R)-1-(4-(piperidine-1-carbonyl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-benzylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-(cyclohexa-1,5-dien-1-yl)-1-methyl-1H-pyrazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-cyclohexyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(2-morpholinoethoxy)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-benzyl-1H-imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((S)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(2-morpholinoethoxy)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; Ethyl 3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1H-indazole-4-carboxylate; 3-(5-(((S)-1-((2-ethyl-4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3,3a,7a-tetrahydro-1H-isoindol-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenoxy)benzoate methyl; 3-(5-(((R)-1-((5-methylisoxazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-morpholinopyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzenesulfonamide; 3-(5-(((S)-1-(3-((1H-pyrazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((6-(diethylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-methoxy-4-methylbenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-isobutyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-chloro-4-hydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((1-(phenylsulfonyl)-1H-pyrrol-2-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-isopropylpiperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((1-(pyrazin-2-yl)-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-isopropyl-1-methyl-1H-pyrazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-isopropylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-(4-bromophenyl)isoxazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-(dimethylamino)pyrimidin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,5-diethylisoxazole-4-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(2H-1,2,3-triazol-2-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3',5-dimethyl-[3,5'-bisoxazole]-4'-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate benzyl; 3-(5-(((R)-1-(imidazo[1,2-a]pyridin-8-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-morpholinopyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,4-dimethoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-isopropylpiperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,5-difluoro-4-methoxybenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (1R,3S)-3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopentane-1-carboxylate; 3-(5-(((R)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-(methylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2,5-dimethyl-1-(5-methylisoxazol-3-yl)-1H-pyrrole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(benzyloxy)-4-methoxybenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(2-(2-oxo-2-(piperidin-1-yl)ethoxy)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1H-imidazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(2-(piperidin-1-yl)thiazole-5-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(2-methyl-1H-imidazol-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(4-pentylbenzoyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-methylimidazo[1,2-a]pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3,3-difluorocyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-4-ethyl-6,6-dimethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-3-methoxybenzonitrile; 2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile; 3-(5-(((R)-1-((2-ethyl-4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(cyclohexylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(4-(pyrrolidine-1-carbonyl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-((3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile; 2-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1H-imidazol-1-yl)acetic acid; 3-(5-(((R)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-(4-fluorophenyl)picolinoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzonitrile; 3-(5-(((S)-1-(5-butyl-4-methoxypyrimidine-2-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzonitrile; Ethyl 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1H-pyrazole-3-carboxylate; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzenesulfonamide; 3-(1-oxo-5-(((S)-1-(4-(2-oxopyrrolidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(3-methyloxetan-3-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((6-morpholinopyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((5-(pyridin-3-yloxy)-1H-indazol-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2,3-dihydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(4-(pent-3-yn-1-yloxy)benzoyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1H-imidazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-morpholinobenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-(benzyloxy)-6-methoxy-1H-indazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate benzyl; 3-(5-(((S)-1-(4-chloro-3-iodobenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-fluoro-4-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-methyl-3-phenyl-1H-pyrazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((6-methoxypyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-(2-morpholinoethoxy)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (1R,3S)-3-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopentane-1-carboxylate methyl; 3-(5-(((R)-1-((1H-imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(1-phenyl-1H-1,2,4-triazole-3-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-neopentylisoxazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((R)-1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-(dimethylamino)pyrimidin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-isobutylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(pyrimidin-5-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-hydroxypyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-aminopyrimidin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(4-methoxyphenyl)-1H-pyrazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-chloro-5-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzenesulfonamide; 3-(5-(((S)-1-(oxazol-4-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(2-(2-oxo-2-(piperidin-1-yl)ethoxy)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(5-propylisoxazole-3-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate methyl; 3-(5-(((R)-1-(2-((1H-1,2,4-triazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile; tert-butyl (1-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopentyl)carbamate; 3-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzonitrile; 3-(5-(((S)-1-(1-methyl-5-phenyl-1H-pyrazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-isopropylisoxazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-3-methoxybenzonitrile; 3-(5-(((S)-1-(2-ethylthiazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-(methylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-hydroxy-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(7-methoxy-1H-indole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-isopropylisoxazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((S)-1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-ethyl-6,6-dimethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-4-ethyl-6,6-dimethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-4-ethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(pyrimidin-5-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-methylisoxazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)picolinonitrile; 3-(1-oxo-5-(((S)-1-(quinoxaline-6-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(difluoromethoxy)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(1-methyl-1H-pyrazol-3-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-morpholinothiazole-4-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((6-fluoropyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4,4-difluorocyclohexyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-ethylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((S)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((S)-1-((S)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-isobutyrylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2,4-difluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carbonitrile; 3-(5-(((R)-1-(4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3,4-difluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((R)-1-((S)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-isobutylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-benzoylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-ethylazepan-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(oxazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1r,3R)-3-methoxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-morpholinobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-(cyclopropylmethyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-oxaspiro[3.3]heptan-6-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperazine-1-carboxylate; 3-(1-oxo-5-(((R)-1-(2-(piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(4-isobutylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(2-(4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 7-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)indoline-1-carboxylate; 3-(5-(((R)-1-(indolin-7-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-ethylindolin-7-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-chloro-4-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((5-fluoropyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1s,3S)-3-methoxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(2-(piperidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperidine-1-carboxylate; 3-(5-(((R)-1-(2-(1-ethylpiperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperidine-1-carboxylate; 3-(5-(((R)-1-(4-(1-ethylpiperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2,4-dimethoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(benzo[d][1,3]dioxol-5-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1r,3R)-3-hydroxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1s,3S)-3-hydroxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-fluoro-4-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-fluoro-2-hydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(3,4,5-trifluorobenzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; (5-(((R)-1-((2,4-dimethylthiazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2,4-dimethylthiazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(pyridin-4-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2,6-difluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-hydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-fluoropyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(quinolin-3-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-methylthiazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(quinolin-2-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-ethylphenyl)piperidine-1-carboxylate; 3-(5-(((R)-1-(3-ethyl-4-(piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-ethyl-4-(1-ethylpiperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(tert-butyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(piperidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3-methoxybicyclo[1.1.1]pentan-1-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-4-fluorophenyl)piperazine-1-carboxylate; 3-(5-(((R)-1-(5-fluoro-2-(piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(4-ethylpiperazin-1-yl)-5-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(1-(trifluoromethyl)cyclopropyl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(benzyloxy)ethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((6-morpholinopyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(3,6-dihydro-2H-pyran-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(5-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate; 3-(5-(((R)-1-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-methoxybenzonitrile; 3-(5-(((R)-1-((1H-benzo[d]imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 5-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-methoxybenzonitrile; 3-(1-oxo-5-(((R)-1-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(1-(2-fluoroethyl)piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(benzo[d]oxazol-5-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(oxetan-3-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(((R)-tetrahydrofuran-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(((S)-tetrahydrofuran-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(cyclopropylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1S)-1-(1-(((1r,4S)-4-methoxycyclohexyl)methyl)piperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1R)-1-(1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,3S,4S)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-isopropylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-(tert-butyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-cyclopropylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-ethyl-4-fluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((S)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((R)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((R)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((1S,3S,4R)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((1S,3S,4R)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((1R,3R,4S)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (S)-3-(5-(((1R,3R,4S)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0189] Embodiment 81. 3-(5-((R)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d; 3-(5-((R)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3,4,4,5,5-d 5 ; 3-(5-(((R)-1-(2-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d; 3-(5-(((R)-1-(2-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3,4,4,5,5-d 5 ; 3-(5-(((R)-1-(4-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d; 3-(5-(((R)-1-(4-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3,4,4,5,5-d 5 ; 3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d; 3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3,4,4,5,5-d 5 ; 3-(5-(((R)-1-(4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d; 3-(5-(((R)-1-(4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3,4,4,5,5-d 5 ; 3-(5-(((R)-1-(((1r,3R)-3-methoxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3-d; and 3-(5-(((R)-1-(((1r,3R)-3-methoxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione-3,4,4,5,5-d 5 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0190] Embodiment 82. A compound of any of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the pharma- ceutically acceptable salt is an acid addition salt.

[0191] Embodiment 83. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

[0192] Embodiment 84. A method for treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0193] Embodiment 85. A method for degrading the WIZ protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0194] Embodiment 86. A method for inhibiting the expression of the WIZ protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0195] Embodiment 87. A method for inhibiting, reducing, or abolishing the activity or expression of the WIZ protein, the method comprising administering to a subject a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0196] Embodiment 88. A method for inducing or promoting fetal hemoglobin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0197] Embodiment 89. A method for reactivating the production or expression of fetal hemoglobin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0198] Embodiment 90. A method for increasing fetal hemoglobin expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0199] Embodiment 91. A method for treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0200] Embodiment 92. A method of treating sickle cell disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0201] Embodiment 93. A method for treating β-thalassemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0202] Embodiment 94. A method for treating a disease or disorder affected by modulation of WIZ protein levels, comprising administering to a patient in need thereof a compound of any one of embodiments 1-82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0203] Embodiment 95. A method for treating or preventing a disorder affected by decreased WIZ protein levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0204] Embodiment 96. A method for reducing WIZ protein levels in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0205] Embodiment 97. A compound according to any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use as a medicament.

[0206] Embodiment 98. A compound of any one of embodiments 1-82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder selected from sickle cell disease and β-thalassemia.

[0207] Embodiment 99. A compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease or disorder in a subject in need thereof.

[0208] Embodiment 100. A compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disorder affected by reduced levels of WIZ protein in a subject in need thereof.

[0209] A compound according to any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is used to inhibit the expression of the WIZ protein in a subject in need thereof.

[0210] A compound according to any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is used to degrade the WIZ protein in a subject in need thereof.

[0211] A compound according to any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is used to inhibit, reduce, or abolish the activity or expression of the WIZ protein in a subject in need thereof.

[0212] A compound according to any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is used to induce or promote fetal hemoglobin in a subject in need thereof.

[0213] A compound according to any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is used to reactivate the production or expression of fetal hemoglobin in a subject in need thereof.

[0214] A compound according to any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which is used to increase the expression of fetal hemoglobin in a subject in need thereof.

[0215] Embodiment 107. A compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a hemoglobinopathy in a subject in need thereof.

[0216] Embodiment 108. A compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating sickle cell disease in a subject in need thereof.

[0217] Embodiment 109. A compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating β-thalassemia in a subject in need thereof.

[0218] Embodiment 110. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0219] Embodiment 111. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin.

[0220] Embodiment 112. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by reactivation of fetal hemoglobin production or expression.

[0221] Embodiment 113. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

[0222] Embodiment 114. The use of a compound of any of embodiments 110 to 113, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0223] Embodiment 115. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0224] Embodiment 116. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by the induction of fetal hemoglobin.

[0225] Embodiment 117. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by reactivation of fetal hemoglobin production or expression.

[0226] Embodiment 118. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

[0227] Embodiment 119. The use of a compound of any of embodiments 115 to 118, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0228] Embodiment 120. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0229] Embodiment 121. Use of a compound of any one of embodiments 1 to 82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder affected by induction of fetal hemoglobin, reactivation of fetal hemoglobin production or expression, or increased fetal hemoglobin expression.

[0230] Embodiment 122. The use of embodiment 120 or 121, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0231] Embodiment 123. A pharmaceutical combination comprising a compound of any of embodiments 1-82, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents.

[0232] The compounds may exist in one of the possible isomers or as a mixture thereof, for example as pure optical isomers or as isomeric mixtures depending on the number of asymmetric centers, such as racemic and diastereomeric mixtures, depending on the selection of starting materials and procedures. The present disclosure is intended to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures and optically pure forms. Optically active (R) and (S) isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain di- or trisubstituted cycloalkyl, one or more cycloalkyl substituents may have cis or trans configurations. The present disclosure encompasses cis and trans configurations of substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also intended to be encompassed. In particular, when a heteroaryl ring containing N as a ring atom is a 2-pyridone, tautomers in which, for example, the carbonyl is depicted as hydroxy (e.g., 2-hydroxypyridine) are encompassed.

[0233] Pharmaceutically acceptable salts As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and are typically not biologically or otherwise undesirable. The compounds of the present disclosure may be capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0234] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, formic acid, trifluoroacetic acid, etc.

[0235] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from groups 1-12 of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0236] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0237] In another aspect, the present disclosure provides an agonist / agonist salt of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutaric acid, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, laurate, lauryl sulfate ... The present invention provides compounds in the form of a carbohydrate, glycerol, sorbitol, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate salt.

[0238] In another aspect, the disclosure provides a compound in the form of a sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, iron salt, silver salt, zinc salt, copper salt, isopropylamine salt, benzathine salt, cholinate salt, diethanolamine salt, diethylamine salt, lysine salt, meglumine salt, piperazine salt or tromethamine salt.

[0239] Preferably, the formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (I The pharma- ceutically acceptable salts of the compounds of formula (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i) and (Ih-ii) are acid addition salts.

[0240] isotope labeled compounds Any formula provided herein is also intended to represent the unlabeled form as well as the isotopically labeled form of the compound. Isotopically labeled compounds have the structure depicted in the formula provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, respectively: 2 H, 3 H, 11 C. 13 C. 14 C. 18 O. 15 N, 18 F, 17 O. 18 O. 35 S, 36 Cl, 123 I, 124 I, 125 I and other isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine. The present disclosure includes various isotopically labeled compounds as defined herein, e.g., 3 H and 14 C, or 2 H and 13including those in which non-radioactive isotopes such as C are present therein. Such isotope-labeled compounds are useful in metabolic studies ( 14 with C), kinetic studies (e.g., 2 with H or 3 with H), in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in the radioactive treatment of patients. Specifically, 18 F compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of formula (I’), formula (I), formula (I-i), formula (I-i-a), formula (I-i-b), formula (I-i-c), formula (I-i-d), formula (I-i-e), formula (I-i-f), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached examples and general schemes (e.g., general schemes 5a and 5b), using appropriate isotope-labeled reagents in place of the previously used unlabeled reagents.

[0241] In one embodiment of any aspect of the present disclosure, the hydrogen in the compound of formula (I’) or formula (I) is present at its normal isotopic abundance. In another embodiment, the hydrogen is isotopically enriched with deuterium (D), and in a detailed embodiment of the present invention, for example, one or more hydrogens in the glutarimide moiety of the compound of formula (I’) or formula (I) are enriched with D, for example,

Chemical formula

[0242] Additionally, heavier isotopes, particularly deuterium (i.e. 2 Substitution with H or D) may result in certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements or improved therapeutic index. In this context, deuterium is a hydroxyl group represented by formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i ... i), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i) and (Ih-ii) are understood to be regarded as substituents of the compounds. The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present disclosure is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0243] Pharmaceutically acceptable solvates according to the present disclosure include, for example, 2 O, d 6 -Acetone, d 6 - DMSO and other crystallization solvents may be isotopically substituted.

[0244] Compounds of the present disclosure containing a group capable of acting as a hydrogen bond donor and / or acceptor, i.e., compounds of formula (I'), (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ii ... The compounds of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) may be capable of forming co-crystals with a suitable co-crystal former. Such cocrystals include those represented by formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ...

[0113] The compounds of formula (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i) and (Ih-ii) may be prepared by known co-crystal formation procedures.Such procedures include the synthesis of (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), Ia-i, ... The method includes contacting a compound of formula (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i) and (Ih-ii) with a co-crystal former and isolating the co-crystal formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0245] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to better illustrate the disclosure and do not pose limitations on the scope of the disclosure as originally claimed.

[0246] Any asymmetric center (e.g., carbon, etc.) of one or more compounds of the present disclosure can be present in racemic or enantioenriched form, e.g., in the (R), (S) or (R,S) configuration. In certain embodiments, e.g., as a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. In certain embodiments, for example, in enantiomerically enriched forms, each chiral center is present in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Thus, the compounds of the present disclosure can be present in racemic mixtures, enantiomerically enriched forms, enantiopure forms, or as mixtures of diastereomers.

[0247] In one embodiment, the compound of formula (I') is a compound of formula (Iia), formula (Iib), formula (I-ii-a), or formula (I-ii-b): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0248] In one embodiment, the compound of formula (Iia) is a compound of formula (Ii-ai) or formula (Ii-aii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0249] In one embodiment, the compound of formula (Iib) is a compound of formula (Ii-bi) or formula (Ii-bii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0250] In one embodiment, the compound of formula (I-ii-a) is a compound of formula (I-ii-ai) or formula (I-ii-aii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0251] In one embodiment, the compound of formula (I-ii-b) is a compound of formula (I-ii-bi) or formula (I-ii-bii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0252] In another embodiment, the compound of formula (I') is a compound of formula (Ii) or formula (I-ii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0253] In the formula of the present application, C-sp 3 Above terms [ka] indicates the absolute stereochemistry of either (R) or (S). 3 Above terms [ka] indicates the absolute stereochemistry of either (R) or (S). 3 Above terms [ka] represents a covalent bond, where the stereochemistry of the bond is not defined. This is the case for C-sp 3 Above terms [ka] is meant to include either the (S) or (R) configuration of each chiral center. Additionally, mixtures may also exist. Thus, mixtures of stereoisomers, e.g., racemates, mixtures of enantiomers, and / or mixtures of diastereomers are encompassed by the present disclosure.

[0254] For the avoidance of doubt, any R group, e.g. R 1 Regarding the bond [ka] When a compound structure is drawn without a defined stereochemistry, as represented by:

[0255] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates, or mixtures thereof.

[0256] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0257] Any resulting racemates of the compounds or intermediates of the present disclosure can be resolved into their optical isomers (enantiomers) by known methods, for example, by separation of the diastereomeric salts obtained with optically active acids or bases, and liberation of the optically active acidic or basic compounds. In particular, the compounds of the present disclosure can be resolved into their optical antipodes by fractional crystallization of salts formed in this way with optically active acids, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using basic moieties. The racemates or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0258] Furthermore, the compounds of the present disclosure, including their salts, may also be obtained in the form of their hydrates, or may include other solvents used in their crystallization. The compounds of the present disclosure may inherently or intentionally form solvates with pharma-ceutically acceptable solvents, including water; thus, the present disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds of the present disclosure (including their pharma-ceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field, such as water, ethanol, etc., which are known to be harmless to recipients. The term "hydrate" refers to a complex when the solvent molecule is water. The presence of solvates can be identified by those skilled in the art by means such as NMR.

[0259] Compounds of the present disclosure, including salts, hydrates and solvates thereof, may inherently or intentionally form polymorphs.

[0260] In the compounds of the present disclosure, the stereocenter at C-3 of the glutarimide moiety (marked with an *) may be prone to epimerization under basic conditions. [ka]

[0261] Separation of diastereomers (or enantiomers as the case may be) at this position can be achieved according to chiral separation techniques known in the art. In particular, separation can be carried out according to Example 26.

[0262] In one embodiment of the compounds of the present disclosure, the absolute configuration at the glutarimide stereocenter (marked above with *) is S.

[0263] In another embodiment of the compounds of the present disclosure, the absolute configuration at the glutarimide stereocenter (marked above with *) is R.

[0264] In one embodiment, there is provided a compound as described in any one of the Examples or according to any of embodiments 1-82, wherein the absolute configuration at the glutarimide stereocenter (marked above with *) is S.

[0265] In another embodiment, there is provided a compound as described in any one of the Examples or according to any of embodiments 1-82, wherein the absolute configuration at the glutarimide stereocenter (marked above with *) is R.

[0266] Method of preparation The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as would be understood by those skilled in the art.

[0267] Generally, compounds of formula (I') and formula (I) can be prepared according to the schemes provided below.

[0268] General Scheme 1 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared as known to those skilled in the art or as disclosed herein. In general, the compounds of the present disclosure are prepared as follows, in Reaction Scheme 1 above:

[0269] In step 1, INT-1 can be reacted with an alcohol partner of formula INT-1A in the presence of a polar solvent such as acetonitrile (ACN) through a metal photoredox reaction, such as an iridium (Ir)-catalyzed photoredox coupling, to provide the cross-coupled ether product INT-2. Removal of the protecting group (e.g., Boc) under acidic conditions can provide the free amine (I)-1 (step 2), which can then be converted to (I)-2 via reductive amination with a suitable aldehyde in the presence of a borohydride reagent such as sodium borohydride acetate (step 3-i), or an alkylation reaction with a suitable alkyl mesylate in the presence of an amine base and a polar solvent such as diisopropylethylamine (DIPEA) and dimethylformamide (DMF) (step 3-ii). If the compound of formula (I)-2 contains an N-protected moiety, such as an N-protected piperazine group, it can be further converted to (I)-3 in step 4 by deprotection (e.g., Boc) under acidic conditions, followed by reductive amination with an appropriate aldehyde and sodium borohydride reagent, or alkylation reaction with an appropriate alkylating reagent, or amide coupling with an appropriate activating agent and base to provide the compound of formula (I)-4. 2 , R 6a , R 6b and R 6c is as defined herein, specifically according to any of the enumerated embodiments 1-80.

[0270] General Scheme 2 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared as known to those skilled in the art or by the methods disclosed herein. In general, the compounds of the present disclosure are prepared as follows, in the above reaction scheme 2: Compounds of formula (I)-1 can be converted to (I)-5 via reductive amination with an appropriate ketone in the presence of a borohydride reagent such as sodium borohydride acetate (step 3-i), or by the addition of K 2 CO 3 (I)-6 can be converted to (I)-7 via an alkylation reaction with an appropriate alkyl iodide in the presence of a base such as dimethylacetamide (DMA) and a polar solvent such as dimethylacetamide (DMA). 2 is as defined herein, specifically according to any of the enumerated embodiments 1-80.

[0271] General Scheme 3 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared as known to those skilled in the art or as disclosed herein. In general, the compounds of the present disclosure are prepared as follows in the above reaction scheme 3: Compound (I)-1 is subjected to an amide coupling reaction with an appropriate carboxylic acid, an activating agent such as HATU, and a base such as DIPEA or NMM to give the amide product (I)-7. For Scheme 3, R 3 is as defined herein, specifically according to any of the enumerated embodiments 1-80.

[0272] General Scheme 4 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared as known to those skilled in the art or as disclosed herein. In general, the compounds of the present disclosure are prepared as follows, in reaction scheme 4 above:

[0273] In step 1, (INT-3) can be reacted with an alcohol partner of formula (INT-1B) in the presence of a polar solvent such as acetonitrile (ACN) in a metal photoredox reaction, such as an iridium (Ir)-catalyzed photoredox coupling, to provide the cross-coupled ether product (4)-I. Removal of the protecting group (e.g., Boc) under acidic conditions can provide the free amine (4)-II (step 2), which can then be converted to (4)-III via reductive amination (step 3-i) with a suitable aldehyde in the presence of a borohydride reagent such as sodium borohydride acetate. Alternatively, (4)-II can be converted to 4-(III) via an alkylation reaction (step 3-ii) with a suitable alkyl mesylate or alkyl halide in the presence of an amine base and a polar solvent such as diisopropylethylamine (DIPEA) and dimethylformamide (DMF) as described in general schemes 1 and 2. Alternatively, (4)-II may be converted to 4-(III) via an amide coupling reaction (step 3-iii) with an appropriate carboxylic acid, an activating agent such as HATU, and a base such as DIPEA or NMM in a polar solvent such as DMF, as described in general schemes 1 and 3. 2 Chlorination with a suitable agent such as HCl and ring-opening of lactone (4)-III gives (4)-IV. Subsequent amidation with INT-IC under acidic conditions and ring-closure by nucleophilic substitution gives the final product of formula (I') or formula (I). For Scheme 4, Y, z, R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , R 1 and R 2 is as defined herein, specifically according to any of the enumerated embodiments 1-80.

[0274] General Schemes 5a and 5b: Deuterated Compounds of the Disclosure Scheme 5a: [ka] Scheme 5b: [ka] Compounds (4)-IV can be prepared according to general scheme 4. Subsequent amidation with deuterated INT-XX-D (prepared according to WO 2012 / 068512) or deuterated INT-XX-Di (prepared according to WO 2012 / 079022) under acidic conditions and ring closure by nucleophilic substitution gives the final compounds of formula (I') (wherein Y, z, R 1 , R 2 , R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 is as defined according to any of embodiments 1 to 80).

[0275] In one embodiment, there is provided a compound of formula INT-2 or a salt thereof. In another embodiment, there is provided a compound of formula (I)-1 or a salt thereof.

[0276] In a further embodiment, a compound of formula (X) or a salt thereof [ka] [In the formula, Y is O and CH 2 , C.F. 2 and CHF; z is an integer from 0 to 2; R X1 and R X2 are each independently hydrogen and C 1 ~C 6 alkyl; R Y1 and R Y2 are each independently hydrogen and C 1~C 6 alkyl; R Z1 and R Z2 are both hydrogen or or R Z1 and R Z2 One of and R Y1 and R Y2 Together with one of 1 ~C 2 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 the other two are both hydrogen; R 1 is hydrogen, and C 1 ~C 6 alkyl; R 2 is hydrogen, a nitrogen protecting group (PG) (preferably tert-butyl carbamate (Boc)), -C(=O)-R 3 , C 3 ~C 8 Cycloalkyl, C 1 ~C 6 Haloalkyl and C 1 ~C 10 alkyl, wherein alkyl is selected from C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and -O-(R 2a ) is substituted with 0 to 1 substituents independently selected from and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 2a is C 1 ~C 6 alkyl, where alkyl is C 6 ~C 10substituted with 0 to 1 substituents independently selected from aryl; R 3 is -CH=CR 3a R 3b , C 6 ~C 10 aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl, where alkyl is selected from 0 to 3 R 3c is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3a and R 3b together with the carbon atoms to which they are attached, C 3 ~C 8 forming a cycloalkyl ring; Each R 3c For each occurrence, -C(=O)-R 3d , N.R. 3e R 3f , C 1 ~C 6 Alkoxyl, -OR 3d , Hydroxyl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C 6 ~C 10 aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; wherein -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R 4a is replaced by, and wherein aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R 4 Replaced with; R 3d is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 3e and R 3f are each independently hydrogen and C 1 ~C 6 alkyl; Each R 4 For each occurrence, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, C 1 ~C 6 Aryl C 6 ~C 10 Alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, -SO 2 R 4c , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C 1 ~C 6 Haloalkoxyl, -C(=O)-O-(R 5 ), -C(=O)-(R 5 ), -C(=O)-NR 6a R 6b , N.R. 6a R 6b, -NH-C(=O)-O-(C 1 ~C 6 alkyl), and C 3 ~C 8 cycloalkyl, where aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R 4a is replaced by wherein alkyl and alkoxyl each independently represent 0 to 1 R 4b is replaced by, and Here, cycloalkyl is -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl and C 1 ~C 6 substituted with 0 to 3 substituents, each independently selected from haloalkyl; Each R 4a For each occurrence, -CN, C 1 ~C 6 Alkoxyl, C 1 ~C 6 Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R 5 ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C 1 ~C 6 Alkyl)amino C 1 ~C 6 Alkyl, C 1 ~C 6 alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 6 cycloalkyl, where alkyl is selected from 0 to 1 R 4b and wherein heteroaryl is substituted with 0 to 3 R 4a-1 Replaced with; Each R 4a-1 For each occurrence, C 1 ~C 6 Alkyl, di(C 1 ~C 6 Alkyl)amino C1 ~C 6 Alkyl, -CN, C 1 ~C 6 Alkoxyl and C 1 ~C 6 haloalkyl; Each R 4b is -CN, halogen, -C(=O)NR 6a R 6b , N.R. 6a R 6b , a 5-10 membered heteroaryl ring containing 1-4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; 1 ~C 6 alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl, C 2 ~C 4 Alkynyl, and C 6 ~C 10 aryl, where aryl is selected from -CN, C 1 ~C 6 Haloalkyl and C 1 ~C 6 substituted with 0 to 1 substituents each independently selected from alkyl; R 4c is C 6 ~C 10 Aryl, Hydroxyl, NH 2 and halogen; R 5 is C 1 ~C 6 Alkyl, C 6 ~C 10 Aryl and C 6 ~C 10 Aryl C 1 ~C 6 alkyl; R 6a and R 6b are each independently hydrogen and C 1 ~C 6 selected from alkyl; or R 6a and R 6btogether with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, where the heterocyclyl is selected from 0-2 R 6c Replaced with; Each R 6c For each occurrence, C 6 ~C 10 Aryl C 1 ~C 6 Alkyl, -C(=O)-O-(C 1 ~C 6 alkyl), -C(=O)-(C 1 ~C 6 alkyl), oxo, and C 1 ~C 6 alkyl, where alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S.

[0277] In one embodiment, z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 One of them is C 1 ~C 2 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 The other two are both hydrogen.

[0278] In one embodiment, z is 1; R Z1 and R Z2 One of and R Y1 and R Y2 One of them is C 1 Forming an alkylene bridging group, R Z1 and R Z2 And R Y1 and R Y2 The other two are both hydrogen.

[0279] In one embodiment, R Z1 and RZ2 are both hydrogen.

[0280] In one embodiment, R 1 is hydrogen.

[0281] In one embodiment, R Z1 and R Z2 are both hydrogen, and R 1 is hydrogen.

[0282] In one embodiment, R Z1 and R Z2 are both hydrogen, and R 1 is hydrogen, and R 2 is hydrogen.

[0283] In a further embodiment, R 1 , R 2 , R Y1 , R Y2 , R X1 , R X2 , R Z1 , R Z2 , Y and z are as defined in any of the enumerated embodiments 1 to 80. In addition, R 2 may be a nitrogen protecting group (PG) (eg, tert-butyl carbamate (Boc)).

[0284] In a further embodiment, the compound of formula (X) has the formula (X)-i [ka] (In the formula, R 1 , R 2 , R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , Y and z are defined by formula (X) above.

[0285] In a further embodiment, the compound of formula (X) has the formula (X)-ii [ka] (In the formula, R 1 , R 2 , R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , Y and z are defined by formula (X) above.

[0286] In a further embodiment of formula (X) (or formula (X)-i or formula (X)-ii), (R)-5-((1-ethylpiperidin-2-yl)methoxy)isobenzofuran-1(3H)-one; (S)-5-((1-ethylpiperidin-2-yl)methoxy)isobenzofuran-1(3H)-one; 5-((R)-1-((S)-1-ethylpiperidin-2-yl)ethoxy)isobenzofuran-1(3H)-one; 5-((S)-1-((S)-1-ethylpiperidin-2-yl)ethoxy)isobenzofuran-1(3H)-one; 5-((S)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)isobenzofuran-1(3H)-one; and 5-((R)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)isobenzofuran-1(3H)-one A compound selected from the following is provided:

[0287] In a further embodiment, the formula (Y) [ka] (In the formula, R 1 , R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , Y and z are defined according to formula (X) above, and PG1 and P.G. 2 are both nitrogen protecting groups as defined herein.

[0288] In one embodiment, PG 1 is a base-labile protecting group, PG 2 is an acid labile protecting group.

[0289] In one embodiment, PG 1 is the SEM protecting group (trimethylsilylethoxymethyl), and PG 2 is a BOC protecting group (tert-butyloxycarbonyl).

[0290] In a further embodiment, the compound of formula (Y) has the formula (Y)-i [ka] (In the formula, R 1 , R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , Y, z, P.G. 1 and P.G. 2 is defined by formula (Y) above.

[0291] In a further embodiment, the compound of formula (Y) has the formula (Y)-ii [ka] (In the formula, R 1 , R X1 , R X2 , R Y1 , R Y2 , R Z1 , R Z2 , Y, z, P.G. 1 and P.G. 2 is defined by formula (Y) above.

[0292] In a further embodiment of formula (X) (or formula (X)-i or formula (X)-ii), (2R)-tert-butyl 2-(((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidine-1-carboxylate; and (2S)-tert-Butyl 2-(((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidine-1-carboxylate A compound selected from the following is provided:

[0293] In a further aspect, the present disclosure provides a process for preparing a compound of formula (I') or formula (I), in free form or in the form of a pharma- ceutically acceptable salt, comprising the steps of: 1) coupling an aryl bromide of formula (INT-1) or formula (INT-3) with an alcohol of formula (INT-1A) or (INT-1B) under photoredox coupling conditions, thereby giving a compound of formula (INT-2) or formula (4)-I as defined herein. The present invention provides a method comprising:

[0294] In a further aspect, the present disclosure provides a process for preparing a compound of formula (I') or formula (I), in free form or in the form of a pharma- ceutically acceptable salt, comprising the steps of: 1) coupling an aryl bromide of formula (INT-3) with an alcohol of formula (INT-1B) under photoredox coupling conditions, thereby providing a compound of formula (4)-I as defined herein; 2) deprotecting the compound of formula (4)-I, thereby providing a compound of formula (4)-II as defined herein; 3) reacting a compound of formula (4)-II under reductive amination conditions, thereby providing a compound of formula (4)-III as defined herein; 4) The compound of formula (4)-III is reacted with SOCl 2 chlorinating with a nucleophilic chlorinating reagent, such as, to give a compound of formula (4)-IV as defined herein; 5) reacting a compound of formula (4)-IV with a compound of formula (INT-1C), thereby giving a compound of formula (I') or formula (I) as defined herein (or formula (I)-8 as depicted in General Scheme 4); and 6) Optionally, purifying the compound of formula (I') or formula (I) as defined herein (or formula (I)-8 as depicted in General Scheme 4). The present invention provides a method comprising:

[0295] In a further aspect, the present disclosure provides a process for preparing a compound of formula (I') or formula (I), in free form or in the form of a pharma- ceutically acceptable salt, comprising the steps of: 1) coupling an aryl bromide of formula (INT-1) with an alcohol of formula (INT-1A) under photoredox coupling conditions, thereby giving a compound of formula (INT-2) as defined herein; 2) deprotecting the compound of formula (INT-2), thereby providing a compound of formula (I)-1 (or formula (I') or formula (I)) as defined herein; 3-i) optionally reacting a compound of formula (I)-1 under reductive amination conditions, thereby giving a compound of formula (I)-2 (or formula (I') or formula (I)) as defined herein; or 3-ii) optionally reacting a compound of formula (I)-1 under alkylation conditions, thereby giving a compound of formula (I)-2 (or formula (I') or formula (I)) as defined herein; or 3-iii) optionally reacting a compound of formula (I)-1 under amide coupling conditions, thereby giving a compound of formula (I)-7 (or formula (I') or formula (I)) as defined herein; 4) optionally deprotecting the compound of formula (I)-2, thereby providing a compound of formula (I)-3 (or formula (I') or formula (I)) as defined herein; and 5) Optionally, reacting a compound of formula (I)-3 under reductive amination conditions, thereby giving a compound of formula (I)-4 (or formula (I') or formula (I)) as defined herein. The present invention provides a method comprising:

[0296] For any of the preceding method steps or below, the photoredox coupling reaction conditions are [Ir{dF(CF 3 )ppy} 2 {dtbbpy}]PF 6 Ir(III) catalysts such as [NiCl 2 The reaction involves the use of a Ni(II) complex such as [4-(4-nitrophenyl)-2,4-diphenyl-1,4-diphenyl ...

[0297] For any of the preceding method steps or below, the reductive amination conditions may comprise reacting the corresponding aldehyde, NaBH(OAc) 3 The reaction involves the use of a suitable hydride reagent, such as, a suitable solvent, such as DMF, and is carried out at room temperature (rt).

[0298] For any of the process steps above or below, the alkylation reaction conditions involve the use of the corresponding sulfonate ester, such as the corresponding mesylate, a suitable base, such as DIPEA, a suitable solvent, such as DMF, and the reaction is carried out under microwave conditions at a suitable temperature, such as 100° C.

[0299] For any of the method steps above or below, the amide coupling reaction conditions involve the use of the corresponding carboxylic acid, an activating agent such as HATU, a suitable base such as DIPEA or NMM, a suitable solvent such as DMF, and the reaction is carried out at a suitable temperature, such as room temperature, for a suitable length of time, for example 12 hours.

[0300] In a further embodiment, a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ii), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Ii ... Methods for preparing compounds of formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) are provided.

[0301] Compounds of formula (INT-1), formula (I)-I, and formula (X) as defined herein are useful in the preparation of the compounds of the present disclosure, for example, compounds of formula (I’), formula (I), formula (I-i), formula (I-i-a), formula (I-i-b), formula (I-i-c), formula (I-i-d), formula (I-i-e), formula (I-i-f), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), and formula (Ih-ii). Accordingly, in one aspect, the present disclosure relates to a compound of formula (INT-1) or formula (I)-I or formula (X) or a salt thereof. In another aspect, the present disclosure relates to the use of a compound of formula (INT-1) or formula (I)-I or formula (X) or a salt thereof in the manufacture of a compound of formula (I’), formula (I), formula (I-i), formula (I-i-a), formula (I-i-b), formula (I-i-c), formula (I-i-d), formula (I-i-e), formula (I-i-f), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), and formula (Ih-ii). The present disclosure further includes any variation of the method, where an intermediate product obtained at any stage thereof is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under the reaction conditions, or the reaction components are used in the form of their salts or optically pure materials.

[0302] Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising one or more compounds described herein or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more pharma- ceutically acceptable carriers. As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, in a form suitable for oral or parenteral administration, together with at least one pharma- ceutically acceptable carrier.

[0303] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful for the preparation or use of a pharmaceutical composition, as known to those skilled in the art (e.g., Remington The Science and Practice of Pharmacy, 22 nd Pharmaceutical Press, 2013, pp. 1049-1070), for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof.

[0304] In some embodiments of the present disclosure, pharmaceutical compositions are provided that include agents effective for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression. Such compositions include, but are not limited to, small molecule compounds (e.g., small molecule compounds that can target WIZ protein for degradation, e.g., via the E3 ubiquitin pathway, e.g., compounds as described herein), siRNA, shRNA, ASO, miRNA, and AMO.

[0305] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In a further embodiment, the present composition comprises at least two pharma- ceutically acceptable carriers, such as those described herein. For the purposes of this disclosure, solvates and hydrates are generally considered to be compositions, unless otherwise indicated. Preferably, the pharma- ceutically acceptable carrier is sterile. The present pharmaceutical composition can be formulated for a particular route of administration, such as oral, parenteral, and rectal administration. In addition, the present pharmaceutical composition may be configured in a solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, without limitation, solutions, suspensions, or emulsions). The present pharmaceutical composition can be subjected to conventional pharmaceutical processes, such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as auxiliary agents, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0306] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient in combination with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colouring matters, flavouring matters and sweetening matters.

[0307] In certain embodiments, the pharmaceutical composition is a capsule containing only the active ingredient.

[0308] Tablets may be either film coated or enteric coated according to methods known in the art.

[0309] Compositions suitable for oral administration include an effective amount of the compounds of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions or solid dispersions. Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide medicamentously elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricants, for example, magnesium stearate, stearic acid or talc. Tablets may be plain or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a long period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be utilized.Formulations for oral use may be provided as hard gelatin capsules in which active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0310] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterile and / or contain auxiliary substances such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredient.

[0311] The composition suitable for transdermal application comprises an effective amount of the compound of the present disclosure together with a suitable carrier.The carrier suitable for transdermal delivery comprises absorbable pharmacologically acceptable solvent that aids the passage through the host's skin.For example, the transdermal device is in the form of a dressing that comprises a backing member, a reservoir that contains the compound, optionally together with a carrier, optionally a rate-controlling barrier that delivers the compound to the host's skin at a controlled and predetermined rate over a long period of time, and a means for fixing the device to the skin.

[0312] Suitable compositions for topical application, such as application to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, such as for delivery by aerosol. Such topical delivery systems may be particularly suitable for skin application, such as for treating skin cancer, for example, for preventive use in sunscreens, lotions, sprays, etc. Thus, they are particularly suitable for use in topical formulations, including cosmetic formulations, well known in the art. They may contain solubilizers, stabilizers, isotonicity enhancers, buffers and preservatives.

[0313] As used herein, topical application may also refer to inhalation or intranasal application, which may conveniently be delivered in the form of a dry powder from a dry powder inhaler (either alone, in a mixture, e.g., a dry blend with lactose, or as mixed component particles, e.g., with phospholipids), or in the form of an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant.

[0314] Formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii ... The compounds of formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) exhibit valuable pharmacological properties, such as WIZ modulating properties or WIZ degrading properties or Hbf inducing properties, as shown, for example, in in vitro tests as provided in the Examples, and are therefore suitable for use in therapy or as research chemicals, for example as tool compounds.

[0315] Additional properties of the disclosed compounds include good potency in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0316] Diseases and Disorders In some embodiments of the present disclosure, a therapeutic agent is provided that is effective for reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression. In further embodiments, the agent is a small molecule (e.g., a small molecule compound that can target WIZ protein for degradation, e.g., via the E3 ubiquitin pathway, e.g., a compound as described herein), siRNA, shRNA, ASO, miRNA, AMO. In some embodiments, the method of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression is for treating hemoglobinopathies, e.g., β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia.

[0317] The compounds of the present disclosure can be used to treat one or more of the diseases or disorders described herein below.In one embodiment, the disease or disorder is affected by the reduction of WIZ protein expression level and / or the induction of fetal hemoglobin protein expression level.In another embodiment, the disease or disorder is a hemoglobinopathy, such as a beta hemoglobinopathy, including sickle cell disease (SCD) and beta-thalassemia.

[0318] How to use In one aspect of the present disclosure, a method of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression is provided, comprising administering to a subject a therapeutically effective amount of an agent, e.g., a small molecule (e.g., a small molecule compound capable of targeting a WIZ protein for degradation, e.g., via the E3 ubiquitin pathway, e.g., a compound as described herein), siRNA, shRNA, ASO, miRNA, AMO. In one embodiment, the method of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression is for treating hemoglobinopathies, e.g., β-hemoglobinopathies, including sickle cell disease (SCD) and β-thalassemia.

[0319] All of the above and following embodiments relating to methods of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression are equally applicable to: Therapeutic agents for use in methods of reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression, e.g., small molecules (e.g., small molecule compounds that can target WIZ protein for degradation, e.g., via the E3 ubiquitin pathway, e.g., compounds as described herein), siRNA, shRNA, ASO, miRNA, AMO; Therapeutic agents for use in the treatment of the aforementioned diseases or disorders according to the present disclosure, such as small molecules (e.g., small molecule compounds capable of targeting WIZ proteins for degradation, e.g., via the E3 ubiquitin pathway, e.g., compounds as described herein), siRNA, shRNA, ASO, miRNA, AMO; Use of agents, e.g., small molecules (e.g., compounds as described herein), siRNAs, shRNAs, ASOs, miRNAs, AMOs, in the treatment of the aforementioned diseases or disorders according to the present disclosure; and The present disclosure relates to pharmaceutical compositions comprising agents for use in the treatment of the aforementioned diseases or disorders, such as small molecules (e.g., small molecule compounds capable of targeting WIZ protein for degradation, e.g., via the E3 ubiquitin pathway, e.g., compounds as described herein), siRNAs, shRNAs, ASOs, miRNAs, and AMOs.

[0320] Considering its activity as a WIZ regulator or decomposer, the compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), The compounds of formula (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i) and (Ih-ii) are useful in treating conditions that can be treated by modulating WIZ protein expression levels, reducing WIZ protein expression levels, or inducing fetal hemoglobin (HbF), such as those found in blood disorders, e.g., inherited blood disorders, e.g., sickle cell disease, or β-thalassemia. In one aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii ... and (Ia-iii), a compound of formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided.

[0321] In another aspect, the disclosure provides a method of treating or preventing a disorder affected by decreased levels of a WIZ protein in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), The present invention provides a method of administering to a subject a compound of Formula Ia-ii), Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), and Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0322] In another aspect, the disclosure provides a method of inhibiting WIZ protein expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I'), Formula (I), Formula (Ii), Formula (Iia), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (Iif), Formula (I-ii), Formula (I-ii-a), Formula (I-ii-b), Formula (I-ii-c), Formula (I-ii-d), Formula (I-ii-e), Formula (I-ii-f), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ia-i), Formula Ia-ii), Formula (Ia-i), Formula (I ... and administering to a subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), and Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0323] In another aspect, the disclosure provides a method of degrading a WIZ protein in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (I ... and (Ia-iii), a compound of formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided.

[0324] In another aspect, the disclosure provides a method of inhibiting, reducing, or eliminating a WIZ protein activity or WIZ protein expression, comprising administering to a patient a compound of Formula (I'), Formula (I), Formula (Ii), Formula (Iia), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (Iif), Formula (I-ii), Formula (I-ii-a), Formula (I-ii-b), Formula (I-ii-c), Formula (I-ii-d), Formula (I-ii-e), Formula (I-ii-f), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ia-i), Formula Ia-ii and (Ia-xiv), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), and (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided.

[0325] In another aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), The present invention provides a method comprising administering to a subject a compound of Formula (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-viii), (Ia-ix), (Ia-x), (Ia-xi), (Ia-xii), (Ia-xiii), (Ia-xiv), (Ie), (If), (Ig), (Ih), (Ih-i), and (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0326] In another aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii ... and a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided.

[0327] In another aspect, the disclosure provides a method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i), formula (I ... and administering to a subject a compound of Formula (Ia-iii), Formula (Ia-iv), Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i), and Formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0328] In another aspect, the disclosure provides a method of treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia The present invention provides a method for treating a subject comprising administering to the subject a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0329] In another aspect, the disclosure provides a method of treating sickle cell disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-m), (Ia-m), (Ia-m), (Ia-m), (Ia-m), (Ia-i ... The present invention provides a method for treating a subject comprising administering to the subject a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0330] In another aspect, the disclosure provides a method of treating β-thalassemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The present invention provides a method for treating a subject comprising administering to the subject a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i), and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0331] In one embodiment, β-thalassemia major or intermedia is the result of homozygous null or compound heterozygous mutations that result in β-globin deficiency and phenotypic β-thalassemia complications, whether or not transfusion dependent.

[0332] In another aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ig), (Ii-h), (Ii-j ... The compounds of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, isomers, and a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0333] In another aspect, the disclosure provides a method of treating or preventing a disorder affected by decreased levels of a WIZ protein in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I'), Formula (I), Formula (Ii), Formula (Iia), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (Iif), Formula (I-ii), Formula (I-ii-a), Formula (I-ii-b), Formula (I-ii-c), Formula (I-ii-d), Formula (I-ii-e), Formula (I-ii-f), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ii), Formula (Ii), Formula (Iia), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (If), Formula (I-ii), Formula (Ii-a), Formula (Ii-b), Formula (Ii-c), Formula (Ii-d), Formula (Ii-e), Formula (Ii-f), Formula (Ia), Formula (Ib ... ), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate or solvate thereof. and administering to a subject a compound, prodrug, stereoisomer, or tautomer of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii) for use in a method comprising administering to a subject a compound, prodrug, stereoisomer, or tautomer of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0334] In another aspect, the disclosure provides a method of inhibiting WIZ protein expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I'), Formula (I), Formula (Ii), Formula (Iia), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (Iif), Formula (I-ii), Formula (I-ii-a), Formula (I-ii-b), Formula (I-ii-c), Formula (I-ii-d), Formula (I-ii-e), Formula (I-ii-f), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ig), Formula (Ii), Formula (Ii), Formula (Ii), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (Iif), Formula (I-ii), Formula (I-ii-a), Formula (I-ii-b), Formula (I-ii-c), Formula (I-ii-d), Formula (I-ii-e), Formula (I-ii-f), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ig ... The compounds of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, isomers, and a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0335] In another aspect, the disclosure provides a method of degrading a WIZ protein in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a compound represented by formula (I'), (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ig), formula (Ii), formula (Ii), formula (Ii), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ig ...). The compounds of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers thereof. A compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-v), (Ia-vii ... and a medicament comprising a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0336] In another aspect, the disclosure provides a method of inhibiting, reducing, or eliminating a WIZ protein activity or WIZ protein expression, comprising administering to a patient a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ii ... (Id), the compound of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug thereof, and wherein the compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i-i), formula (Ia-ii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0337] In another aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If ...d), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If), formula (If A compound of formula (Ia-d), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate or prodrug thereof. , stereoisomer, or tautomer of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i-i), formula (Ia-ii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0338] In another aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (D), formula (D), formula (E), formula (E), formula (F ...). The compounds of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, and wherein the compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula Ia-ii), formula (Ia-i-i), formula (Ia-ii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0339] In another aspect, the disclosure provides a method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), A compound of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, isomer, or derivative thereof. and a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0340] In another aspect, the disclosure provides a method of treating a hemoglobinopathy, e.g., a β-hemoglobinopathy, in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id ... The compounds of formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or pharma- ceutically acceptable salts, hydrates, solvates, protons, etc. thereof. and administering to a subject a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The present invention provides a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0341] In another aspect, the disclosure provides a method of treating sickle cell disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia

[0023] The compounds of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or pharma- ceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers thereof. and administering to a subject a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-v), (Ia-vii ... and a medicament comprising a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0342] In another aspect, the disclosure provides a method of treating β-thalassemia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (I a-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or mixture thereof. and administering to a subject a compound of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii), (Ia-v), (Ia-vii ... and a medicament comprising a compound of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0343] In one embodiment, β-thalassemia major or intermedia is the result of homozygous null or compound heterozygous mutations that result in β-globin deficiency and phenotypic β-thalassemia complications, whether or not transfusion dependent.

[0344] Dosage A pharmaceutical composition or combination of the present disclosure may be in a unit dosage of about 1-1000 mg of one or more active ingredients, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient for a subject of about 50-70 kg. The therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated or its severity.

[0345] The above cited dosage properties are demonstrable in in vitro and in vivo tests, advantageously using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g. aqueous solutions, and in vivo either enterally or parenterally, advantageously intravenously, e.g. as a suspension or in aqueous solution. The dosage in vitro is about 10 -3 Molar ~ 10 -9 A therapeutically effective amount in vivo may range from about 0.1 to 500 mg / kg, or from about 1 to 100 mg / kg, depending on the route of administration.

[0346] The activity of the compounds according to the present disclosure can be determined by the in vitro methods described in this Example.

[0347] Combination therapy In another aspect, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-i ... In one embodiment, the present invention provides a pharmaceutical combination comprising a compound of formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents. In one embodiment, the additional therapeutic agent is a myelosuppressant, such as hydroxyurea.

[0348] Combination therapy includes administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second, different anti-neoplastic agent or a therapeutic agent that targets Hbf or another cancer target) and non-pharmacological therapies (such as, but not limited to, surgery or radiation therapy). For example, the compounds of the present application can be used in combination with other pharmacologic active compounds, preferably compounds capable of enhancing the effect of the compounds of the present application.

[0349] The compounds of the present disclosure may be administered simultaneously with, before or after one or more other therapeutic agents.The compounds of the present disclosure may be administered separately, by the same or different administration route, or together with other agents in the same pharmaceutical composition.The therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with the compounds of the present disclosure. Thus, in one embodiment, the present disclosure provides a therapeutically effective amount of a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia-i ... The present invention provides a combination comprising a compound of formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) or a pharma- ceutically acceptable salt thereof and one or more additional therapeutically active agents.

[0350] In one embodiment, the disclosure provides a compound of formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ig ... The present invention provides a product comprising a compound of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) and at least one other therapeutic agent. In one embodiment, the therapy is the treatment of a disease or condition modulated by WIZ.The products provided as combination formulations include those of formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi), (Ia-vii ... The compounds of formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) may be combined together in the same pharmaceutical composition with one or more other therapeutic agents. or a compound represented by the formula (I'), (I), (Ii), (Iia), (Iib), (Iic), (Iid), (Iie), (Iif), (I-ii), (I-ii-a), (I-ii-b), (I-ii-c), (I-ii-d), (I-ii-e), (I-ii-f), (Ia), (Ib), (Ic), (Id), (Ia-i), (Ia-ii), (Ia-iii), (Ia-iv), (Ia-v), (Ia-vi ... The present invention also includes compositions comprising a compound of Formula (Ia-v), Formula (Ia-vi), Formula (Ia-vii), Formula (Ia-viii), Formula (Ia-ix), Formula (Ia-x), Formula (Ia-xi), Formula (Ia-xii), Formula (Ia-xiii), Formula (Ia-xiv), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ih-i) and Formula (Ih-ii) and one or more other therapeutic agents in separate forms, for example in the form of a kit.

[0351] In one embodiment, the present disclosure provides a compound represented by formula (I'), formula (I), formula (Ii), formula (Iia), formula (Iib), formula (Iic), formula (Iid), formula (Iie), formula (Iif), formula (I-ii), formula (I-ii-a), formula (I-ii-b), formula (I-ii-c), formula (I-ii-d), formula (I-ii-e), formula (I-ii-f), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ia-i), formula (Ia-ii), formula (Ia The present invention provides a pharmaceutical composition comprising a compound of formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii) and one or more additional therapeutic agents. Optionally, the pharmaceutical composition may comprise a pharma- ceutical acceptable carrier as described above.

[0352] In one embodiment, the disclosure provides two or more separate pharmaceutical compositions, at least one of which is a compound of Formula (I'), Formula (I), Formula (Ii), Formula (Iia), Formula (Iib), Formula (Iic), Formula (Iid), Formula (Iie), Formula (Iif), Formula (I-ii), Formula (I-ii-a), Formula (I-ii-b), Formula (I-ii-c), Formula (I-ii-d), Formula (I-ii-e), Formula (I-ii-f), Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie ... A kit is provided comprising a pharmaceutical composition comprising a compound of formula (Ia-i), formula (Ia-ii), formula (Ia-iii), formula (Ia-iv), formula (Ia-v), formula (Ia-vi), formula (Ia-vii), formula (Ia-viii), formula (Ia-ix), formula (Ia-x), formula (Ia-xi), formula (Ia-xii), formula (Ia-xiii), formula (Ia-xiv), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (Ih-i) and formula (Ih-ii). In one embodiment, the kit comprises a means for keeping the compositions separately, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, as typically used for packaging tablets, capsules and the like.

[0353] The kits of the present disclosure may be used to administer different dosage forms, e.g., oral and parenteral, or the individual compositions may be administered at different dosage intervals, or the individual compositions may be dosed relative to one another. To aid in compliance, the kits of the present disclosure typically include administration instructions.

[0354] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present disclosure and the other therapeutic agent may be combined as a combination therapy: (i) prior to release of the combination product to the physician (e.g., in the case of a kit containing the compound of the present disclosure and the other therapeutic agent); (ii) immediately prior to administration by the physician (or under the guidance of the physician); or (iii) by the patient himself / herself, e.g., during sequential administration of the compound of the present disclosure and the other therapeutic agent.

[0355] Preparation of compounds It is understood that in the following description, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0356] Those skilled in the art will also understand that during the processes described below, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, etc. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.

[0357] Protective groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protective groups is described in detail in JFW MacOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; TW Greene and PG M Huts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; PJ Kocienski, "Protecting Groups", Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0358] The protecting group may also be a polymeric resin, such as Wang resin or 2-chlorotrityl chloride resin.

[0359] The following reaction schemes illustrate methods for making the compounds of the present disclosure. It is understood that those skilled in the art will be able to make these compounds by similar methods or by methods known to those skilled in the art. In general, starting components and reagents can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, Strem, and other commercial vendors, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described in this disclosure.

[0360] Analytical methods, materials, and instruments Reagents and solvents were used as received from commercial suppliers unless otherwise noted. Proton nuclear magnetic resonance (NMR) spectra were obtained on either a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer unless otherwise noted. Spectra are given in parts per million (δ) and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts are reported in parts per million relative to dimethylsulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26) or other solvents as indicated in the NMR spectral data. A small amount of dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). Chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v12.

[0361] Mass spectra (ESI-MS) were collected using a Waters system (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ion unless otherwise noted. Samples were dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and injected directly onto the column using an automated sample handler. The analysis is performed on a Waters Acquity UPLC system (Column: Waters Acquity UPLC BEH C18 1.7 μm, 2.1×30 mm; Flow rate: 1 mL / min; 55° C. (column temperature); Solvent A: 0.05% formic acid in water, Solvent B: 0.04% formic acid in MeOH; Gradient 95% solvent A from 0 to 0.10 min; 95% solvent A to 20% solvent A from 0.10 to 0.50 min; 20% solvent A to 5% solvent A from 0.50 to 0.60 min; Hold at 5% solvent A from 0.6 to 0.8 min; 5% solvent A to 95% solvent A from 0.80 to 0.90 min; and Hold 95% solvent A from 0.90 to 1.15 min.

[0362] Abbreviation: ACN Acetonitrile AcOH Acetic acid AIBN Azobisisobutyronitrile aq. aqueous solution B 2 pin 2 Bis(pinacolato)diboron Boc 2 O Di-tert-butyl dicarbonate Bn Benzyl BnBr Benzyl bromide br Wide line d double line dd Double line double line ddd double line double line double line ddq quad doublet doublet ddt triple line double line dq Double of qu...

Claims

1. A compound of formula (I') or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 [In the formula, Y is O, CH ２ , C.F. ２ and CHF; z is an integer from 0 to 2; R Ｘ１ and R Ｘ２ are each independently hydrogen and C １ ~C ６ alkyl; R Ｙ１ and R Ｙ２ are each independently hydrogen and C １ ~C ６ alkyl; R Ｚ１ and R Ｚ２ are both hydrogen or or R Ｚ１ and R Ｚ２ One of and R Ｙ１ and R Ｙ２ Together with one of them, it becomes C １ ~C ２ forming an alkylene bridging group, R Ｚ１ and R Ｚ２ And R Ｙ１ and R Ｙ２ the other two are both hydrogen; R １ is hydrogen and C １ ~C ６ alkyl; R ２ is hydrogen, -C(=O)-R ３ , C ３ ~C ８ Cycloalkyl, C １ ~C ６ Haloalkyl and C １ ~C １０ alkyl, wherein said alkyl is selected from ６ ~C １０ aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; ３ ~C ８ Cycloalkyl and -O-(R ２ａ ) is substituted with 0 to 1 substituents independently selected from wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ２ａ is C １ ~C ６ alkyl, wherein said alkyl is C ６ ~C １０ substituted with 0 to 1 substituents independently selected from aryl; R ３ is -CH=CR ３ａ R ３ｂ , C ６ ~C １０ aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; ３ ~C ８ Cycloalkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 3 R ３ｃ is replaced by, and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ａ and R ３ｂ together with the carbon atom to which they are attached, C ３ ~C ８ forms a cycloalkyl ring; Each R ３ｃ is, for each occurrence, -C(=O)-R ３ｄ , N.R. ３ｅ R ３ｆ , C １ ~C ６ Alkoxyl, -O-R ３ｄ , hydroxyl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ cycloalkyl; wherein the -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R ４ａ is replaced by, and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ｄ is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R ３ｅ and R ３ｆ are each independently hydrogen and C １ ~C ６ alkyl; Each R ４ For each occurrence, C ６ ~C １０ Aryl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C １ ~C １０ Alkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, -SO ２ R ４ｃ , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C １ ~C ６ Haloalkoxyl, -C(=O)-O-(R ５ ), -C(=O)-(R ５ ), -C(=O)-NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , -NH-C(=O)-O-(C １ ~C ６ alkyl), and C ３ ~C ８ cycloalkyl, where said aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R ４ａ is replaced by wherein the alkyl and alkoxyl each independently represent 0 to 1 R ４ｂ is replaced by, and wherein the cycloalkyl is —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxyl, Hydroxyl and C １ ~C ６ substituted with 0 to 3 substituents each independently selected from haloalkyl; R ４ａ For each occurrence, -CN, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R ５ ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, C １ ~C ６ alkyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C ３ ~C ６ cycloalkyl, where said alkyl is selected from 0 to 1 R ４ｂ and wherein said heteroaryl is substituted with 0 to 3 R ４ａ－１ is replaced by; R ４ａ－１ For each occurrence, C １ ~C ６ Alkyl, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, -CN, C １ ~C ６ Alkoxyl and C １ ~C ６ haloalkyl; R ４ｂ Each occurrence represents -CN, halogen, -C(=O)NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; １ ~C ６ alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C ３ ~C ８ Cycloalkyl, C ２ ~C ４ Alkynyl, and C ６ ~C １０ aryl, wherein said aryl is selected from -CN, １ ~C ６ Haloalkyl, and C １ ~C ６ substituted with 0 to 1 substituents each independently selected from alkyl; R ４ｃ is C ６ ~C １０ Aryl, Hydroxyl, NH ２ and halogen; R ５ is C １ ~C ６ Alkyl, C ６ ~C １０ Aryl, and C ６ ~C １０ Aryl C １ ~C ６ alkyl; R ６ａ and R ６ｂ are each independently hydrogen and C １ ~C ６ selected from alkyl; or R ６ａ and R ６ｂ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0 to 1 additional heteroatom selected from N, O, and S, wherein said heterocyclyl is substituted with 0 to 2 R ６ｃ ; R ６ｃ For each occurrence, C ６ ~C １０ Aryl C １ ~C ６ Alkyl, -C(=O)-O-(C １ ~C ６ alkyl), -C(=O)-(C １ ~C ６ alkyl), oxo, and C １ ~C ６ alkyl, wherein said alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S.

2. A compound of formula (I) according to claim 1 or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】 [In the formula, Y is O, CH ２ , and C.F. ２ Selected from: z is an integer from 0 to 2; R Ｘ１ and R Ｘ２ are each independently hydrogen and C １ ~C ６ alkyl; R Ｙ１ and R Ｙ２ are each independently hydrogen and C １ ~C ６ alkyl; R １ is hydrogen and C １ ~C ６ alkyl; R ２ is hydrogen, -C(=O)-R ３ , C ３ ~C ８ Cycloalkyl, C １ ~C ６ Haloalkyl and C １ ~C １０ alkyl, wherein said alkyl is selected from ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ substituted with 0 to 1 substituents independently selected from cycloalkyl; wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ is -CH=CR ３ａ R ３ｂ , C ６ ~C １０ aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; ３ ~C ８ Cycloalkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 3 R ３ｃ is replaced by, and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ａ and R ３ｂ together with the carbon atom to which they are attached, C ３ ~C ８ forming a cycloalkyl ring; Each R ３ｃ is, for each occurrence, -C(=O)-R ３ｄ , N.R. ３ｅ R ３ｆ , C １ ~C ６ Alkoxyl, -O-R ３ｄ , hydroxyl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ cycloalkyl; wherein the -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R ４ａ is replaced by, and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ｄ is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R ３ｅ and R ３ｆ are each independently hydrogen and C １ ~C ６ alkyl; Each R ４ For each occurrence, C ６ ~C １０ Aryl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C １ ~C １０ Alkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, -SO ２ R ４ｃ , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C １ ~C ６ Haloalkoxyl, -C(=O)-O-(R ５ ), -C(=O)-(R ５ ), -C(=O)-NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , -NH-C(=O)-O-(C １ ~C ６ alkyl), and C ３ ~C ８ cycloalkyl, where said aryl, -O-aryl, arylalkyl-O-, -O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R ４ａ is replaced by wherein the alkyl and alkoxyl each independently represent 0 to 1 R ４ｂ is replaced by, and wherein the cycloalkyl is —CN, C １ ~C ６ Alkyl, C １ ~C ６ substituted with 0 to 3 substituents each independently selected from alkoxyl, and hydroxyl; R ４ａ For each occurrence, -CN, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R ５ ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 1 R ４ｂ and wherein said heteroaryl is substituted with 0 to 3 R ４ａ－１ is replaced by; R ４ａ－１ For each occurrence, C １ ~C ６ Alkyl, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, -CN, C １ ~C ６ Alkoxyl and C １ ~C ６ haloalkyl; R ４ｂ Each occurrence is represented by -CN, -C(=O)NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; １ ~C ６ alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C ３ ~C ８ Cycloalkyl, C ２ ~C ４ Alkynyl, and C ６ ~C １０ aryl, wherein said aryl is selected from -CN, １ ~C ６ Haloalkyl, and C １ ~C ６ substituted with 0 to 1 substituents each independently selected from alkyl; R ４ｃ is C ６ ~C １０ Aryl, Hydroxyl, NH ２ and halogen; R ５ is C １ ~C ６ Alkyl, C ６ ~C １０ Aryl, and C ６ ~C １０ Aryl C １ ~C ６ alkyl; R ６ａ and R ６ｂ are each independently hydrogen and C １ ~C ６ selected from alkyl; Or R ６ａ and R ６ｂ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, wherein said heterocyclyl contains 0-2 R ６ｃ is replaced by; R ６ｃ For each occurrence, C ６ ~C １０ Aryl C １ ~C ６ Alkyl, -C(=O)-O-(C １ ~C ６ alkyl), -C(=O)-(C １ ~C ６ alkyl), oxo, and C １ ~C ６ alkyl, wherein said alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S.

3. Formula (I-i) 【Chemistry 3】 Or formula (I-ii) 【Chemistry 4】 [In the formula, Y, R Ｘ１ , R Ｘ２ , R Ｙ１ , R Ｙ２ , R １ , R ２ and z is defined as any one of [1] to [4], or a pharma- ceutically acceptable salt thereof.

4. During the ceremony, Y is O, CH ２ , and C.F. ２ Selected from: z is an integer from 0 to 2; R Ｘ１ and R Ｘ２ each independently represents hydrogen and C １ ~C ６ alkyl; R Ｙ１ and R Ｙ２ each independently represents hydrogen and C １ ~C ６ alkyl; R １ is hydrogen and C １ ~C ６ alkyl; R ２ is hydrogen, -C(=O)-R ３ , C ３ ~C ８ Cycloalkyl, and C １ ~C １０ alkyl, wherein said alkyl is selected from ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ substituted with 0 to 1 substituents independently selected from cycloalkyl; and wherein said aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently comprise 0 to 5 R ４ is replaced by; R ３ But, C ６ ~C １０ aryl, a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; ３ ~C ８ Cycloalkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 3 R ３ｃ is replaced by, and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ｃ However, for each occurrence, NR ３ｅ R ３ｆ , C １ ~C ６ Alkoxyl, -O-R ３ｄ , hydroxyl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S), C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ cycloalkyl; wherein the -O-aryl, arylalkyl-O-, and -O-heteroaryl each independently represent 0 to 3 R ４ａ is replaced by, and wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ｄ is a 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R ３ｅ and R ３ｆ each independently represents hydrogen and C １ ~C ６ alkyl; R ４ However, for each occurrence, C ６ ~C １０ Aryl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, C １ ~C １０ Alkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, -SO ２ R ４ｃ , halogen, hydroxyl, -CN, N, O, and S independently selected from -O-4 to 6 membered heterocyclyl, oxo, C １ ~C ６ Haloalkoxyl, -C(=O)-O-(R ５ ), -C(=O)-(R ５ ), -C(=O)-NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , -NH-C(=O)-O-(C １ ~C ６ alkyl), and C ３ ~C ８ cycloalkyl, where said aryl, —O-aryl, arylalkyl-O—, —O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R ４ａ is replaced by wherein the alkyl and alkoxyl each independently represent 0 to 1 R ４ｂ is replaced by, and wherein the cycloalkyl is -CN, C １ ~C ６ Alkyl, and C １ ~C ６ substituted with 0 to 2 substituents each independently selected from alkoxyl; R ４ａ However, for each occurrence, -CN, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R ５ ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 1 R ４ｂ and wherein said heteroaryl is substituted with 0 to 3 R ４ａ－１ is replaced by; R ４ａ－１ However, for each occurrence, C １ ~C ６ Alkyl, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, -CN, C １ ~C ６ Alkoxyl and C １ ~C ６ haloalkyl; R ４ｂ Each occurrence of -CN, -C(=O)NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; -C(=O)-OH; １ ~C ６ alkoxyl, 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; C ３ ~C ８ Cycloalkyl, C ２ ~C ４ Alkynyl, and C ６ ~C １０ aryl, where the aryl is selected from -CN, １ ~C ６ Haloalkyl and C １ ~C ６ substituted with 0 to 1 substituents each independently selected from alkyl; R ４ｃ But, C ６ ~C １０ Aryl, Hydroxyl, NH ２ and halogen; R ５ But, C １ ~C ６ Alkyl, C ６ ~C １０ Aryl, and C ６ ~C １０ Aryl C １ ~C ６ alkyl; R ６ａ and R ６ｂ each independently represents hydrogen and C １ ~C ６ selected from alkyl; Or R ６ａ and R ６ｂ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N, O, and S, wherein the heterocyclyl is selected from 0-2 R ６ｃ is replaced by; R ６ｃ However, for each occurrence, C ６ ~C １０ Aryl C １ ~C ６ Alkyl, -C(=O)-O-(C １ ~C ６ alkyl), -C(=O)-(C １ ~C ６ alkyl), oxo, and C １ ~C ６ alkyl, wherein said alkyl is substituted with 0-1 substituents independently selected from -CN and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; A compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. During the ceremony, Y is O and CH ２ Selected from ； z is an integer from 0 to 2; R Ｘ１ and R Ｘ２ each independently represents hydrogen and C １ ~C ６ alkyl; R Ｙ１ and R Ｙ２ each independently represents hydrogen and C １ ~C ６ alkyl; Here, R Ｘ１ and R Ｘ２ Both are C １ ~C ６ If R is alkyl, then Ｙ１ and R Ｙ２ are both hydrogen, and where R Ｘ１ and R Ｘ２ If both R and R are hydrogen, then R Ｙ１ and R Ｙ２ Both are C １ ~C ６ is alkyl; R １ is hydrogen and C １ ~C ６ alkyl; R ２ is hydrogen, -C(=O)-R ３ , C ３ ~C ８ Cycloalkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ substituted with 0 to 1 substituents independently selected from cycloalkyl; and wherein said aryl, heteroaryl, heterocyclyl, and cycloalkyl each independently comprise 0 to 5 R ４ is replaced by; R ３ is C ６ to C １０ a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, and C ３ to C ８ cycloalkyl, and C １ to C ３ alkyl, wherein said alkyl is substituted with 0 to 2 R ３ｃ and wherein the aryl, heteroaryl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ３ｃ However, for each occurrence, C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, and C ３ ~C ８ cycloalkyl; wherein the aryl, heteroaryl, and cycloalkyl each independently represent 0 to 5 R ４ is replaced by; R ４ However, for each occurrence, C ６ ~C １０ Aryl, —O—C ６ ~C １０ Aryl, C １ ~C ６ Aryl C ６ ~C １０ alkyl-O-, -O-(5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S), 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O, C １ ~C １０ Alkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, -SO ２ R ４ｃ , halogen, hydroxyl, -CN, oxo, C １ ~C ６ Haloalkoxyl, -C(=O)-O-(R ５ ), -C(=O)-NR ６ａ R ６ｂ , N.R. ６ａ R ６ｂ , -NH-C(=O)-O-(C １ ~C ６ alkyl), and C ３ ~C ８ cycloalkyl, where said aryl, —O-aryl, arylalkyl-O—, —O-heteroaryl, heteroaryl, and heterocyclyl are each independently selected from 0 to 3 R ４ａ is replaced by wherein the alkyl and alkoxyl each independently represent 0 to 1 R ４ｂ is replaced by, and wherein said cycloalkyl is substituted with 0 to 1 substituents independently selected from: —CN; R ４ａ However, for each occurrence, -CN, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkyl, halogen, hydroxyl, -C(=O)-O-(R ５ ), 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 1 R ４ｂ and wherein said heteroaryl is substituted with 0 to 3 R ４ａ－１ is replaced by; R ４ａ－１ However, for each occurrence, C １ ~C ６ Alkyl, di(C １ ~C ６ Alkyl)amino C １ ~C ６ Alkyl, -CN, C １ ~C ６ Alkoxyl and C １ ~C ６ haloalkyl; R ４ｂ Each occurrence of -CN, -C(=O)NR ６ａ R ６ｂ , a 5-10 membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S; -C(=O)-OH, a 4-6 membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S; ３ ~C ８ Cycloalkyl, C ２ ~C ４ Alkynyl, and C ６ ~C １０ aryl, where the aryl is selected from -CN, １ ~C ６ Haloalkyl and C １ ~C ６ substituted with 0 to 1 substituents each independently selected from alkyl; R ４ｃ But, C ６ ~C １０ Aryl, NH ２ and halogen; R ５ But, C １ ~C ６ Alkyl, and C ６ ~C １０ Aryl C １ ~C ６ alkyl; R ６ａ and R ６ｂ each independently represents hydrogen and C １ ~C ６ selected from alkyl; Or R ６ａ and R ６ｂ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl containing 0-1 additional heteroatoms selected from N and O, wherein the heterocyclyl is selected from 0-2 R ６ｃ is replaced by; R ６ｃ However, for each occurrence, C ６ ~C １０ Aryl C １ ~C ６ Alkyl, -C(=O)-O-(C １ ~C ６ alkyl), -C(=O)-(C １ ~C ６ alkyl), oxo, and C １ ~C ６ alkyl, wherein said alkyl is substituted with 0-1 substituents independently selected from 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

6. In the formula, R ３ is a 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from phenyl, N, O, and S; a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N and O; ３ ~C ６ Cycloalkyl, and C １ ~C ６ alkyl, wherein said alkyl is selected from 0 to 3 R ３ｃ is replaced by, and wherein the phenyl, heteroaryl, heterocyclyl, and cycloalkyl each independently represent 0 to 4 R ４ 6. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, substituted with:

7. In the formula, R ２ is unsubstituted C １ ~C ６ C substituted with alkyl or 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S １ ~C １０ Alkyl, or -C(=O)-R ３ and In the formula, R ３ is substituted with a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; １ ~C ６ is alkyl, wherein each occurrence of said heterocyclyl is independently selected from piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, dihydroisoxazolyl, tetrahydropyran, pyrrolidinyl, and 2-oxaspiro[3.3]heptanyl; and wherein said heterocyclyl, at each occurrence, independently represents 0 to 4 R ４ wherein R ４ A compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein:

8. In the formula, R ２ But, C １ ~C ６ Alkyl and -(CH ２ )-phenyl, wherein said phenyl is selected from 0 to 4 occurrences of R ４ 8. The compound according to claim 1, wherein the compound is selected from the group consisting of:

9. 3-(5-(((R)-1-((1-cyclohexyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-5-phenyl-1H-pyrazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; Methyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenoxy)benzoate; 3-(5-(((R)-1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(3-(pyrrolidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-((1H-pyrazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((3-(m-tolyl)-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(2H-1,2,3-triazol-2-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-methoxy-4-methylbenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(2-methyl-1H-imidazol-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-((1H-imidazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-isobutyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((2S)-1-((1-(cyclohex-3-en-1-ylmethyl)piperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((6-(diethylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-chloro-6-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((5-(benzyloxy)-6-methoxy-1H-indazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-benzylpiperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-morpholinobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((R)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-butyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperazine-1-carboxylate; 3-(5-(((R)-1-(3-((1H-imidazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(3-(pyrrolidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(pyrrolidine-1-carbonyl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-benzylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-(cyclohexa-1,5-dien-1-yl)-1-methyl-1H-pyrazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-cyclohexyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(2-morpholinoethoxy)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-benzyl-1H-imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((S)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(2-morpholinoethoxy)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((R)-1-ethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; Ethyl 3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1H-indazole-4-carboxylate; 3-(5-(((S)-1-((2-ethyl-4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; Methyl 4-(4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3,3a,7a-tetrahydro-1H-isoindol-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenoxy)benzoate; 3-(5-(((R)-1-((5-methylisoxazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1H-pyrrolo[2,3-b]pyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-morpholinopyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzenesulfonamide; 3-(5-(((S)-1-(3-((1H-pyrazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((6-(diethylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-methoxy-4-methylbenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-isobutyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-benzyl-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-chloro-4-hydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((1-(phenylsulfonyl)-1H-pyrrol-2-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((6-(pyrrolidin-1-yl)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-isopropylpiperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((1-(pyrazin-2-yl)-1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-isopropyl-1-methyl-1H-pyrazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-isopropylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-(4-bromophenyl)isoxazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-(dimethylamino)pyrimidin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,5-diethylisoxazole-4-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(2H-1,2,3-triazol-2-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3',5-dimethyl-[3,5'-biisoxazole]-4'-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate benzyl; 3-(5-(((R)-1-(imidazo[1,2-a]pyridin-8-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-morpholinopyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,4-dimethoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(4-methylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-isopropylpiperidin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,5-difluoro-4-methoxybenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (1R,3S)-3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopentane-1-carboxylate; 3-(5-(((R)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-(methylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2,5-dimethyl-1-(5-methylisoxazol-3-yl)-1H-pyrrole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1H-pyrazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(benzyloxy)-4-methoxybenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(2-(2-oxo-2-(piperidin-1-yl)ethoxy)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1s,4S)-4-methoxycyclohexyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1H-imidazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(2-(piperidin-1-yl)thiazole-5-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(2-methyl-1H-imidazol-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(4-pentylbenzoyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-methylimidazo[1,2-a]pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3,3-difluorocyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-4-ethyl-6,6-dimethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-3-methoxybenzonitrile; 2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile; 3-(5-(((R)-1-((2-ethyl-4-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(cyclohexylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(4-(pyrrolidine-1-carbonyl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-((3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile; 2-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1H-imidazol-1-yl)acetic acid; 3-(5-(((R)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-(4-fluorophenyl)picolinoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzonitrile; 3-(5-(((S)-1-(5-butyl-4-methoxypyrimidine-2-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzonitrile; Ethyl 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1H-pyrazole-3-carboxylate; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzenesulfonamide; 3-(1-oxo-5-(((S)-1-(4-(2-oxopyrrolidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(3-methyloxetan-3-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3,5-dimethyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((6-morpholinopyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((5-(pyridin-3-yloxy)-1H-indazol-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2,3-dihydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(4-(pent-3-yn-1-yloxy)benzoyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1H-imidazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-morpholinobenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-(benzyloxy)-6-methoxy-1H-indazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate benzyl; 3-(5-(((S)-1-(4-chloro-3-iodobenzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-fluoro-4-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-methyl-3-phenyl-1H-pyrazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((6-methoxypyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-(2-morpholinoethoxy)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (1R,3S)-3-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopentane-1-carboxylate; 3-(5-(((R)-1-((1H-imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(1-phenyl-1H-1,2,4-triazole-3-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-neopentylisoxazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((R)-1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-(dimethylamino)pyrimidin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-isobutylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(pyrimidin-5-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-hydroxypyridin-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-aminopyrimidin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(4-methoxyphenyl)-1H-pyrazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-chloro-5-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzenesulfonamide; 3-(5-(((S)-1-(oxazol-4-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(2-(2-oxo-2-(piperidin-1-yl)ethoxy)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(5-propylisoxazole-3-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate methyl; 3-(5-(((R)-1-(2-((1H-1,2,4-triazol-1-yl)methyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 2-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile; tert-butyl(1-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)cyclopentyl)carbamate; 3-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)benzonitrile; 3-(5-(((S)-1-(1-methyl-5-phenyl-1H-pyrazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(5-isopropylisoxazole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-((2-oxo-1,2-dihydropyridin-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-3-methoxybenzonitrile; 3-(5-(((S)-1-(2-ethylthiazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((2-(methylamino)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-hydroxy-5-(5-(trifluoromethyl)-1H-tetrazol-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(7-methoxy-1H-indole-3-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-isopropylisoxazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3,5-dimethylisoxazol-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((S)-1-((S)-1-ethylpyrrolidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4-ethyl-6,6-dimethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-4-ethyl-6,6-dimethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-methyltetrahydro-2H-pyran-4-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-4-ethylmorpholin-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((S)-1-(pyrimidin-5-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-((5-methylisoxazol-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2S)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)picolinonitrile; 3-(1-oxo-5-(((S)-1-(quinoxaline-6-carbonyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(difluoromethoxy)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-(1-methyl-1H-pyrazol-3-yl)benzoyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(2-morpholinothiazole-4-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((S)-1-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-ethyl-3,3-dimethylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((6-fluoropyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4,4-difluorocyclohexyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-ethylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-((S)-1-((R)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((S)-1-((S)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-isobutyrylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2,4-difluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentane-1-carbonitrile; 3-(5-(((R)-1-(4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3,4-difluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((R)-1-((S)-1-ethylpiperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-isobutylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-benzoylpiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-Ethylazepan-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(Oxazole-5-carbonyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1r,3R)-3-Methoxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-Morpholinobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-(Cyclopropylmethyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-Oxaspiro[3.3]heptan-6-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(2-((((2R)-2-((((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl; 3-(1-Oxo-5-(((R)-1-(2-(Piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(4-Isobutylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-Oxo-5-(((R)-1-(2-(4-((Tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 7-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)indoline-1-carboxylate tert-butyl; 3-(5-(((R)-1-(indolin-7-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((1-ethylindolin-7-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-chloro-4-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((5-fluoropyridin-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1s,3S)-3-methoxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(2-(piperidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 4-(2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperidine-1-carboxylate tert-butyl; 3-(5-(((R)-1-(2-(1-ethylpiperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-butyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)phenyl)piperidine-1-carboxylate; 3-(5-(((R)-1-(4-(1-ethylpiperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2,4-dimethoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(benzo[d][1,3]dioxol-5-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1r,3R)-3-hydroxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(((1s,3S)-3-hydroxycyclobutyl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-fluoro-4-methoxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-fluoro-2-hydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(3,4,5-trifluorobenzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2,4-dimethylthiazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(pyridin-4-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2,6-difluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-hydroxybenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2-fluoropyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(quinolin-3-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-methylthiazol-2-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(quinolin-2-ylmethyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; tert-butyl 4-(4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-ethylphenyl)piperidine-1-carboxylate; 3-(5-(((R)-1-(3-ethyl-4-(piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(3-ethyl-4-(1-ethylpiperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(tert-butyl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(piperidin-1-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3-methoxybicyclo[1.1.1]pentan-1-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-butyl 4-(2-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-4-fluorophenyl)piperazine-1-carboxylate; 3-(5-(((R)-1-(5-fluoro-2-(piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(4-ethylpiperazin-1-yl)-5-fluorobenzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(4-(1-(trifluoromethyl)cyclopropyl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((4-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(2-(benzyloxy)ethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-((6-morpholinopyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(3,6-dihydro-2H-pyran-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; tert-Butyl 4-(5-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate; 3-(5-(((R)-1-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 4-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-methoxybenzonitrile; 3-(5-(((R)-1-((1H-benzo[d]imidazol-5-yl)methyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 5-(((2R)-2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)methyl)piperidin-1-yl)methyl)-2-methoxybenzonitrile; 3-(1-oxo-5-(((R)-1-(4-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(1-(2-fluoroethyl)piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(benzo[d]oxazol-5-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(oxetan-3-ylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(1-(oxetan-3-ylmethyl)piperidin-4-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(((R)-tetrahydrofuran-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(((R)-1-(((S)-tetrahydrofuran-3-yl)methyl)piperidin-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(cyclopropylmethyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1S)-1-(1-(((1r,4S)-4-methoxycyclohexyl)methyl)piperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1R)-1-(1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidin-2-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((1R,3S,4S)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-isopropylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-(tert-butyl)piperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(((R)-1-(4-(4-cyclopropylpiperazin-1-yl)benzyl)piperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((1-ethyl-4-fluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-((4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((S)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((S)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((R)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((R)-1-ethyl-4,4-difluoropiperidin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((1S,3S,4R)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (S)-3-(5-(((1S,3S,4R)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; (R)-3-(5-(((1R,3R,4S)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (S)-3-(5-(((1R,3R,4S)-2-ethyl-2-azabicyclo[2.2.1]heptan-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2. The compound of claim 1, selected from:

10. The compound according to any one of claims 1 to 9, wherein the pharma- ceutically acceptable salt is an acid addition salt.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

12. 11. A pharmaceutical composition for treating or preventing a disease or disorder in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

13. A pharmaceutical composition for degrading WIZ protein in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

14. A pharmaceutical composition for inhibiting WIZ protein expression in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

15. 11. A pharmaceutical composition for inducing or promoting fetal hemoglobin in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

16. 11. A pharmaceutical composition for reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

17. 11. A pharmaceutical composition for increasing fetal hemoglobin expression in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

18. 11. A pharmaceutical composition for treating a hemoglobinopathy in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

19. 11. A pharmaceutical composition for treating sickle cell disease in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

20. 11. A pharmaceutical composition for treating β-thalassemia in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.

21. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use as a medicament.

22. 11. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder selected from sickle cell disease and β-thalassemia.

23. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in treating or preventing a disorder affected by reduced WIZ protein levels in a subject in need thereof.

24. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in inhibiting WIZ protein expression in a subject in need thereof.

25. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in degrading WIZ protein in a subject in need thereof.

26. 11. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in inducing or promoting fetal hemoglobin in a subject in need thereof.

27. 11. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in reactivating fetal hemoglobin production or expression in a subject in need thereof.

28. 11. A compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in increasing fetal hemoglobin expression in a subject in need thereof.

29. 11. A compound according to any of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, for use in treating a hemoglobinopathy in a subject in need thereof.

30. 11. A pharmaceutical combination comprising a compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents.

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