3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their medical uses

Abstract

The present application relates to compounds of formula (I), pharmaceutical compositions containing them, and their use in reducing widely interspaced 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. [Formula 1] TIFF2024520654000227.tif32170

Description

[Technical field]

[0001] Claiming priority This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 196,422, filed June 3, 2021, the disclosure of which is incorporated by reference in its entirety herein.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on Jun. 3, 2021, is named PAT059130-US-PSP_SL.txt, and is 4,096 bytes in size.

[0003] The present disclosure relates to 3-(5-oxy)-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]

[0004] 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.

[0005] 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 that have been targeted clinically and preclinically 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, 101(1), ... al., 2015, Blood, 126(16), 1930-1939). Furthermore, 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 targeting G9a / GLP histone methyltransferase to genomic loci to regulate chromatin structure and transcription (Bian, Chen, et al. (2015), eLife 2015;4:e05606). Summary of the Invention

[0006] The present disclosure relates to 3-(5-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds that are effective in reducing WIZ protein expression levels and / or inducing fetal hemoglobin (HbF) expression, pharma- ceutically acceptable salts thereof, compositions thereof, and uses thereof in therapy for the conditions and purposes detailed above.

[0007] 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, Each R 1 is hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 is hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 10 Alkyl, -SO 2 R 6 , -C(=O)-R 2a , -C(=O)-OR 2a , and -C(=O)NR 2b R 2c Selected from; Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; R 2a is C 1 ~C 6 alkyl, and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 2b and R 2c is hydrogen, and C 1 ~C 6 are each independently selected from alkyl; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; R 6 is C 3 ~C 8 Cycloalkyl, C 1 ~C 6 alkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 6 ~C 10 aryl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1 or 2, With the proviso that formula (I') does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione.

[0008] In a second aspect, the disclosure provides a compound of formula (I″) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof: [ka] (In the formula, Each R 1 is hydrogen, C 1 ~C 6Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 is hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 10 Alkyl, -SO 2 R 6 , -C(=O)-R 2a , -C(=O)-OR 2a , and -C(=O)NR 2b R 2c Selected from; Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; R 2a is C 1 ~C 6alkyl, and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 2b and R 2c is hydrogen, and C 1 ~C 6 are each independently selected from alkyl; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; R 6 is C 3 ~C 8 Cycloalkyl, C 1 ~C6 alkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 6 ~C 10 aryl; n is 0, 1, 2, 3, 4, or 5; and m is 1 or 2.

[0009] In a third aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof: [ka] (In the formula, Each R 1 is hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 is hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C6 Alkynyl, and C 1 ~C 10 alkyl, Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; n is 0, 1, 2, 3 or 4; and m is 0, 1 or 2, With the proviso that the compound of formula (I) does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione.

[0010] In a fourth aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier or excipient.

[0011] In a fifth aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0012] In a sixth aspect, the present disclosure provides a method of degrading WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0013] In a seventh aspect, the disclosure provides a method of inhibiting WIZ protein expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0014] In an eighth aspect, the present disclosure provides a method of inhibiting, reducing or eliminating WIZ protein activity or WIZ protein expression, comprising administering to a subject a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0015] In a ninth aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0016] In a tenth aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0017] In a further aspect, the disclosure provides a method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0018] In a further aspect, the disclosure provides a method of 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 (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0019] In a further aspect, the disclosure provides a method of treating sickle cell disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0020] In a further aspect, the disclosure provides a method of treating β-thalassemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0021] In a further aspect, the disclosure provides a method of treating a disease or disorder affected by modulation of WIZ protein levels, comprising administering to a patient in need thereof a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0022] In a further aspect, the disclosure provides a method of treating or preventing a disorder affected by a decrease in WIZ protein levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0023] In a further aspect, the disclosure provides a method of reducing WIZ protein levels in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0024] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use as a medicament.

[0025] In a further aspect, the disclosure provides a compound of Formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder.

[0026] In a further aspect, the disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), 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.

[0027] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), 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.

[0028] In a further aspect, the disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease or disorder affected by decreased levels of WIZ protein.

[0029] In a further aspect, the disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting WIZ protein expression in a subject in need thereof.

[0030] In a further aspect, the present disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in degrading a WIZ protein in a subject in need thereof.

[0031] In a further aspect, the disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting, reducing, or eliminating WIZ protein activity or WIZ protein expression in a subject in need thereof.

[0032] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inducing or promoting fetal hemoglobin in a subject in need thereof.

[0033] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in reactivating fetal hemoglobin production or expression in a subject in need thereof.

[0034] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in increasing fetal hemoglobin production or expression in a subject in need thereof.

[0035] In a further aspect, the disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment or prevention of a disease or disorder affected by inhibition of WIZ protein expression.

[0036] In a further aspect, the disclosure provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment or prevention of a disease or disorder affected by degradation of the WIZ protein.

[0037] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a hemoglobinopathy.

[0038] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of sickle cell disease.

[0039] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of β-thalassemia.

[0040] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by increased fetal hemoglobin expression.

[0041] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating a disease or disorder affected by inhibition, reduction, or elimination of WIZ protein activity or WIZ protein expression.

[0042] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by the induction or promotion of fetal hemoglobin.

[0043] In a further aspect, the disclosure provides a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by reactivation of fetal hemoglobin production or expression.

[0044] In a further aspect, the disclosure provides the use of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0045] In a further aspect, the disclosure provides the use of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by inducing or promoting fetal hemoglobin.

[0046] In a further aspect, the disclosure provides for the use of a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reactivating fetal hemoglobin production or expression.

[0047] In a further aspect, the disclosure provides the use of a compound of Formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by increasing fetal hemoglobin expression.

[0048] In a further aspect, the disclosure provides the use of a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0049] In a further aspect, the disclosure provides the use of a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by inducing fetal hemoglobin.

[0050] In a further aspect, the disclosure provides for the use of a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reactivating fetal hemoglobin production or expression.

[0051] In a further aspect, the disclosure provides the use of a compound of Formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by increasing fetal hemoglobin expression.

[0052] In a further aspect, the disclosure provides the use of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), 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.

[0053] In a further aspect, the disclosure provides for the use of a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder affected by inducing fetal hemoglobin, reactivating fetal hemoglobin production or expression, or increasing fetal hemoglobin expression.

[0054] In a further aspect, the disclosure provides a pharmaceutical combination comprising a compound of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents.

[0055] Various aspects of the disclosure are set forth in the specification and claims.

[0056] 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.

[0057] 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]

[0058] [Figure 1-1] Figure 1: Figure 1A depicts a 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 depicts a bar graph showing HbF+ cell frequency due to shRNA-mediated WIZ deficiency in erythroid cells from human mobilized peripheral blood CD34+. Figure 1C depicts a bar graph showing HbF+ cell frequency due to CRISPR / Cas9-mediated WIZ deficiency in erythroid cells from human mobilized peripheral blood CD34+. [Figure 1-2] (As stated above.) [Figure 1-3] (As stated above.) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] 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.

[0060] definition Unless otherwise specified, the terms "compounds of the present disclosure", "compounds of the disclosure", or "compound of the disclosure" refer to compounds of formula (I'), (I"), (I), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-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.

[0061] 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 more than one subgroup, the last named group is the point of attachment of the group, e.g., "alkylaryl" means a monovalent group of formula alkyl-aryl-, while "arylalkyl" means a monovalent group of formula aryl-alkyl-. Furthermore, the use of terms designating monovalent groups where divalent groups are appropriate shall be construed as designating the respective divalent group, 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 more than one (e.g., at least one) of the grammatical referent of the article.

[0062] The term "and / or" means either "and" or "or" unless otherwise indicated.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] "Alkenyl" means a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, and hexenyl. Alkenyl groups can be unsubstituted or substituted and can be straight or branched chain. The term "C 2 ~C 6 Alkenyl" should be construed accordingly.

[0067] C 2 ~C 6Examples of alkenyl include, but are not limited to, ethenyl (or vinyl), propenyl (e.g., prop-1-enyl, prop-2-enyl), butadienyl (e.g., buta-1,3-dienyl), butenyl (e.g., but-1-en-1-yl, but-2-en-1-yl but-3-en-1-yl), pentenyl (e.g., pent-1-en-1-yl, pent-2-en-2-yl), hexenyl (e.g., hex-1-en-2-yl, hex-2-en-1-yl), 1-ethylprop-2-enyl, 1,1-(dimethyl)prop-2-enyl, 1-ethylbut-3-enyl, and 1,1-(dimethyl)but-2-enyl.

[0068] "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 6 "Alkynyl" should be construed accordingly. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, and hexynyl. Alkynyl groups can be unsubstituted or substituted. "C 2 ~C 6 Examples of "alkynyl" include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl and but-2-ynyl.

[0069] 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.

[0070] As used herein, the term "C 1 ~C 6 "Haloalkoxyl" refers to a C alkyl group, as defined herein, substituted with one or more halo groups. 1 ~C 6 It means an alkoxy group. 1 ~C 6 Examples of haloalkoxyl groups 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. 1 ~C 6 One or more of the halo groups of the haloalkoxyl is fluoro. For example, C 1 ~C 6 Haloalkoxyl may be selected from trifluoromethoxy, difluoromethoxy, fluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, and pentafluoroethoxy.

[0071] The term "halo" means fluorine, chlorine, bromine or iodine.

[0072] 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 11 Cycloalkyl, C 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 11 Cycloalkyl" and "C 3 ~C 8 "Cycloalkyl" is a monocyclic or hydrocarbon radical of 3 to 11 and 3 to 8 carbon atoms, respectively.

[0073] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropylcyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, spiro[2.3]hexanyl, spiro[3.3]heptyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, spiro[4.4]nonanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[1.1.1]pentanyl, and derivatives thereof.

[0074] C 3 ~C 11Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexanyl, spiro[3.3]heptyl, spiro[3.4]octanyl, spiro[2.5]octanyl, spiro[3.5]nonanyl, spiro[4.5]decanyl, spiro[5.5]undecanyl, spiro[4.4]nonanyl, 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.

[0075] C 3 ~C 8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[3.3]heptanyl, and cyclooctyl.

[0076] C 3 ~C 6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] "Heterocyclyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, and sulfur (O, N, and S), with no delocalized π-electrons (aromaticity) shared between ring carbons or heteroatoms. The terms "4-11 membered heterocyclyl" and "4-6 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. The heterocyclyl may be attached via a carbon atom or a heteroatom. The term polycyclic encompasses bridged, fused, and spirocyclic heterocyclyls.

[0078] 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-dioxolaniyl, and the like. Examples of the aryl include imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), 2-oxaspiro[3.3]heptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), 7-oxaspiro[3.5]nonanyl (e.g., 7-oxaspiro[3.5]nonan-2-yl), 1-oxa-7-azaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, and 7-azaspiro[3.5]nonanyl.

[0079] Examples of 4-11 membered heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl). Examples of such an alkyl group include 2-oxaspiro[3.3]heptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), 7-oxaspiro[3.5]nonanyl (e.g., 7-oxaspiro[3.5]nonan-2-yl), 1-oxa-7-azaspiro[3.5]nonanyl, 2-azaspiro[3.3]heptanyl (e.g., 2-azaspiro[3.3]heptan-6-yl), 2,7-diazaspiro[3.5]nonanyl, and 7-azaspiro[3.5]nonanyl.

[0080] Examples of 4-6 membered heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (eg, 3,6-dihydro-2H-pyranyl).

[0081] 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. Examples of aryl include, but are not limited to, 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). Examples include, but are not limited to, 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. Examples include, but are not limited to, 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-tetrahydronapth-2-yl, 1,4-ethano-1,2,3,4-tetrahydronapth-10-yl), and the like. The term "C 6~C 10 "Aryl" should be construed accordingly.

[0082] C 6 ~C 10 Examples of aryl include, but are not limited to, phenyl and naphthyl. 6 ~C 10 Aryl is phenyl.

[0083] As used herein, the term "heteroaryl" is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Examples include, but are not limited to, 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, aryl ... Examples of thiadiazinyl include 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, and 1,3,4-thiadiazolyl, tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, and azecinyl.

[0084] 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). Examples include, but are not limited to, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, ... Examples of such aryl groups include xalinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, imidazothiazolyl, triazolopyridinyl, and triazolopyrimidinyl.

[0085] 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). Examples include, but are not limited to, carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, phenanthrolinyl, and the like.

[0086] 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). Examples include, but are not limited to, 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.

[0087] 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.

[0088] The term "5- to 10-membered heteroaryl" should be construed accordingly.

[0089] 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, aryl, 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).

[0090] "Cyano" or "-CN" refers to a substituent having a carbon atom connected to a nitrogen atom with a triple bond, e.g., -C≡N.

[0091] As used herein, the term "C 1 ~C 3 "Alkylene" refers to a straight or branched hydrocarbon chain divalent radical, containing only carbon and hydrogen atoms, free of unsaturation, having from 1 to 3 carbon atoms. 1 ~C 2 Alkylene" should be construed accordingly.

[0092] As used herein, the term "optionally substituted" includes unsubstituted or substituted.

[0093] As used herein, [ka] indicates the point of attachment of that particular group to the base molecule.

[0094] As used herein, the term nitrogen protecting group (abbreviated as PG) of a compound of formula (X) or (Y) or any intermediate in any of the general schemes 1-4 and sub-formulas thereof refers to a group that is supposed to protect a functional group of concern, e.g., an amino group, from undesired side reactions, such as acylation, etherification, esterification, oxidation, solvolysis, and similar reactions. It can be removed under deprotection conditions. Depending on the protecting group utilized, one skilled in the art will know how to remove the protecting group to obtain the free amine NH 2 It will be known by reference to known procedures how groups can be obtained. 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.

[0095] 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 C 1 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).

[0096] According to the present disclosure, the preferred nitrogen protecting group (PG) can be selected from the group including tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), paramethoxybenzyl (PMB), methyloxycarbonyl, trimethylsilylethoxymethyl (SEM) and benzyl. The nitrogen protecting group (PG) is preferably tert-butyloxycarbonyl (Boc) or trimethylsilylethoxymethyl (SEM).

[0097] In some embodiments, the compounds of the present disclosure are selective over other proteins.

[0098] As used herein, the term "therapeutic agent," in the context of methods 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 lower activity levels of a WIZ protein compared to levels in the absence of the substance.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] Enumerated Embodiments Embodiment 1. A compound of formula (I') or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: [ka] Each R 1 is hydrogen, C 1 ~C6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 is hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 10 Alkyl, -SO 2 R 6 , -C(=O)-R 2a , -C(=O)-OR 2a , and -C(=O)NR 2b R 2c Selected from; Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; R 2a is C 1 ~C 6alkyl, and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 2b and R 2c is hydrogen, and C 1 ~C 6 are each independently selected from alkyl; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; R 6 is C 3 ~C 8 Cycloalkyl, C 1 ~C6 alkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 6 ~C 10 aryl, for example, R 6 is C 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1 or 2; With the proviso that the compound of formula (I') does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione.

[0115] Embodiment 2. A compound of formula (I″) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: [ka] Each R 1 is hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 is hydrogen, C3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 10 Alkyl, -SO 2 R 6 , -C(=O)-R 2a , -C(=O)-OR 2a , and -C(=O)NR 2b R 2c Selected from; Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; R 2a is C 1 ~C 6 alkyl, and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 2b and R 2c is hydrogen, and C 1 ~C 6 are each independently selected from alkyl; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where C 6 ~C 10Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; R 6 is C 3 ~C 8 Cycloalkyl, C 1 ~C 6 alkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 6 ~C 10 aryl, for example, R 6 is C 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl; n is 0, 1, 2, 3, 4, or 5; and m is 1 or 2).

[0116] Embodiment 3. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: [ka] Each R 1 is hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 is hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 alkyl, Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl; Here, C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; n is 0, 1, 2, 3 or 4; and m is 0, 1 or 2; With the proviso that the compound of formula (I) does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione.

[0117] Embodiment 4. A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1 or 2.

[0118] Embodiment 5.R 2 But, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 alkyl, wherein C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 R alkyl occurs independently 0 to 5 times, e.g., 0 to 4, 0 to 3, 0 to 2, 0 to 1 times. 3 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of the preceding embodiments, wherein

[0119] Embodiment 6. Formula (I) is a compound of formula (IA): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of the preceding embodiments,

[0120] Embodiment 7. Formula (I) is formula (IB): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5, wherein:

[0121] Embodiment 8. Formula (I) is a compound of formula (IC): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5, wherein:

[0122] Embodiment 9. Formula (I) is a compound of formula (ID): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5, wherein:

[0123] Embodiment 10. Formula (IC-i): [ka] A compound of formula (I'), (I'') or (I) according to any one of embodiments 1 to 6, and 8, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0124] Embodiment 11. Formula (IC-ii): [ka] A compound of formula (I'), (I'') or (I) according to any one of embodiments 1 to 5, 7, and 8, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0125] Embodiment 12. Formula (ID-i): [ka] A compound of formula (I'), (I'') or (I) according to any one of embodiments 1 to 6, and 9, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0126] Embodiment 13. Formula (ID-ii): [ka] A compound of formula (I'), (I'') or (I) according to any one of embodiments 1 to 5, 7, and 9, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0127] Embodiment 14. Each R 1 But hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 with the same carbon atom to which they are attached, C 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 together with the adjacent carbon atoms to which they are attached, C 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 But hydrogen, C 3 ~C 11 Cycloalkyl, C 1 ~C 6 haloalkyl, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; C2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 alkyl, Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 R alkyl occurs 0 to 5 times, 3 Replaced by; Each R 3 But, C 1 ~C 6 alkoxyl, halo, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where 4 to 11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl, independently, occurs 0 to 4 times in R 4 Replaced by; Each R 4 But, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl occurs 0 to 3 times in R 5 Replaced by; Each R 5 But -CN,C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; n is 0, 1, 2, 3, 4, or 5; and A compound of formula (I'), (I'') or (I) according to any one of embodiments 1, 2, 3, and 5-13, wherein m is 0, 1 or 2, e.g., m is 1 or 2, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0128] Embodiment 15. Each R 1 But hydrogen, C 1 ~C 6 Alkyl, hydroxyl, halo, and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 with the same carbon atom to which they are attached, C 3 ~C 6 or two R on adjacent carbon atoms form a cycloalkyl; 1 together with the adjacent carbon atoms to which they are attached, C 3 ~C 6 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 together with the non-adjacent carbon atoms to which they are attached, C 1 ~C 3 forming an alkylene bridge; R 2 But hydrogen, C 3 ~C 11 Cycloalkyl, C 1 ~C 6 haloalkyl, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 alkyl, Here, C 3 ~C 11 Cycloalkyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 R alkyl occurs 0 to 5 times, 3 Replaced by; Each R3 But, C 1 ~C 6 alkoxyl, halo, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where 4 to 11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl, each independently, occurs 0 to 3 times in R 4 Replaced by; Each R 4 But, C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl; n is 0, 1, 2, 3, 4, or 5; and A compound of formula (I'), (I'') or (I) according to any one of embodiments 1, 2, 3, and 5-14, wherein m is 0, 1 or 2, e.g., m is 1 or 2, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0129] Embodiment 16. Each R 1 But hydrogen, C 1 ~C 6 Alkyl, hydroxyl, fluoro, and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 with the same carbon atom to which they are attached, C 3 ~C 6 or two R on adjacent carbon atoms form a cycloalkyl; 1 together with the adjacent carbon atoms to which they are attached, C 3 ~C 6 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 together with the non-adjacent carbon atoms to which they are attached, C 1 ~C 2 forming an alkylene bridge; R 2 But hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 2 ~C 6 Alkynyl, and C 1 ~C 6 alkyl, wherein C 3 ~C 11 Cycloalkyl occurs 0 to 3 times in R 3 is replaced by C 1 ~C 6 Alkyl occurs 0 to 1 times in R 3a is replaced by C 2 ~C 6 Alkynyl occurs 0-1 times in R 3b Replaced by; Each R 3 But, C 1 ~C 6 independently selected from alkoxyl, and fluoro; R 3a is a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where 4 to 11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl, each independently, occurs 0 to 3 times in R 4 Replaced by; R 3b But, C 1 ~C 6 Alkyl, and C 3 ~C 8 Cycloalkyl, preferably C 3 ~C 8 cycloalkyl; Each R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, fluoro, and C 3 ~C 8 cycloalkyl; n is 0, 1, 2 or 3; and A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1.

[0130] Embodiment 17. Each R 1 But hydrogen, C 1 ~C 6 Alkyl, hydroxyl, fluoro, and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 with the same carbon atom to which they are attached, C 3 ~C 6 Forming a cycloalkyl; R 2 But, C 3 ~C 8 cycloalkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; C 2 ~C 6 Alkynyl, and C 1 ~C 6 alkyl, wherein C 3 ~C 8 Cycloalkyl occurs 0 to 3 times in R 3 is replaced by C 1 ~C 6 Alkyl occurs 0 to 1 times in R 3a is replaced by C 2 ~C 6 Alkynyl occurs 0-1 times in R 3b Replaced by; Each R 3 But, C 1 ~C 6 independently selected from alkoxyl, and fluoro; R 3a C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl occurs 0 to 3 times in R 4 are independently substituted by; R 3b But, C 1 ~C 6 Alkyl, and C 3 ~C 8 Cycloalkyl, preferably C 3 ~C 8 cycloalkyl; Each R 4 But, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, fluoro, and C 3 ~C 8 cycloalkyl; n is 0, 1, 2 or 3; and A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1.

[0131] Embodiment 18.R 2 But non-substituted C 1 ~C 6 Alkyl, or -(CH 2 )-R 3 where R 3 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of the preceding embodiments, wherein:

[0132] Embodiment 19.R 2 But non-substituted C 1 ~C 6 Alkyl, or -(CH 2 )-R 3a where R 3a or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of the preceding embodiments, wherein is defined according to any one of embodiments 16 and 17.

[0133] Embodiment 20.R 2 But non-substituted C 1 ~C 6 Alkyl, [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of the preceding embodiments, selected from:

[0134] Embodiment 21.R 2 A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, and t-butyl.

[0135] Embodiment 22. A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein m is 1.

[0136] Embodiment 23. A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein n is 0, 1, 2 or 3, e.g., n is 1.

[0137] Embodiment 24.R 1 But, C 1 ~C 6 Alkyl, hydroxyl, halo, and C 1 ~C 6 or two R on the same carbon atom. 1 with the same carbon atom to which they are attached, C 3 ~C 8A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which forms a cycloalkyl.

[0138] Embodiment 25.R 1 But, C 1 ~C 4 Alkyl, e.g., methyl, C 1 ~C 4 alkoxyl, e.g., methoxyl, and fluoro; or two R on the same carbon atom 1 with the same carbon atom to which they are attached, C 3 ~C 6 A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which forms a cycloalkyl.

[0139] Embodiment 26. Formula (I) is a compound of formula (Ii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5 and 14 to 25, wherein R 1a is hydrogen and C 1 ~C 6 independently selected from alkyl; R 1b is hydrogen and C 1 ~C 6 independently selected from alkyl; or R on the same carbon atom 1a and R 1b C, along with the same carbon atom to which they are attached. 3 ~C 6 Forming a cycloalkyl; R 1c is hydrogen and C 1 ~C6 independently selected from alkyl; R 1d is hydrogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 independently selected from: alkoxyl; or R on the same carbon atom 1c and R 1d C, along with the same carbon atom to which they are attached. 3 ~C 6 Forming a cycloalkyl; R 1e is hydrogen and C 1 ~C 6 alkyl; and R 2 is defined according to any one of the preceding embodiments).

[0140] Embodiment 27. Formula (I) is a compound of formula (IA-i): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 6, and 14 to 26, wherein R 1a is hydrogen and C 1 ~C 6 independently selected from alkyl; R 1b is hydrogen and C 1 ~C 6 independently selected from alkyl; or R on the same carbon atom 1a and R 1b C, along with the same carbon atom to which they are attached. 3 ~C 6 Forming a cycloalkyl; R 1c is hydrogen and C 1 ~C 6 independently selected from alkyl; R 1dis hydrogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 independently selected from: alkoxyl; or R on the same carbon atom 1c and R 1d C, along with the same carbon atom to which they are attached. 3 ~C 6 Forming a cycloalkyl; R 1e is hydrogen and C 1 ~C 6 alkyl; and R 2 is defined according to any one of the preceding embodiments).

[0141] Embodiment 28. Formula (I) has formula (IA-ii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 6, 8, 10, and 14 to 27, wherein

[0142] Embodiment 29. Formula (I) is a compound of formula (IA-iii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 6, 9, 12, and 14 to 27, wherein

[0143] Embodiment 30. Formula (I) is a compound of formula (IB-i): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5, 7, and 14 to 26, wherein R 1a is hydrogen and C 1 ~C 6 independently selected from alkyl; R 1b is hydrogen and C 1 ~C 6 independently selected from alkyl; or R on the same carbon atom 1a and R 1b C, along with the same carbon atom to which they are attached. 3 ~C 6 Forming a cycloalkyl; R 1c is hydrogen and C 1 ~C 6 independently selected from alkyl; R 1d is hydrogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 independently selected from: alkoxyl; or R on the same carbon atom 1c and R 1d C, along with the same carbon atom to which they are attached. 3 ~C 6 Forming a cycloalkyl; R 1e is hydrogen and C 1 ~C 6 alkyl; and R 2 is defined according to any one of the preceding embodiments).

[0144] Embodiment 31. Formula (I) is a compound of formula (IB-ii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5, 7, 8, 11, 14 to 26, and 30, wherein

[0145] Embodiment 32. Formula (I) is a compound of formula (IB-iii): [ka] or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, according to any one of embodiments 1 to 5, 7, 9, 13, 14 to 26, and 30, wherein

[0146] Embodiment 33.R 1a and R 1b A compound of formula (I'), (I'') or (I) according to any one of embodiments 26-32, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein are both hydrogen.

[0147] Embodiment 34.R 1e C 1 ~C 6 is alkyl, R 1a , R 1b , R 1c , and R 1d A compound of formula (I'), (I'') or (I) according to any one of embodiments 26-33, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein are all hydrogen.

[0148] Embodiment 35.R 1a and R 1b But hydrogen and C 1 ~C 6 R independently selected from alkyl, or R on the same carbon atom 1a and R 1b with the same carbon atom to which they are attached, C 3 ~C6 Form a cycloalkyl, R 1c , R 1d , and R 1e A compound of formula (I'), (I'') or (I) according to any one of embodiments 26-32, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein are all hydrogen.

[0149] Embodiment 36.R 1c and R 1d But hydrogen, C 1 ~C 6 Alkyl and C 1 ~C 6 each independently selected from alkoxyl, e.g., R 1c is hydrogen and R 1d C 1 ~C 6 Alkyl or C 1 ~C 6 alkoxyl or R on the same carbon atom 1c and R 1d with the same carbon atom to which they are attached, C 3 ~C 6 Form a cycloalkyl, R 1a , R 1b , and R 1e A compound of formula (I'), (I'') or (I) according to any one of embodiments 26-32, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein are all hydrogen.

[0150] Embodiment 37. Each R 3 is a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; 3 ~C 8 cycloalkyl, and halo, where 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl, each independently, occurs 0 to 2 times in R 4 and each R 4 But, C 1 ~C 6 Alkyl, C1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, independently selected from cycloalkyl.

[0151] Embodiment 38. Each R 4 But, C 1 ~C 6 A compound of formula (I'), (I'') or (I) according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: 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, R is 1A, R is 1A, R is 1B, R is 1C, R is 1D, R is 1E, R is 1F, R is 1G, R is 1H ...

[0152] Embodiment 39. The glutarimide moiety of a compound of formula (I'), (I'') or (I) is [ka] The compound according to any of the preceding embodiments,

[0153] Embodiment 40. The glutarimide moiety of a compound of formula (I'), (I'') or (I) is [ka] The compound according to any of the preceding embodiments,

[0154] Embodiment 41. The glutarimide moiety of a compound of formula (I'), (I'') or (I) is [ka] The compound according to any of the preceding embodiments,

[0155] Embodiment 42. A compound of formula (I'), (I'') or (I) according to any one of embodiments 1-3, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

[0156] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0157] Embodiment 43. A compound of formula (I'), (I'') or (I) according to any one of embodiments 1-3 and 42, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the absolute configuration at the glutarimide stereocenter is S.

[0158] Embodiment 44. A compound of formula (I'), (I'') or (I) according to any one of embodiments 1-3 and 42, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the absolute configuration of the glutarimide stereocenter is R.

[0159] Embodiment 45. A compound of formula (I'), (I'') or (I) according to any one of embodiments 1-3, and 42-44, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from:

[0160] [ka] [ka] [ka]

[0161] Embodiment 46. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharma- ceutically acceptable carrier or excipient.

[0162] Embodiment 47. A method for treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0163] Embodiment 48. A method for degrading a WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0164] Embodiment 49. A method for inhibiting WIZ protein expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0165] Embodiment 50. A method for inhibiting, reducing, or eliminating WIZ protein activity or WIZ protein expression, comprising administering to a subject a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0166] Embodiment 51. A method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0167] Embodiment 52. A method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0168] Embodiment 53. A method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0169] Embodiment 54. A method of 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 according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0170] Embodiment 55. 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 according to any one of embodiments 1-45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0171] Embodiment 56. A method of treating β-thalassemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0172] Embodiment 57. A method of treating a disease or disorder affected by modulation of WIZ protein levels, comprising administering to a patient in need thereof a compound according to any one of embodiments 1-45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0173] Embodiment 58. A method for treating or preventing a disorder affected by a decrease in WIZ protein levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0174] Embodiment 59. 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 according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0175] Embodiment 60. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use as a medicament.

[0176] Embodiment 61. A compound according to any one of embodiments 1-45, 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.

[0177] Embodiment 62. A compound according to any one of embodiments 1 to 45, 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.

[0178] Embodiment 63. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disorder affected by a decrease in WIZ protein levels in a subject in need thereof.

[0179] Embodiment 64. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting WIZ protein expression in a subject in need thereof.

[0180] Embodiment 65. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in degrading a WIZ protein in a subject in need thereof.

[0181] Embodiment 66. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inhibiting, reducing, or eliminating WIZ protein activity or WIZ protein expression in a subject in need thereof.

[0182] Embodiment 67. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in inducing or promoting fetal hemoglobin in a subject in need thereof.

[0183] Embodiment 68. A compound according to any one of embodiments 1 to 45 or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use in reactivating fetal hemoglobin production or expression in a subject in need thereof.

[0184] Embodiment 69. A compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in increasing fetal hemoglobin expression in a subject in need thereof.

[0185] Embodiment 70. A compound according to any one of embodiments 1 to 45, 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.

[0186] Embodiment 71. A compound according to any one of embodiments 1 to 45, 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.

[0187] Embodiment 72. A compound according to any one of embodiments 1 to 45, 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.

[0188] Embodiment 73. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0189] Embodiment 74. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by inducing or promoting fetal hemoglobin.

[0190] Embodiment 75. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reactivating fetal hemoglobin production or expression.

[0191] Embodiment 76. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by increasing fetal hemoglobin expression.

[0192] Embodiment 77. The use according to any one of embodiments 73 to 76, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0193] Embodiment 78. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reduced WIZ protein levels, inhibition of WIZ protein expression, or degradation of WIZ protein.

[0194] Embodiment 79. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by inducing fetal hemoglobin.

[0195] Embodiment 80. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by reactivating fetal hemoglobin production or expression.

[0196] Embodiment 81. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a disease or disorder affected by increasing fetal hemoglobin expression.

[0197] Embodiment 82. The use according to any one of embodiments 78 to 81, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0198] Embodiment 83. Use of a compound according to any one of embodiments 1 to 45, 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.

[0199] Embodiment 84. Use of a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease or disorder affected by inducing fetal hemoglobin, reactivating fetal hemoglobin production or expression, or increasing fetal hemoglobin expression.

[0200] Embodiment 85. The use according to any one of embodiments 83 and 84, wherein the disease or disorder is selected from sickle cell disease and β-thalassemia.

[0201] Embodiment 86. A pharmaceutical combination comprising a compound according to any one of embodiments 1 to 45, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents.

[0202] Embodiment 87. A compound of formula (I) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof for use as a medicament. [ka] (In the formula, Each R 1 is hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 together with the non-adjacent carbon atoms to which they are attached form a bridged ring (e.g., C 1 ~C 3 alkylene bridge ring); R 2 is hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 alkyl, Here, C 3 ~C 11 Cycloalkyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently occurs 0 to 5 (or 0 to 4, 0 to 3, 0 to 2, or 0 to 1) times. 3 Replaced by; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C3 ~C 8 cycloalkyl, where C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; n is 0, 1, 2, 3, or 4; and m is 0, 1 or 2.

[0203] Embodiment 88. A compound of formula (I) as defined by embodiment 87, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method as defined by any one of embodiments 61 to 72.

[0204] Embodiment 89. The method defined by any one of embodiments 47 to 59, wherein the compound is defined by embodiment 87.

[0205] Embodiment 90. Use of a compound of formula (I) as defined by embodiment 87, or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in a method as defined by any one of embodiments 73 to 85.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] Preferably, the pharma- ceutically acceptable salts of the compounds of formula (I′), (I″), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii) are acid addition salts.

[0214] 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 13 Such isotope-labeled compounds include those in which non-radioactive isotopes, such as C, are present. 14 C), reaction kinetic studies (e.g. 2 H or 3 H), drug or substrate tissue distribution assays, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in radioactive treatment of patients. 18F compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formulae (I'), (I'', (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples and general schemes (e.g., general schemes 5a and 5b), using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0215] In one embodiment of any aspect of the disclosure, hydrogen in a compound of formula (I'), (I'') or formula (I) is present in its normal isotopic abundance. In another embodiment, hydrogen is isotopically enriched with deuterium (D), and in particular embodiments of the invention, for example, one or more hydrogens in a glutarimide moiety in a compound of formula (I) are isotopically enriched in D, e.g., [ka] It is.

[0216] Additionally, heavier isotopes, particularly deuterium (i.e. 2Substitution with H or D) may result in certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or improved therapeutic index. In this context, it is understood that deuterium is considered as a substituent of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii). The concentration of such heavy isotopes, particularly deuterium, may be defined by an 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).

[0217] 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.

[0218] Compounds of the present disclosure that include groups capable of acting as hydrogen bond donors and / or acceptors, for example, compounds of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii), may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii) by known co-crystal formation procedures. Such procedures include contacting a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii) with a co-crystal former under crystallization conditions by grinding, heating, co-sublimation, co-melting, or in solution, and isolating the co-crystal thereby formed. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0219] 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.

[0220] 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.

[0221] In the compounds of the formula according to any one of the aspects, embodiments or claims of the present application, C-sp 3 Above terms [ka] indicates either (R) or (S) absolute stereochemistry. In the compounds of the formula in any one of the aspects, embodiments or claims of the present application, C-sp 3 Above terms [ka] indicates either (R) or (S) absolute stereochemistry. In the compounds of the formula in any one of the aspects, embodiments or claims of the present application, C-sp 3 Above terms [ka] represents a covalent bond where the stereochemistry of the bond is undefined. This is the C-sp 3 Above terms [ka] is meant to include either the (S) or (R) configuration of each chiral center, or a mixture thereof. Thus, mixtures of stereoisomers, e.g., mixtures of enantiomers such as racemates and / or mixtures of diastereoisomers, are encompassed by the present disclosure.

[0222] 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.

[0223] 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.

[0224] 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 liberating 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.

[0225] 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.

[0226] Compounds of the present disclosure, including salts, hydrates and solvates thereof, may inherently or intentionally form polymorphs.

[0227] In the compounds of the present disclosure, as exemplified by formula (I), the stereocenter at the 3-position of the glutarimide moiety (marked with an *) may be prone to epimerization under basic conditions. [ka]

[0228] 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, such as chiral SFC. For example, separation may be carried out according to Example 65.

[0229] In one embodiment of the compounds of the present disclosure, the absolute configuration at the glutarimide stereocenter (marked above with *) is S.

[0230] In another embodiment of the compounds of the present disclosure, the absolute configuration at the glutarimide stereocenter (marked above with *) is R.

[0231] In one embodiment, there is provided a compound as described in any one of the Examples or according to any of embodiments 1-42, wherein the absolute configuration at the glutarimide stereocenter (marked above with *) is S.

[0232] In another embodiment, there is provided a compound as described in any one of the Examples or according to any of embodiments 1-42, wherein the absolute configuration at the glutarimide stereocenter (marked above with *) is R.

[0233] 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.

[0234] Generally, compounds of formula (I'), (I'') and (I) can be prepared according to the schemes provided below.

[0235] General Scheme 1 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, the compounds of the present disclosure are prepared in Reaction Scheme 1 above as follows:

[0236] Metal photoredox reactions such as iridium (Ir) catalyzed photoredox coupling of INT-1 with an alcohol partner of formula INT-1A in the presence of a polar solvent such as acetonitrile (ACN) can provide the cross-coupled ether product (I)-2 in step 1. Removal of the protecting group (e.g., Boc) under acidic conditions can provide the free amine (I)-3 (step 2), which can then be converted to (I)-4 by alkylation reaction with a suitable alkyl bromide or alkyl mesylate in the presence of an amine base and a polar solvent such as diisopropylethylamine (DIPEA) and acetonitrile (ACN) or dimethylformamide (DMF) (step 3-i), or by reductive amination with a suitable aldehyde in the presence of a borohydride reagent such as sodium borohydride acetate (step 3-ii). With reference to Scheme 1, R 1 , R 2 , m and n are as defined herein according to any one of the specifically recited embodiments 1-45.

[0237] General Scheme 2 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, the compounds of the present disclosure, particularly non-linear R 1 and / or R 2 Compounds containing the group are prepared in Reaction Scheme 2 above as follows: Compounds of (I)-3 are prepared by the reaction of K with an appropriate non-linear alkyl iodide or mesylate. 2 CO 3(I)-5 can be converted to (I)-6 by an alkylation reaction (step 3-iii) in the presence of a base such as dimethylacetamide (DMA) and a polar solvent such as dimethylacetamide (DMA), or by reductive amination (step 3-iv) with an appropriate ketone in the presence of a borohydride reagent such as sodium borohydride acetate. 1 , R 2 , m and n are as defined herein according to any one of the specifically recited embodiments 1-45.

[0238] General Scheme 3 [ka] The starting materials for the above reaction schemes are commercially available or can be prepared according to methods known to those skilled in the art or by methods disclosed herein. In general, the compounds of the present disclosure are prepared in Reaction Scheme 3 above as follows:

[0239] Metal photoredox reactions such as iridium (Ir) catalyzed photoredox coupling of (INT-3) with an alcohol partner of formula (INT-1B) in the presence of a polar solvent such as acetonitrile (ACN) can yield the cross-coupled ether product (I)-7 in step 1. Removal of the protecting group (e.g., Boc) under acidic conditions can provide the free amine (I)-8 (step 2), which can then be converted to (I)-9 by reductive amination (step 3-i) with a suitable aldehyde in the presence of a borohydride reagent such as sodium borohydride acetate. Alternatively, (I)-8 can be converted to (I)-9 by alkylation reaction (step 3-ii) with a suitable alkyl mesylate or halide (e.g., iodide) 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. 2Chlorination and ring opening of lactone (I)-9 with a suitable agent such as affords (I)-10. Subsequent ring closure by amidation and nucleophilic substitution (lactam formation) using INT-IC under basic conditions affords the final product of formula (I), formula (I') or formula (I''). With reference to Scheme 3, R 1 , R 2 , m and n are as defined herein according to any one of the specifically recited embodiments 1-45.

[0240] General Schemes 4a, 4b and 4c: Deuterated Compounds of the Disclosure Scheme 4a: [ka] Scheme 4b: [ka] Compounds (I)-10 can be prepared according to general scheme 3. Subsequent ring closure by amidation and nucleophilic substitution under basic conditions using deuterated INT-D (prepared according to WO 2012 / 068512) or deuterated INT-Di (prepared according to WO 2012 / 079022) gives the final deuterated compounds of formula (I), (I'), or (I''), i.e. (I)-12-i and (I)-12-ii, where R 1 , R 2 , m and n are as defined by any one of the enumerated embodiments 1 to 45.

[0241] Scheme 4c: [ka] Compound (I) can be prepared according to any of the general schemes 1 to 3. 3and the like, gives rise to the final deuterated compound of formula (I), formula (I′) or formula (I″), i.e., (I)-12-iii, where R 1 , R 2 , m and n are as defined by any one of the enumerated embodiments 1 to 45.

[0242] Therefore, in one embodiment, the present disclosure provides 1 , R 2 , m and n are as defined by any one of the enumerated embodiments 1 to 45.

[0243] In one embodiment, there is provided a compound of formula (X') or a salt thereof: [ka] (In the formula, Each R 1 is hydrogen, C 1 ~C 6 Alkyl, Hydroxyl, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxyl and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 ' is a nitrogen protecting group, e.g., Boc, hydrogen, C 3 ~C11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 10 Alkyl, -SO 2 R 6 , -C(=O)-R 2a , -C(=O)-OR 2a , and -C(=O)NR 2b R 2c Selected from; Here, C 3 ~C 11 Cycloalkyl, 4-11 membered heterocyclyl, C 2 ~C 6 Alkynyl, and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; R 2a is C 1 ~C 6 alkyl, and 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; R 2b and R 2c is hydrogen, and C 1 ~C 6 are each independently selected from alkyl; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S, 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 3 ~C 8 cycloalkyl, where C 6 ~C 10Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; R 6 is C 3 ~C 8 Cycloalkyl, C 1 ~C 6 alkyl, 4-6 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, and C 6 ~C 10 aryl, for example, R 6 is C 3 ~C 8 Cycloalkyl and C 1 ~C 6 alkyl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1 or 2.

[0244] In one embodiment, there is provided a compound of formula (X) or a salt thereof: [ka] (In the formula, Each R 1 is hydrogen, C 1 ~C 6 Alkyl, hydroxyl, halo, and C 1 ~C 6 or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, 1 C, along with the same carbon atom to which they are attached. 3 ~C 8 or two R on adjacent carbon atoms form a cycloalkyl; 1 C, along with the adjacent carbon atoms to which they are attached. 3 ~C 8 Forming a cycloalkyl; or two R on non-adjacent carbon atoms 1 form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R 2 ' is a nitrogen protecting group, e.g., Boc, hydrogen, C 3 ~C 11 cycloalkyl, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; C 1 ~C 6 Haloalkyl, C 2 ~C 6 Alkenyl, and C 1 ~C 10 alkyl, Here, C 3 ~C 11 Cycloalkyl and C 1 ~C 10 Each alkyl group independently represents 0 to 5 occurrences of R 3 Replaced by; Each R 3 is C 1 ~C 6 Alkoxyl, Halo, C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from N, O, and S; 4-11 membered heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S; C 3 ~C 8 Cycloalkyl and C 2 ~C 6 alkynyl, wherein C2 ~C 6 Alkynyl is a group consisting of 0 to 1 occurrences of R 4 where C 6 ~C 10 Aryl, 5-10 membered heteroaryl, 4-11 membered heterocyclyl, and C 3 ~C 8 Cycloalkyl is independently selected from 0 to 4 occurrences of R 4 Replaced by; Each R 4 is C 1 ~C 10 Alkyl, C 1 ~C 6 Alkoxyl, halo, and C 3 ~C 8 cycloalkyl, where C 3 ~C 8 Cycloalkyl can occur 0-3 times. 5 Replaced by; Each R 5 -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxyl, Hydroxyl, and C 1 ~C 6 haloalkyl; n is 0, 1, 2, 3, or 4; and m is 0, 1 or 2.

[0245] In a further embodiment, the compound of formula (X') or formula (X) has the formula (X)-i [ka] (wherein R 1 , R 2 ', m and n are as defined according to formula (X') or formula (X) above).

[0246] In a further embodiment, the compound of formula (X') or formula (X) has the formula (X)-ii [ka] (wherein R 1 , R 2 ', m and n are as defined according to formula (X') or formula (X) above).

[0247] In further embodiments of formula (X′), (X), (X)-i or (X)-ii, R 2 ' is a nitrogen protecting group, e.g., Boc, hydrogen, and unsubstituted C 1 ~C 10 is selected from alkyl.

[0248] In further embodiments of formula (X), there is provided a compound selected from:

[0249] [ka] [ka] [ka] [ka] [ka]

[0250] In a further embodiment, there is provided a compound of formula (Y) [ka] (In the formula, R 1 , m and n are as defined above in formula (X') or formula (X); and PG 1 and P.G. 2 each of which is independently a nitrogen protecting group as defined herein.

[0251] In one embodiment, PG 2 is a base-labile protecting group, PG 1 is an acid labile protecting group.

[0252] In one embodiment, PG 2 is the SEM protecting group (trimethylsilylethoxymethyl), and PG 1 is the BOC protecting group (tert-butyloxycarbonyl).

[0253] In a further embodiment, the compound of formula (Y) is of formula (Y)-i [ka] (In the formula, R 1 ,m,n,PG 1 and P.G. 2 is defined according to formula (Y) above).

[0254] In a further embodiment, the compound of formula (Y) is of formula (Y)-ii [ka] (In the formula, R 1 ,m,n,PG 1 and P.G. 2 is defined according to formula (Y) above).

[0255] In further embodiments of formula (Y), there is provided a compound selected from: [ka] [ka] [ka] [ka]

[0256] In a further aspect, the disclosure provides a process for the preparation of a compound of formula (I'), (I''), or (I) in free form or in a pharma- ceutically acceptable salt form, comprising the steps of: 1) coupling of an aryl bromide of formula (INT-1) or (INT-3) with an alcohol of formula (INT-1A) or (INT-1B) under photoredox coupling conditions to give a compound of formula (I)-2 or formula (I)-7 as defined herein.

[0257] In a further aspect, the disclosure provides a process for the preparation of a compound of formula (I'), (I'') or (I) in free form or in a pharma- ceutically acceptable salt form, comprising the steps of: 1) coupling of an aryl bromide of formula (INT-3) with an alcohol of formula (INT-1B) under photoredox coupling conditions to give a compound of formula (I)-7 as defined herein; 2) deprotecting the compound of formula (I)-7 to give a compound of formula (I)-8 as defined herein; 3-i) reacting a compound of formula (I)-8 under reductive amination conditions to give a compound of formula (I)-9 as defined herein; or 3-ii) reacting a compound of formula (I)-8 under alkylation conditions to give a compound of formula (I)-9 as defined herein; 4) The compound of formula (I)-9 is reacted with SOCl 2 to provide a compound of formula (I)-10 as defined herein; 5) reacting a compound of formula (I)-10 with a compound of formula (INT-1C) to give a compound of formula (I'), (I'') or (I) as defined herein; 6) optionally purifying the compound of formula (I'), (I'') or (I) as defined herein; and 7) Optionally, separating the resulting stereoisomers, for example by chromatography, for example by chiral chromatorgraphy.

[0258] In a further aspect, the disclosure provides a process for the preparation of a compound of formula (I'), (I''), or (I) in free form or in a pharma- ceutically acceptable salt form, comprising the steps of: 1) coupling of an aryl bromide of formula (INT-1) with an alcohol of formula (INT-1A) under photoredox coupling conditions to give a compound of formula (I)-2 as defined herein; 2) deprotecting the compound of formula (I)-2 to give a compound of formula (I)-3; 3-i) reacting a compound of formula (I)-3 under reductive amination conditions to give a compound of formula (I) as defined herein; or 3-ii) reacting a compound of formula (I)-3 under alkylation conditions to give a compound of formula (I'), (I'') or (I) as defined herein; 4) optionally purifying the compound of formula (I'), (I'') or (I) as defined herein; and 5) Optionally, separating the resulting stereoisomers, for example by chromatography, for example by chiral chromatography.

[0259] 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 ...

[0260] For any of the preceding method steps or below, the reductive amination conditions may comprise the reaction of a corresponding aldehyde or ketone, 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).

[0261] For any of the preceding process steps 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.

[0262] In a further embodiment, there is provided a process for the preparation of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) in free form or in a pharma- ceutically acceptable salt form according to general Schemes 1-4.

[0263] Compounds of formula (X'), (X), (X)-i, (X)-ii, (Y), (Y)-i, and (Y)-ii as defined herein are useful in the preparation of compounds of the present disclosure, such as compounds of (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii). Thus, in one aspect, the present disclosure relates to a compound of formula (X'), (X), (X)-i, (X)-ii, (Y), (Y)-i, or (Y)-ii, or a salt thereof. In another aspect, the disclosure relates to the use of a compound of formula (X'), (X), (X)-i, (X)-ii, (Y), (Y)-i, or (Y)-ii, or a salt thereof, in the manufacture of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii). The disclosure further includes any variation of the process, in which an intermediate product obtained at any stage thereof is used as a starting material to carry out the remaining steps, or a starting material is formed in situ under the reaction conditions, or a reaction component is used in the form of its salt or optically pure material.

[0264] 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.

[0265] 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.

[0266] 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, including, but 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).

[0267] 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 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- ceutical acceptable carrier is sterile. The pharmaceutical composition can be formulated for a particular route of administration, such as oral, parenteral, and rectal administration. In addition, the pharmaceutical composition of the present disclosure may be configured in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). The 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.

[0268] 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.

[0269] In certain embodiments, the pharmaceutical composition is a capsule containing only the active ingredient.

[0270] Tablets may be either film coated or enteric coated according to methods known in the art.

[0271] 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 such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are 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 can be utilized.Formulations for oral use can be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] The compounds of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii), in free form or in the form of a pharma- ceutically acceptable salt, exhibit valuable pharmacological properties, e.g., 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, e.g., as tool compounds.

[0277] Additional properties of the disclosed compounds include good potency in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0278] Diseases and Disorders 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.

[0279] How to use In one aspect of the 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). 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.

[0280] 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 proteins for degradation, e.g., via the E3 ubiquitin pathway, e.g., compounds as described herein); Therapeutic agents for use in the treatment of the aforementioned diseases or disorders according to the present disclosure, e.g., small molecules (e.g., small molecule compounds that can target WIZ proteins for degradation, e.g., via the E3 ubiquitin pathway, e.g., compounds as described herein); Use of an agent, e.g., a small molecule (e.g., a compound as described herein), in the treatment of the aforementioned diseases or disorders according to the present disclosure; and A pharmaceutical composition comprising 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) for use in the treatment of the aforementioned diseases or disorders according to the present disclosure.

[0281] In view of their activity as WIZ modulators or degraders, the compounds of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), and (ID-ii), in free or pharma- ceutically acceptable salt form, 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 in hematological disorders, e.g., inherited hematological 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 to the subject a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0282] In another aspect, the disclosure provides a method of treating or preventing a disorder affected by a decrease in WIZ protein levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0283] In another aspect, the disclosure provides a method of inhibiting WIZ protein expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0284] In another aspect, the disclosure provides a method of degrading WIZ protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0285] In another aspect, the disclosure provides a method of inhibiting, reducing or eliminating WIZ protein activity or WIZ protein expression, comprising administering to a subject a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0286] In another aspect, the disclosure provides a method of inducing or promoting fetal hemoglobin in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0287] In another aspect, the disclosure provides a method of reactivating fetal hemoglobin production or expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0288] In another aspect, the disclosure provides a method of increasing fetal hemoglobin expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0289] 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 to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0290] In another aspect, the disclosure provides 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 formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0291] In another aspect, the disclosure provides a method of treating β-thalassemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0292] In one embodiment, β-thalassemia major or intermediate is the result of homozygous null or compound heterozygous mutations that occur together with β-globin deficiency and the phenotypic complications of β-thalassemia, whether or not transfusion dependent.

[0293] In another aspect, the disclosure provides a method for treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The present invention provides a compound of formula (I'), (I"), (I'', (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating or preventing a disease or disorder in a subject having

[0294] In another aspect, the disclosure provides a method for treating WI in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Provided is a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for treating or preventing a disorder affected by reduced levels of Z protein.

[0295] In another aspect, the disclosure provides a method for treating a disease comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The present invention provides a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of inhibiting expression of a WIZ protein in a subject comprising administering to said subject a therapeutically effective amount thereof.

[0296] In another aspect, the disclosure provides a method for treating a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Provided is a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for degrading a target WIZ protein of interest.

[0297] In another aspect, the disclosure provides a method for detecting the activity of a WIZ protein or a WI comprising administering to a subject a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Provided is a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of inhibiting, reducing, or eliminating Z protein expression.

[0298] In another aspect, the disclosure provides a method for treating a disease comprising, or requiring, administering to a subject a therapeutically effective amount of a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The present invention provides a compound of formula (I'), (I"), (I'', (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of inducing or promoting fetal hemoglobin in a subject receiving

[0299] In another aspect, the disclosure provides a method for treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, a compound of formula (I'), (I"), (I'', (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is provided for use in a method of reactivating fetal hemoglobin production or expression in a subject having

[0300] In another aspect, the disclosure provides a method for treating a disease comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The present invention provides a compound of formula (I'), (I"), (I"), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of increasing fetal hemoglobin expression in a subject comprising administering to the subject an effective amount of at least one compound selected from the group consisting of ribozymes, ribozymes, and ribozymes.

[0301] In another aspect, the disclosure provides a method for treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, a compound of formula (I'), (I"), (I'', (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is provided for use in a method for treating a hemoglobinopathy, e.g., a β-hemoglobinopathy.

[0302] In another aspect, the disclosure provides a method for treating a rheumatoid arthritis comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Provided is a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating sickle cell disease in a subject in need thereof.

[0303] In another aspect, the disclosure provides a method for treating a rheumatoid arthritis comprising administering to a subject a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Provided is a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method of treating β-thalassemia in a subject in need thereof.

[0304] 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.

[0305] 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.

[0306] 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.

[0307] The activity of the compounds according to the present disclosure can be determined by the in vitro methods described in this Example.

[0308] Combination therapy In another aspect, the disclosure provides a pharmaceutical combination comprising a compound of formula (I'), (I'), (I"), (I'', (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii), or a pharma- ceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents for simultaneous, separate or sequential use in therapy. In certain embodiments, the additional therapeutic agent is a myelosuppressant, such as hydroxyurea.

[0309] 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.

[0310] The compounds of the present disclosure may be administered either simultaneously with, before or after one or more other therapeutic agents. The compounds of the present disclosure may be administered individually, by the same or different routes of administration, or together in the same pharmaceutical composition as the other agents. The therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that are therapeutically active or have enhanced 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 combination comprising a therapeutically effective amount of a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) or a pharma- ceutically acceptable salt thereof, and one or more additional therapeutically active agents.

[0311] In one embodiment, the present disclosure provides a product comprising a compound of formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition modulated by WIZ. Products provided as combined formulations include compositions comprising a compound of Formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) and another therapeutic agent together in the same pharmaceutical composition or compositions comprising a compound of Formula (I'), (I''), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) and another therapeutic agent in separate forms, for example, in the form of a kit.

[0312] In one embodiment, the disclosure provides a pharmaceutical composition comprising a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii) and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharma- ceutically acceptable carrier as described above.

[0313] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I'), (I"), (I), (Ii), (IA), (IA-i), (IA-ii), (IA-iii), (IB), (IB-i), (IB-ii), (IB-iii), (IC), (IC-i), (IC-ii), (ID), (ID-i), or (ID-ii). In one embodiment, the kit comprises a means for keeping the compositions separate, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules, and the like.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] The protecting group may also be a polymeric resin, such as Wang resin or 2-chlorotrityl chloride resin.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] Abbreviation: ACN Acetonitrile AcOH Acetic acid AIBN Azobisisobutyronitrile aq. aqueous solution B 2 pin 2 Bis(pinacolato)diboron BAST Bis(2-methoxyethyl)aminosulfur trifluoride 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 quartet dt triple line double line dtbbpy 4,4'-di-tert-butyl-2,2'-dipyridyl dtd double line triple line double line Cs 2 CO 3 Cesium Carbonate DCE 1,2-dichloroethane DCM Dichloromethane DHP Dihydropyran DIBAL-H Diisobutylaluminum hydride DIPEA (DIEA) Diisopropylethylamine DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMP Dess-Martin Periodinane or 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DMSO Dimethyl sulfoxide EC 50 50% effective concentration ELSD Evaporative Light Scattering Detector EtOH Ethanol Et 2 O Diethyl ether Et 3 N-Triethylamine EtOAc Ethyl acetate HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl Hydrogen chloride hept septet HPLC High Performance Liquid Chromatography h or hr Time HRMS high-resolution mass spectrometry g grams g / min gram per minute I C 50 50% inhibitory concentration IPA (iPrOH) Isopropyl alcohol Ir[(dF(CF3)ppy)2dtbbpy]PF6 [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate K 2 CO 3 Potassium carbonate KI Potassium iodide KOAc Potassium Acetate K 3 PO 4 Tripotassium phosphate LCMS Liquid Chromatography Mass Spectrometry LDA Lithium diisopropylamide m multiplet MeCN Acetonitrile MeOH Methanol mg milligram MHz Megahertz min mL Milliliters mmol M Molar concentration MS mass spectrometry NaH Sodium hydride NaHCO 3 Sodium bicarbonate NaBH(OAc) 3 Sodium triacetoxyborohydride Na 2 SO 4 Sodium sulfate NBS N-Bromosuccinimide NiCl 2 (glyme) Nickel(II) chloride ethylene glycol dimethyl ether complex NMM N-Methylmorpholine NMP N-Methyl-2-pyrrolidone NMR nuclear magnetic resonance on overnight Pd / C Palladium Carbon PdCl 2 (dppf)·DCM [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0) PMB Paramethoxybenzyl q quartet qd doublet quartet quint quintet quintd double line quintuplet rbf round bottom flask RockPhos G3 Pd [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]palladium(II) methanesulfonate rt or rt Room temperature Rt retention time s single line i 2-(Trimethylsilyl)ethoxymethyl SnBu 3 Tributyltin t triple line td double line triple line tdd double line double line triple line TBAI Tetrabutylammonium iodide TEA (NEt 3 ) Triethylamine TFA Trifluoroacetic acid TFE Trifluoroethanol TfOH Triflic Acid THF Tetrahydrofuran THP Tetrahydropyran TMP 2,2,6,6-Tetramethylpiperidine Ts Tosil tt Triple line of triple lines ttd Double line triple line triple line TLC Thin Layer Chromatography UPLC Ultra High Performance Liquid Chromatography XPhos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) μL or uL microliter μW or uW microwave

[0324] General Methods I-Representative Procedures for Photoredox Catalysis with Lactones In a 40 mL vial, add 5-bromoisobenzofuran-1(3H)-one (1 equiv.), alcohol building block (1–1.1 equiv.), NiCl 2 (glyme) (0.05 equivalents), dtbbpy (0.05 equivalents), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6 (0.01 equiv.). ACN (0.186-0.3 M) was then added, followed by 2,2,6,6-tetramethylpiperidine (1.05 equiv.). The reaction flask was evacuated and backfilled with nitrogen three times. The resulting mixture was placed in a PennOC ml 450 nm photoreactor under blue LED light at room temperature for 18 h. The reaction mixture was filtered, concentrated, and purified by reverse phase HPLC or silica gel chromatography to give the amino-ether lactone.

[0325] General Method II - Representative Procedure for Boc Deprotection The amino-ether lactone (1 equiv.) was suspended in dioxane (0.1-25 M) and TFE (0.59-1.75 M). 4M HCl in dioxane (6 equiv.) was then added and the resulting mixture was stirred at room temperature for 18-37 h. The reaction mixture was concentrated under reduced pressure to give the free amino-ether lactone. The resulting product was carried on to the next step without purification.

[0326] General Method III - Representative Procedure for Reductive Amination The free amino-ether lactone (1 equiv.) was suspended in DMF (0.1-0.2 M). The aldehyde (1.5 equiv.) was added. The reaction was stirred at room temperature for 15 min and then NaBH(OAc) 3 (2 equiv.) was added. The reaction was stirred at room temperature for 1-18 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The combined extracts were passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography to give the lactone.

[0327] General method IV-SOCl 2 Representative procedure for lactone ring opening To a solution of the lactone (1 eq.) in dichloroethane (0.1 M) and EtOH (0.1 M) stirred at 70° C., thionyl chloride (12 eq.) was added and the resulting mixture was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and EtOAc, and quenched with saturated aqueous sodium bicarbonate. The reaction mixture was extracted three times with EtOAc and the combined organic layers were passed through a phase separator and concentrated to give the α-chloro-ester. The crude material was either purified by silica gel chromatography or used directly in the next step without purification.

[0328] General Methods Representative Procedures for V-Lactam Ring Closure 3-Aminopiperidine-2,6-dione hydrochloride (2 eq.) was dissolved in DMF (0.25 M) in a 2 mL microwave vial. DIPEA (5 eq.) was then added and the reaction was degassed and backfilled with nitrogen three times. The resulting mixture was stirred at room temperature for 15 min. α-Chloro-ester (1 eq.) was dissolved in DMF (0.17 M) and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 85° C. for 18 h and then at 150° C. for 2 h under microwave irradiation. The reaction mixture was concentrated on CELITE® and purified by silica gel chromatography or reverse phase HPLC to give the lactam product.

[0329] General Method VI - Representative Procedure for Photoredox Catalysis with 3-(5-Bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione In a capped vial, add 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1 equiv.), alcohol building block (1–1.2 equiv.), dtbbpy (0.05 equiv.), NiCl 2 (glyme) (0.05 equivalents), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6 (0.01 equiv.) was added. ACN (0.2-0.3 M) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-Tetramethylpiperidine (1.05-1.5 equiv.) was added. The resulting mixture was placed in a PennOC ml 450 nm photoreactor under blue LED light for 18 hours at room temperature. The reaction mixture was filtered, concentrated and purified by reverse phase HPLC or silica gel chromatography to give the SEM protected glutarimide, Boc protected amine and isoindoline derivatives.

[0330] General Method VII - Representative Procedure for Total Deprotection To a solution of a compound containing SEM-protected glutarimide and Boc-protected amine (1 equiv.) in ACN (0.2-0.3 M) was added methanesulfonic acid (5-10.9 equiv.). The resulting mixture was stirred at room temperature for 18 h and then cooled to 0° C. Triethylamine (10-15 equiv.) was then added, followed by N1,N2-dimethylethane-1,2-diamine (1.6-3 equiv.). The reaction mixture was then stirred at room temperature for 2-70 h. The reaction was quenched with aqueous base, extracted with DCM and a polar protic solvent, and either concentrated to give the free amine or purified by silica gel chromatography to give the free amine product.

[0331] General Method VIII - Representative Procedure for Mesylation To a solution of the alcohol (1 eq.) in DCM (0.5 M) were successively added dropwise DIPEA (2 eq.), 1-methylimidazole (2 eq.) and methanesulfonyl chloride (1.5 eq.). The reaction was stirred at room temperature for 18 h. The reaction was diluted with DCM (20 mL). The organic layer was washed three times with 1 M aqueous HCl and twice with saturated aqueous sodium bicarbonate. The organic layer was passed through a phase separator and concentrated to give the mesylate product.

[0332] General Method IX - Representative Procedure for Alkylation with Alkyl Mesylates Piperidine (1 eq) and mesylate (1.5 eq) were added to a microwave vial and suspended in ACN (0.2M). DIPEA (2 eq) was added and the reaction was degassed and back-filled with nitrogen three times. The reaction was stirred at 140° C. under microwave irradiation for 2-10 hours. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography to give the alkylated piperidine compound.

[0333] General Method X - Representative Procedure for Reduction Amination The free amino-ether lactone (1 equiv.) was suspended in DMF (0.15-0.178 M). 3 (2 equiv.) was added followed by the aldehyde (1.5 equiv.). The reaction was stirred at room temperature for 1-18 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography to give the lactone product.

[0334] Stereochemical representation The compounds of formula (I) have an asymmetric carbon atom * and has at least two asymmetric carbon atoms as shown below: [ka] .

[0335] Throughout the following synthesis section describing the synthetic preparation of compounds of formula (I), compounds depicted with the bond from the N atom of the oxoisoindolinyl moiety to the C atom of the glutarimide moiety shown as planar shall be taken to mean a compound mixture comprising both the (R) and (S) stereoisomers with respect to this stereocenter. For illustrative purposes, this can be shown with reference to Example 29: [ka] .

[0336] Thus, Example 29 (named 3-(5-(((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione) exists as a diastereomeric mixture of both (R)-3-(5-(((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and (S)-3-(5-(((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0337] When the compounds are separated into individual diastereomers or further mixtures of diastereomers, (R * ,S * The stereochemical configuration of diastereomers designated as (R ) indicates that the relative stereochemistry is known (as depicted by the wedge bonds), but the absolute stereochemistry is not known. * ,S *Any reference to a compound designated as 3-(5-(((3S * ,4S * This compound has been named as)-1-ethyl-4-fluoropiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and can be illustrated with reference to Example 55, which shows that the groups attached to the 3- and 4-positions of the piperidinyl moiety are represented by wedged bonds and the relative stereochemistry is known: [ka] This shall be interpreted to mean that the compound is either 3-(5-(((3S,4S)-1-ethyl-4-fluoropiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione or 3-(5-(((3R,4R)-1-ethyl-4-fluoropiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (taking into account the planar bond of the glutarimide moiety, as explained above). The same interpretation shall apply throughout the following sections of the synthesis of all compounds.

[0338] If the absolute stereochemistry of a particular chiral carbon atom in a diastereoisomeric compound or mixture of compounds is known, (R * ,S * ) designation may be replaced with the absolute (R,S) designation to indicate that a compound has a known absolute stereochemistry at that particular position.

[0339] Preparation of intermediates Preparation of rac-3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (INT-XX) [ka] Step 1. Ethyl 4-bromo-2-(chloromethyl)benzoate (1-1b) A stirred suspension of 5-bromophthalide 1-1a (1200 g, 5.633 mol) in EtOH (12 L) was heated to 68-72 °C. Then, SOCl 2 (2.40 L, 33.0 mol) was added dropwise over 7 h. The reaction mixture was concentrated under reduced pressure to approximately 4 L, then water (5 L) and MTBE (5 L) were added. The resulting mixture was stirred for 40 min. The phases were separated and the aqueous phase was extracted with MTBE (1×5 L). The combined organic layers were washed with 5% NaHCO 3 Wash with aqueous solution (5 L) and add Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated to dryness to give 1-1b as a light brown solid. MS[M+Na] + =298.9. 1 H NMR(400MHz,chloroform-d)δ 7.85(d,J=8.4Hz,1H),7.72(d,J=2.0Hz,1H),7.52(dd,J=8.3,2.0Hz,1H),5.00(s,2H),4.38(q,J=7.1Hz,2H),1.40(t,J=7.1Hz,3H).

[0340] Step 2. 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (INT-XX) 3-Aminopiperidine-2,6-dione hydrochloride 1-1c (596.3 g, 3.623 mol) in DMF (5.0 L) and i-Pr 2 To a stirred suspension of NEt (2.50 L, 14.3 mol) was added 1-1b (1000 g, 3.623 mmol) and the resulting reaction mixture was stirred at 85-90 °C for 24 h. The reaction mixture was then allowed to cool to room temperature, water (20 L) was added and the resulting mixture was stirred for 12 h. The precipitate formed was filtered and washed with water (5 L) and MeOH (2 L). This crude solid was slurried in MeOH (5 L) for 1 h, filtered and washed with MeOH (2 L). The resulting solid was then taken up in EtOAc (10 L) and stirred for 1 h. The resulting suspension was then filtered, washed with EtOAc (5 L) and dried under reduced pressure at 45-50 °C to give INT-XX as an off-white solid. MS [M+1] + =323.2. 1H NMR (400MHz, DMSO-d 6 )δ 10.99(s,1H),7.91-7.88(m,1H),7.72(dd,J=8.1,1.6Hz,1H),7.67(d,J=8.0Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.47(d,J=17 .7Hz,1H),4.34(d,J=17.7Hz,1H),2.98-2.83(m,1H),2.65-2.55(m,1H),2.45-2.29(m,1H),2.01(dtd,J=12.7,5.3,2.3Hz,1H).

[0341] Preparation of rac-3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (INT-1) [ka] To a stirred solution of INT-XX (10.0 g, 30.9 mmol) and DBU (6.9 mL, 46 mmol) in DMF (95 mL) was added SEMCl (6.6 mL, 37 mmol) at 0° C., and the resulting reaction mixture was allowed to warm to room temperature and then stirred for 5 h. An additional portion of DBU (3.5 mL, 23 mmol) and SEMCl (3.3 mL, 19 mmol) was added and stirring was continued for an additional 2 h. The reaction mixture was then saturated with NH 4 The mixture was quenched with aqueous Cl (250 mL) and extracted with EtOAc (×3). 2 SO 4 The crude material was dissolved in a minimum amount of EtOAc (about 50 mL) and concentrated to dryness. 2 O:heptane (v / v=1:2, 400 mL) was added. The resulting cloudy solution was allowed to stand overnight at -5°C. The precipitate that formed was filtered, washed with heptane (x3) and dried under vacuum to give INT-1 as an off-white solid. MS [M+H] + =453.4. 1H NMR(400MHz,chloroform-d)δ 7.75(d,J=8.6Hz,1H),7.66-7.61(m,2H),5.37-5.09(m,3H),4.48(d,J=16.2Hz,1H),4.32(d,J=16.2Hz,1H),3.74-3.50(m, 2H),3.11-2.98(m,1H),2.94-2.83(m,1H),2.33(qd,J=13.2,4.7Hz,1H),2.24-2.15(m,1H),0.97-0.90(m,2H),0.00(s,9H).

[0342] Preparation of 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (INT-2) [ka] Step 1: tert-Butyl (3R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate (1) In a 40 mL vial, 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (4.00 g, 8.82 mmol), (R)-1-boc-3-hydroxypiperidine (1.78 g, 8.82 mmol), dtbbpy (118 mg, 0.441 mmol), NiCl 2 (glyme) (97 mg, 0.441 mmol), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6(99 mg, 0.088 mmol) was added. ACN (29.4 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-Tetramethylpiperidine (1.56 mL, 9.26 mmol) was added. The reaction was placed in a PennOC m1 450 nm photoreactor under blue LED light for 18 hours. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (3R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate 1 as a yellow solid. LCMS [M+H-156.3] + :418.3. 1 H NMR (400 MHz, CDCl 3 )δ 7.79(dd,J=8.4,1.8Hz,1H),7.05-6.99(m,1H),6.96(s,1H),5.25(d,J=9.4Hz,1H),5.23-5.14(m ,2H),4.47-4.39(m,1H),4.38-4.24(m,2H),3.95(q,J=8.6Hz,3H),3.66-3.59(m,2H),3.35-3.16( m,1H),3.06-2.98(m,1H),2.94-2.83(m,1H),2.38-2.26(m,1H),2.23-2.14(m,1H),2.10-2.04(m, 1H),1.91-1.72(m,2H),1.61-1.50(m,1H),1.42(s,9H),0.94(dd,J=9.2,7.3Hz,2H),0.00(s,9H).

[0343] Step 2: 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (INT-2) To tert-butyl (3R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate 1 (4.7 g, 8.2 mmol) dissolved in ACN (27 mL) was added methanesulfonic acid (5.8 mL, 89 mmol). The reaction was stirred at room temperature overnight. The reaction was cooled to 0° C. and triethylamine (16.0 mL, 115 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (1.41 mL, 13.1 mmol). The reaction was stirred at room temperature for 2 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted 3 times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-100% ethanol with 1% TEA in dichloromethane) to give 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 as a cream solid. LCMS [M+H] + :344.3.

[0344] Preparation of (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one (INT-20) [ka] Step 1: tert-Butyl (R)-4-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (19) In a 40 mL capped vial, add 5-bromoisobenzofuran-1(3H)-one (220 mg, 1.03 mmol), tert-butyl (4R)-4-hydroxy-6-azaspiro[2.5]octane-6-carboxylate (CAS no. 1205542-21-7) (246 mg, 1.08 mmol), dtbbpy (28 mg, 0.10 mmol), NiCl 2 (glyme) (23 mg, 0.10 mmol), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6(23 mg, 0.021 mmol) was added. ACN (4.4 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-tetramethylpiperidine (0.18 mL, 1.1 mmol) was then added. The reaction was placed in a PennOC m1 450 nm photoreactor under blue LED light for 18 hours. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give the product tert-butyl (R)-4-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate 19 as a light cream solid. LCMS [M+H-tert-butyl] + :304.2. 1 H NMR (400 MHz, CDCl 3 )δ 7.83(d,J=8.5Hz,1H),7.02(dd,J=8.5,2.1Hz,1H),6.91(d,J=2.2Hz,1H),5.24(s,2H),4.21 -3.63(m,3H),3.46-3.00(m,2H),1.55-0.99(m,11H),0.77-0.65(m,1H),0.62-0.44(m,3H).

[0345] Step 2: (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one (INT-20) tert-Butyl (R)-4-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate 19 (228 mg, 0.63 mmol) was dissolved in dioxane (3.2 mL) and trifluoroethane (0.5 mL). 4M HCl in dioxane (0.95 mL, 3.8 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was concentrated to give (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one INT-20 as a pale yellow oil. The material was used directly in the next reaction. LCMS [M+H] + :260.2.

[0346] Preparation of (R)-sec-butyl methanesulfonate (INT-27) [ka] Compound INT-27 was made according to general method VIII from (R)-butan-2-ol (0.2 mL, 2.177 mmol) to give (R)-sec-butyl methanesulfonate INT-27 as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ 4.77(h,J=6.3Hz,1H),3.02(s,3H),1.82-1.63(m,2H),1.44(d,J=6.3Hz,3H),1.01(t,J=7.4Hz,3H).

[0347] Preparation of the enantiomer of 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one (INT-33) [ka] Step 1: tert-Butyl 7-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-5-azaspiro[2.5]octane-5-carboxylate (31) Compound 31 was made according to general method I starting from 5-bromoisobenzofuran-1(3H)-one (0.2 g, 0.939 mmol) and tert-butyl 7-hydroxy-5-azaspiro[2.5]octane-5-carboxylate (CAS no. 2167476-06-2) (235 mg, 1.03 mmol). The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl 7-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-5-azaspiro[2.5]octane-5-carboxylate 31 as a yellow oil. LCMS [M+H t-butyl] + :304.3.

[0348] Step 2: 5-((5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one (32) tert-Butyl 7-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-5-azaspiro[2.5]octane-5-carboxylate 31 (271 mg, 0.754 mmol) was suspended in dioxane (7.54 mL). 4M HCl in dioxane (1.13 mL, 4.52 mmol) was added and the reaction was stirred at room temperature for 18 hours. Trifluoroethanol (2 mL) was added followed by additional 4M HCl in dioxane (1.13 mlL, 4.52 mmol). The reaction was stirred at room temperature for 72 hours. The reaction was concentrated to give 5-((5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one 32) as a white solid. The material was used directly in the next reaction. LCMS [M+H] + :260.1.

[0349] Step 3: Enantiomer of 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one (INT-33) Compound INT-33 was made according to general method X starting from 5-((5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one 32 (196 mg, 0.754 mmol) and acetaldehyde (63.9 μL, 1.13 mmol). The crude material was purified by silica gel chromatography (0-100% 3:1 EtOAc:EtOH with 1% TEA in heptane) to give 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one INT-33 as an orange oil. LCMS [M+H] + :288.2. 1 H NMR (400 MHz, CDCl 3)δ 7.55(d,J=8.5Hz,1H),6.83-6.74(m,1H),6.74-6.64(m,1H),4.98(s,2H),4.46- 4.38(m,1H),3.00-2.92(m,1H),2.32-2.16(m,2H),2.08(dd,J=11.4,1.3Hz,1H) ,1.99-1.91(m,1H),1.87-1.80(m,1H),1.66-1.58(m,1H),1.30-1.23(m,1H),0. 83(t,J=7.2Hz,2H),0.29-0.00(m,5H).The enantiomeric mixture of isomers was purified by chiral SFC [column 21 Chiralpak IG;CO 2 Cosolvent 10mM NH 3 containing 25% MeOH; 80 g / min at 125 bar] to give two single enantiomers: Peak 1: Enantiomer 1 of 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one) as an orange oil; Peak 2: Enantiomer 2 of 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one) as an orange oil.

[0350] Preparation of 5-(((1S,5S,6R)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one and 5-(((1R,5R,6S)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one [ka] Step 1: rac-tert-butyl (1R,5R,6S)-5-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-3-azabicyclo[4.1.0]heptane-3-carboxylate (38) In a 40 mL capped vial, 5-bromoisobenzofuran-1(3H)-one (225 mg, 1.056 mmol), rac-tert-butyl (1R,5R,6S)-5-hydroxy-3-azabicyclo[4.1.0]heptane-3-carboxylate (CAS no. 2305079-71-2; also known as 5-exo-hydroxy-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester) (248 mg, 1.16 mmol), dtbbpy (28 mg, 0.11 mmol), NiCl 2 (glyme) (23 mg, 0.11 mmol), and Ir[(dF(CF 3 )ppy) 2dtbbpy]PF 6 (24 mg, 0.021 mmol) was added. ACN (4.5 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-tetramethylpiperidine (0.19 mL, 1.11 mmol) was then added. The reaction was placed in a PennOC m1 450 nm photoreactor under blue LED light at room temperature for 18 hours. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give rac-tert-butyl (1R,5R,6S)-5-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-3-azabicyclo[4.1.0]heptane-3-carboxylate 38 as a yellow oil. LCMS [M+H-tert-butyl] + :290.0.

[0351] Step 2: rac-5-(((1R,5R,6S)-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one (39) Compound 39 was made following general method II starting from rac-tert-butyl (1R,5R,6S)-5-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-3-azabicyclo[4.1.0]heptane-3-carboxylate 38 (224 mg, 0.65 mmol). The reaction was concentrated to give rac-5-(((1R,5R,6S)-3-azabicyclo[4.1.0]heptane-5-yl)oxy)isobenzofuran-1(3H)-one 39 as a yellow oil. The material was used directly in the next reaction. LCMS [M+H] + :246.2.

[0352] Step 3: 5-(((1S,5S,6R)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one and 5-(((1R,5R,6S)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one Compound INT-40 was made according to general method X starting from rac-5-(((1R,5R,6S)-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one 39 (159 mg, 0.65 mmol) and acetaldehyde (55 μL, 0.974 mmol). The crude material was purified by silica gel chromatography (0-100% ethyl acetate in heptane) to give rac-5-(((1R,5R,6S)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-40 as a light yellow oil. LCMS [M+H] + :274.2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 8.7, 2.1 Hz, 1H), 7.05-6.98 (m, 1H), 5.28 (s, 2H), 4.66-4.38 (m, 1H), 2.87-2.79 (m, 1H), 2.77-2.65 (m, 2H), 2.36 (d, J = 58.0 Hz, 3H), 1.69-1.50 (m, 1H), 1.32-1.21 (m, 1H), 1.16-1.00 (m, 3H), 0.82-0.71 (m, 1H), 0.57-0.47 (m, 1H). The enantiomeric mixture of isomers was analyzed by chiral SFC [column 21 × 250 mm IH; CO 2 co-solvent 0.5% IPA in 12% MeOH; 80 g / min, 100 bar, 35° C. to give two single enantiomers: 5-(((1S * ,5S * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-40 Peak 1, Rt = 2.18 min; 5-(((1R * ,5R * ,6S *)-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-40 Peak 2, Rt = 2.34 min was obtained. The absolute stereochemistry of the two enantiomers corresponding to the two product peaks was not determined.

[0353] Preparation of 5-(((1S,5R,6R)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one and 5-(((1R,5S,6S)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one (INT-47) [ka] Step 1: rac-tert-butyl (1R,5S,6S)-5-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-3-azabicyclo[4.1.0]heptane-3-carboxylate (45) In a 40 mL capped vial, 5-bromoisobenzofuran-1(3H)-one (225 mg, 1.06 mmol), rac-tert-butyl (1R,5S,6S)-5-hydroxy-3-azabicyclo[4.1.0]heptane-3-carboxylate (CAS no. 2305079-37-0; also known as 5-endo-hydroxy-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester) (248 mg, 1.16 mmol), dtbbpy (28 mg, 0.11 mmol), NiCl 2 (glyme) (23 mg, 0.11 mmol), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6 (24 mg, 0.021 mmol) was added. ACN (4.5 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-tetramethylpiperidine (0.19 mL, 1.11 mmol) was then added. The reaction was placed in a PennOC ml 450 nm photoreactor under blue LED light at room temperature for 18 hours. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give rac-tert-butyl (1R,5S,6S)-5-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-3-azabicyclo[4.1.0]heptane-3-carboxylate 45 as a light yellow solid. LCMS [M+H-tert-butyl] + :290.3.

[0354] Step 2: rac-5-(((1R,5S,6S)-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one (46) Compound 46 was made following general method II starting from rac-tert-butyl (1R,5S,6S)-5-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)-3-azabicyclo[4.1.0]heptane-3-carboxylate 45 (302 mg, 0.87 mmol). The reaction was concentrated to give rac-5-(((1R,5S,6S)-3-azabicyclo[4.1.0]heptane-5-yl)oxy)isobenzofuran-1(3H)-one 46 (214 mg, 0.874 mmol) as a yellow oil. The material was used directly in the next reaction. LCMS [M+H] + :246.2.

[0355] Step 3: 5-(((1S,5R,6R)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one and 5-(((1R,5S,6S)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one Compound INT-47 was made according to general method X starting from rac-5-(((1R,5S,6S)-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one 46 (214 mg, 0.87 mmol) and acetaldehyde (74 μL, 1.31 mmol). The crude material was purified by silica gel chromatography (0-20% methanol in DCM) to give rac-5-(((1R,5S,6S)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-47 as an orange oil. LCMS [M+H] + The enantiomeric mixture of isomers was analyzed by chiral SFC [column 21 × 250 mm IH; CO 2 co-solvent 0.5% IPA in 12% MeOH; 80 g / min, 100 bar, 35° C. to give two single enantiomers: 5-(((1S * ,5R * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-47 Peak 1, Rt = 1.55 min; 5-(((1R * ,5S * ,6S* )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-47 Peak 2, Rt = 1.70 min was obtained. The absolute stereochemistry of the two enantiomers corresponding to the two product peaks was not determined.

[0356] Preparation of (1r,3r)-3-ethoxycyclobutyl methanesulfonate (INT-55) [ka] A 40 mL vial was charged with (1r,3r)-3-ethoxycyclobutan-1-ol (570 mg, 4.9 mmol), DIPEA (1.3 mL, 7.4 mmol), DMAP (60 mg, 0.49 mmol) and DCM (3.0 mL). MsCl (0.42 mL, 5.4 mmol) was added and the reaction was stirred at 0° C. for 1 h and at room temperature for 5 h. The reaction was diluted with saturated NaHCO 3 The mixture was quenched with aqueous solution of 1,000 ml of ethyl acetate and extracted three times with DCM. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give (1r,3r)-3-ethoxycyclobutyl methanesulfonate INT-55 as a brown oil. The material was carried on to the next step without purification. 1 H NMR (400 MHz, CDCl 3 )δ 5.21(tt,J=7.0,5.0Hz,1H),4.28-4.14(m,1H),3.41(q,J=7.0Hz,2H),3.01(s,3H),2.62-2.45(m,4H),1.22(t,J=7.0Hz,3H).

[0357] Preparation of ((1r,3r)-3-Methoxycyclobutyl)methyl methanesulfonate (INT-58) [ka] Step 1: ((1r,3r)-3-Methoxycyclobutyl)methanol (57) trans-3-Methoxycyclobutane-1-carboxylic acid (175 mg, 1.35 mmol) was dissolved in THF (4.5 mL) and cooled to 0° C. 1M Borane tetrahydrofuran complex in THF (4.0 mL, 4.0 mmol) was added dropwise. The reaction was stirred at room temperature for 36 h. The reaction was cooled to 0° C., quenched with methanol (3.26 mL, 81 mmol) and stirred at room temperature for 2 h. The reaction was concentrated to dryness and then redissolved in methanol (5 mL). The reaction was stirred at room temperature for 18 h. The reaction was concentrated to give ((1r,3r)-3-methoxycyclobutyl)methanol 57 (156 mg, 1.35 mmol) as a clear oil. The material was carried on crude to the next step.

[0358] Step 2: ((1r,3r)-3-Methoxycyclobutyl)methyl methanesulfonate (INT-58) Compound INT-58 was made according to general method VIII starting from ((1r,3r)-3-methoxycyclobutyl)methanol 57 (156 mg, 1.345 mmol) to give ((1r,3r)-3-methoxycyclobutyl)methyl methanesulfonate INT-58 as a pale yellow oil. 1 H NMR (400MHz, CD 3 OD)δ 4.26(d,J=6.8Hz,2H),4.02(p,J=6.7Hz,1H),3.24(s,3H),3.09(s,3H),2.67-2.57(m,1H),2.23-2.10(m,4H).

[0359] Preparation of 7-oxaspiro[3.5]nonan-2-yl methanesulfonate (INT-60) [ka] Compound INT-60 was made according to general method VIII starting from 7-oxaspiro[3.5]nonan-2-ol (60 mg, 0.42 mmol) to give 7-oxaspiro[3.5]nonan-2-yl methanesulfonate INT-60 as an orange oil. 1 H NMR (400 MHz, CDCl 3)δ 5.05(p,J=7.2Hz,1H),3.67-3.56(m,4H),3.01(s,3H),2.53-2.43(m,2H),2.17-2.09(m,2H),1.70-1.60(m,4H).

[0360] Preparation of 3,3-difluorocyclobutyl methanesulfonate (INT-62) [ka] Compound INT-62 was made according to general method VIII starting from 3,3-difluorocyclobutan-1-ol (150 mg, 1.39 mmol) to give 3,3-difluorocyclobutyl methanesulfonate INT-62 as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ 5.04-4.94(m,1H),3.19-3.09(m,2H),3.07(s,3H),3.02-2.85(m,2H).

[0361] Preparation of ((1r,4r)-4-Methoxycyclohexyl)methyl methanesulfonate (INT-64) [ka] Compound INT-64 was made according to general method VIII starting from ((1r,4r)-4-methoxycyclohexyl)methanol (250 mg, 1.73 mmol) to give ((1r,4r)-4-methoxycyclohexyl)methyl methanesulfonate INT-64 as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ 4.06(d,J=6.4Hz,2H),3.37(s,3H),3.17-3.06(m,1H),3.02(s,3H),2.18-2.09(m ,2H),1.94-1.85(m,2H),1.82-1.70(m,1H),1.31-1.18(m,2H),1.16-1.04(m,2H).

[0362] Preparation of cyclobutyl methanesulfonate (INT-66) [ka] Compound INT-66 was made following general method VIII starting from cyclobutanol (0.2 mL, 2.55 mmol) to afford cyclobutyl methanesulfonate INT-66 as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ 4.99(pd,J=7.5,1.0Hz,1H),3.00(s,3H),2.48-2.26(m,4H),1.95-1.82(m,1H),1.71-1.56(m,1H).

[0363] Preparation of (S)-sec-butyl methanesulfonate (INT-68) [ka] Compound INT-68 was made following general method VIII starting from (S)-butan-2-ol (0.2 mL, 2.17 mmol) to give (S)-sec-butyl methanesulfonate INT-68 as an orange oil. 1 H NMR (400 MHz, CDCl 3 )δ 4.77(h,J=6.3Hz,1H),3.02(s,3H),1.85-1.63(m,2H),1.44(d,J=6.3Hz,3H),1.01(t,J=7.4Hz,3H).

[0364] Preparation of rac-tert-butyl (3R,5S)-3-hydroxy-5-methylpiperidine-1-carboxylate (INT-108) [ka] To a solution of rac-(3R,5S)-5-methylpiperidin-3-ol (245 mg, 1.62 mmol) in MeOH (2.5 mL), Na 2 CO 3 (257 mg, 2.42 mmol) and di-tert-butyl dicarbonate (529 mg, 2.42 mmol) were added. The reaction mixture was stirred at room temperature overnight. 2 The mixture was diluted with 200 mL of DCM (5.0 mL) and extracted three times with DCM. The organic layers were combined and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give rac-tert-butyl (3R,5S)-3-hydroxy-5-methylpiperidine-1-carboxylate INT-108 as a colorless oil. The material was carried on to the next step without purification.

[0365] Preparation of the enantiomers of tert-butyl 4,4-dimethyl-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidine-1-carboxylate (INT-118) [ka] In a 40 mL capped vial, add 5-bromoisobenzofuran-1(3H)-one (0.5 g, 2.347 mmol), rac-tert-butyl 3-hydroxy-4,4-dimethylpiperidine-1-carboxylate (592 mg, 2.58 mmol), dtbbpy (63 mg, 0.235 mmol), NiCl 2 (glyme) (52 mg, 0.235 mmol), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6 (53 mg, 0.047 mmol) was added. ACN (9.99 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-tetramethylpiperidine (0.416 mL, 2.464 mmol) was then added. The reaction was placed in a PennOC m1 450 nm photoreactor under blue LED light at room temperature for 18 hours. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl 4,4-dimethyl-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidine-1-carboxylate INT-118 as a cream colored solid. LCMS [M+H-tert-butyl] + :306.2. 1 H NMR (400 MHz, CDCl 3)δ 7.85(d,J=8.5Hz,1H),7.09(dd,J=8.6,2.1Hz,1H),7.00(s,1H),5.26(s,2H),3.98(dd,J=7.7,3.4Hz,1H),3.61-3.28(m,3H) ,1.76-1.64(m,1H),1.60-1.52(m,2H),1.49-1.31(m,9H),1.12(s,3H),1.10(s,3H). ChiralPak IG;CO 2 Co-solvent 15% 1:1 methanol:iPrOH; 80 g / min at 125 bar] to give two enantiomers: Peak 1: Enantiomer 1 of tert-butyl 4,4-dimethyl-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidine-1-carboxylate as a pale yellow clear oil (364 mg, 1.007 mmol); Peak 2: Enantiomer 2 of tert-butyl 4,4-dimethyl-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidine-1-carboxylate (214 mg, 0.592 mmol) as a pale yellow clear oil.

[0366] Preparation of 5-((4,4-dimethylpiperidin-3-yl)oxy)isobenzofuran-1(3H)-one (INT-119) [ka] Compound INT-119 was made following general method II starting from tert-butyl 4,4-dimethyl-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidine-1-carboxylate INT-118 peak 1 (364 mg, 1.007 mmol). The reaction was concentrated to give 5-((4,4-dimethylpiperidin-3-yl)oxy)isobenzofuran-1(3H)-one INT-119 as a cream solid. The material was used directly in the next reaction. LCMS [M+H] + :262.4.

[0367] Preparation of 5-((4,4-dimethylpiperidin-3-yl)oxy)isobenzofuran-1(3H)-one (INT-120) [ka] Compound INT-120 was made following general method II starting from tert-butyl 4,4-dimethyl-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)piperidine-1-carboxylate INT-118 peak 2 (214 mg, 0.592 mmol). The reaction was concentrated to give 5-((4,4-dimethylpiperidin-3-yl)oxy)isobenzofuran-1(3H)-one INT-120 as a cream solid. The material was used directly in the next reaction. LCMS [M+H] + :262.0.

[0368] Preparation of rac-tert-butyl (3R,5R)-3-hydroxy-5-methylpiperidine-1-carboxylate (INT-133) [ka] To a solution of rac-(3R,5R)-5-methylpiperidin-3-ol (251 mg, 2.2 mmol) in EtOH (6 mL) was added a solution of boc-anhydride (523 mg, 2.4 mmol) in EtOH (3 mL) via syringe. The reaction was stirred at room temperature for 20 hours. The reaction was concentrated to give rac-tert-butyl (3R,5R)-3-hydroxy-5-methylpiperidine-1-carboxylate INT-133 (520 mg, 2.42 mmol). The material was used directly in the next reaction without purification. 1 H NMR (400 MHz, CDCl 3 )δ 4.06-3.85(m,2H),2.99(dd,J=13.6,1.9Hz,1H),2.45(s,1H),2.00(dtd,J=10.7,6.7,3.8Hz,1H),1.85(dd t,J=13.7,4.1,2.1Hz,1H),1.65(d,J=25.6Hz,1H),1.46(s,9H),1.32-1.17(m,2H),0.89(d,J=6.7Hz,3H).

[0369] Preparation of rac-tert-butyl 5-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (INT-139) [ka] In a 40 mL vial, add 7-azaspiro[3.5]nonan-5-ol (50 mg, 0.22 mmol), di-tert-butyl dicarbonate (57 mg, 0.26 mmol), Na 2 CO 3 (27 mg, 0.26 mmol) and MeOH (1.0 mL). The reaction mixture was stirred vigorously at room temperature for 18 h. The reaction mixture was diluted with brine and extracted 4 times with DCM. The organic layers were combined, passed through a phase separator and concentrated to give tert-butyl 5-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate INT-139 as a racemic mixture. The material was used directly in the next step without purification. 1 H NMR (400 MHz, CDCl 3 )δ 3.58(dd,J=5.8,2.7Hz,1H),3.54-3.43(m,2H),3.28(dd,J=13.5,2.8Hz,1H),3.13(ddd,J=13.1,9.2, 3.5Hz,1H),2.16-2.06(m,1H),2.00-1.82(m,4H),1.77-1.63(m,3H),1.54-1.49(m,1H),1.47(s,9H).

[0370] Preparation of benzyl (3S,4S)-4-fluoro-3-hydroxypiperidine-1-carboxylate and benzyl (3R,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate (INT-146) [ka] Step 1: rac-Benzyl (1R,6S)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (145) N 2 To a suspension of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (8 g, 36.8 mmol) in dry DCM (80 mL) at 0° C. below was added m-CPBA (9.53 g, 44.2 mmol, 85%). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with DCM (20 mL) and saturated Na 2 S 2 O 3 The organic layers were combined and washed with saturated NaHCO 3 Wash with aqueous solution (2×80 mL), brine (80 mL), and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated to give rac-benzyl (1R,6S)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate 145 as a yellow oil. The material was used in the next step without purification. 1 H NMR (400 MHz, CDCl 3 )δ 7.43-7.29(m,5H),5.13(s,2H),4.06-3.72(m,2H),3.53(br s,1H),3.34-3.16(m,3H),2.19-1.84(m,2H)

[0371] Step 2: Benzyl (3S,4S)-4-fluoro-3-hydroxypiperidine-1-carboxylate and benzyl (3R,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate rac-Benzyl (1R,6S)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate 145 (8 g, 34.3 mmol) and Et 3 A neat mixture of N 3HF (5.5 g, 34.3 mmol) was stirred at 100 °C for 16 h. 20% BF in DCM 3 Et 2 O (80 mL, 129.7 mmol) was added to the reaction mixture at room temperature, and the reaction mixture was then saturated with NaHCO 3 The organic layers were combined, washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The crude material was purified by reverse phase HPLC (20-50% ACN in water with 0.1% formic acid). Fractions containing pure product were concentrated to remove ACN and lyophilized to give rac-benzyl (3R,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate INT-146 as a yellow oil. LCMS [M+H] + :254.1. 1 H NMR (400MHz, DMSO-d 6 )δ 7.45-7.26(m,5H),5.46(d,J=4.4Hz,1H),4.57-4.32(m,1H),3.88-3.64(m,2H ),3.49-3.40(m,1H),3.26-2.71(m,2H),2.07-1.98(m,1H),1.64-1.34(m,1H).

[0372] The racemic mixture of isomers was subjected to chiral SFC [column: Chiralpak AD 250 × 30 mm ID; CO 2 Co-solvent 0.1%NH 3 H 2 70 g / min, 100 bar, 25° C.] to give two enantiomers: INT-146 peak 1 as a yellow oil, Rt=2.1 min, LCMS [M+H] + :254.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.42-7.27 (m, 5H), 5.46 (d, J=4.8 Hz, 1H), 5.07 (s, 2H), 4.55-4.32 (m, 1H), 3.85-3.62 (m, 2H), 3.56-3.42 (m, 1H), 3.16-2.84 (m, 2H), 2.05-1.92 (m, 1H), 1.54-1.51 (m, 1H); INT-146 peak 2 was obtained as a yellow oil, Rt=3.9 min. LCMS [M+H] + :254.1. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.42-7.27(m,5H), 5.46(d,J=4.8Hz,1H), 5.07(s,2H), 4.55-4.32(m,1H), 3.85-3.62(m,2H), 3.56-3.42(m,1H), 3.16-2.84(m,2H), 2.05-1.92(m,1H), 1.54-1.51(m,1H). The absolute stereochemistry of the two enantiomers corresponding to the two product peaks was not determined.

[0373] Synthesis of benzyl (3S,4R)-4-fluoro-3-hydroxypiperidine-1-carboxylate and benzyl (3R,4S)-4-fluoro-3-hydroxypiperidine-1-carboxylate (INT-155) [ka] The enantiomeric mixture of INT-155 (900 mg, 3.55 mmol) was subjected to chiral SFC [column: 250 mm × 30 mm, 5 um DAICEL CHIRALPAK AD-H; CO 2 Co-solvent 30% MeOH + 0.1%NH 3 H 20; 60 g / min at 100 bar] to give the two enantiomers. INT-155 Peak 1, Rt=5.76 min, as a colorless oil; LCMS [M+23] + :276.2. 1 H NMR (400 MHz, CDCl 3 )δ 7.46-7.27(m,5H),5.15(s,2H),4.94-4.70(m,1H),3.88-3.57(m,3H),3.49-3.36(m,2H),2.26-2.04(m,2H),1.89-1.68(m,1H). 19 F NMR (377MHz, CDCl 3 ) δ -201.8.INT-155 Peak 2, Rt=6.65 min as a brown oil. LCMS [M+23] + :276.2. 1 H NMR (400 MHz, CDCl 3 )δ 7.52-7.29(m,5H),5.16(s,2H),4.93-4.74(m,1H),3.95-3.57(m,3H),3.50-3.35(m,2H),2.23-2.04(m,2H),1.94-1.68(m,1H). 19 F NMR (377MHz, CDCl 3 ) δ −201.8. The absolute stereochemistry of the two enantiomers corresponding to the two product peaks was not determined.

[0374] Synthesis of (3R,5S)-1-benzyl-3-(benzyloxy)-5-fluoropiperidine (INT-164), (3R,5R)-1-benzyl-3-(benzyloxy)-5-fluoropiperidine (INT-165), and (2S,4R)-1-benzyl-4-(benzyloxy)-2-(fluoromethyl)pyrrolidine (165) [ka] (Bis-(2-methoxyethyl)amino)sulfur trufluoride (11.32 mL, 61.39 mmol) was added to a solution of ((4R)-1-benzyl-4-(benzyloxy)pyrrolidin-2-yl)methanol (17.9 g, 60.2 mmol) in THF (180 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was diluted with EtOAc (200 mL), washed with brine (3×50 mL), and diluted with Na 2 SO 4The crude material was purified by silica gel chromatography (0-40% EtOAc in petroleum ether) and the fractions containing the product were concentrated. The resulting material was then further purified by reverse phase HPLC (60-80% ACN in water with 0.05% ammonia hydroxide as a modifier). The fractions containing the pure product were concentrated to give (3R,5S)-1-benzyl-3-(benzyloxy)-5-fluoropiperidine INT-164 as a light yellow oil, (3R,5R)-1-benzyl-3-(benzyloxy)-5-fluoropiperidine INT-165 as a light yellow oil, and (2S,4R)-1-benzyl-4-(benzyloxy)-2-(fluoromethyl)pyrrolidine 165 as a light yellow oil. (3R,5S)-1-benzyl-3-(benzyloxy)-5-fluoropiperidine INT-164: LCMS [M+H] + : 300.4. H NMR (400 MHz, CDCl 3 )δ 7.40-7.27(m,10H),4.73-4.44(m,3H),3.62-3.59(m,3H),3.10(br s,2H),2.63-2.50(m,1H),2.23-1.90(m,2H),1.53-1.41(m,1H). 19 F NMR (377MHz, CDCl 3 )δ -183.33. (3R,5R)-1-benzyl-3-(benzyloxy)-5-fluoropiperidine INT-165: LCMS [M+H] + :300.4. 1 H NMR (400 MHz, CDCl 3 )δ 7 7.27(s,10H),5.01-4.81(m,1H),4.54(d,J=1.6Hz,2H),3.92-3.85(m,1H),3.70-3.5 9(m,2H),2.98-2.80(m,2H),2.54-2.35(m,1H),2.31-2.16(m,2H),1.76-1.60(m,1H). 19 F NMR (377MHz, CDCl 3 )δ -182.2. (2S,4R)-1-benzyl-4-(benzyloxy)-2-(fluoromethyl)pyrrolidine 165: LCMS [M+H] + :300.3. 1 H NMR (400 MHz, CDCl 3 )δ 7.41-7.28(m,10H),4.67-4.34(m,4H),4.17-4.00(m,2H),3.71-3.44(m,1H),3.15-3. 11(m,1H),3.08-2.87(m,1H),2.54-2.36(m,1H),2.27-2.23(m,1H),1.89-1.75(m,1H).

[0375] Preparation of tert-butyl 6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate and tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (INT-174A and INT-174B) [ka] A solution of tert-butyl 2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (2 g, 10.24 mmol) in 50 ml of anhydrous THF was cooled to 0° C. in an ice-water bath. 3 A 1M solution of the BH 2 -THF complex (21.0 mL, 20.5 mmol) was added and stirring was continued for 2 h at 0 °C. 3 THF-H 2 The mixture was destroyed by careful addition of 2H2O (1:1 mixture, 100 mL). 3M NaOH solution (3 mL, 8 mmol) was added, followed by dropwise addition of 50% hydrogen peroxide (3.0 mL, 44 mmol) and the mixture was maintained at 35-40 °C with stirring for 1.5 h. After cooling to room temperature, potassium carbonate (0.92 g, 6.7 mmol) was added and the THF was removed under reduced pressure. The remaining solution was poured into an Erlenmeyer flask containing methylene chloride and water. The organic layer was extracted and the aqueous layer was back extracted with additional DCM. The combined organic extracts were poured into a phase separator and concentrated to give the regioisomeric mixture of products INT-174A and INT174B as a colorless oil. This material was carried on crude to the next step without further purification.

[0376] Preparation of final compounds Example 1: 3-(5-(((R)-1-ethylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-3) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (18.6 mg, 0.054 mmol) and bromoethane (7.9 mg, 0.072 mmol) were dissolved in ACN (0.5 mL) in a reaction vial equipped with a stir bar. DIPEA (0.03 mL, 0.2 mmol) was added and the reaction was stirred at room temperature for 1 h and then heated to 60 °C overnight. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in dichloromethane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-ethylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-3 as a white solid. LCMS [M+H] + :372.6. 1 H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.61(d,J=8.4Hz,1H),7.19(d,J=2.1Hz,1H),7.05(dd,J=8.4,2.2Hz, 1H),5.07(dd,J=13.3,5.1Hz,1H),4.50(dt,J=8.8,4.6Hz,1H),4.43-4.22(m,2H),3 .03-2.81(m,2H),2.72-2.55(m,2H),2.43-2.31(m,3H),2.15-1.94(m,4H),1.78-1. 67(m,1H),1.53(dd,J=13.3,10.0Hz,1H),1.44-1.31(m,1H),0.99(t,J=7.2Hz,3H).

[0377] Example 2: 3-(5-(((S)-1-ethylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-6) [ka] Step 1: tert-Butyl (3S)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate (4) In a 40 mL vial, add 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (220.2 mg, 0.486 mmol), tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (116.4 mg, 0.578 mmol), dtbbpy (9.5 mg, 0.035 mmol), NiCl 2 (glyme) (9.3 mg, 0.042 mmol), and Ir[(dF(CF 3 )ppy) 2 dtbbpy]PF 6 (5.7 mg, 5.1 μmol) was added. The reaction was degassed and backfilled with nitrogen three times. ACN (2.5 mL) was added followed by 2,2,6,6-tetramethylpiperidine (0.09 mL, 0.5 mmol). The reaction was placed in a PennOC m1 450 nm photoreactor under blue LED light at room temperature for 18 h. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (3S)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate 4 as a yellow foam. LCMS [M+H-156.3] + :418.2.

[0378] Step 2: 3-(1-oxo-5-(((S)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (5) Compound 5 was prepared according to general method VII starting from tert-butyl (3S)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)piperidine-1-carboxylate 4 (315.6 mg, 0.550 mmol). The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOH:Et in dichloromethane). 3N (v / v=100:1)) to give 3-(1-oxo-5-(((S)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione 5 as a slightly off-white solid. LCMS [M+H] + :344.6. 1 H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.63(d,J=8.4Hz,1H),7.20(d,J=2.2Hz,1H),7.07(dd,J=8. 4,2.2Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.48(s,1H),4.43-4.22(m,2H) ,3.17(d,J=12.4Hz,1H),2.98-2.80(m,2H),2.75-2.55(m,4H),2.38(dd,J= 13.1,4.5Hz,1H),2.08-1.92(m,2H),1.78-1.67(m,1H),1.67-1.44(m,2H).

[0379] Step 3: 3-(5-(((S)-1-ethylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-6) 3-(1-oxo-5-(((S)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione 5 (56.9 mg, 0.166 mmol) and bromoethane (22.3 mg, 0.205 mmol) were dissolved in ACN (1.0 mL) in a reaction vial equipped with a stir bar. DIPEA (0.10 mL, 0.573 mmol) was added and the reaction was stirred at 60 °C for 24 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in dichloromethane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((S)-1-ethylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-6 as an off-white solid. LCMS [M+H] + :372.3. 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.61(d,J=8.4Hz,1H),7.19(d,J=2.2Hz,1H),7.05(dd,J=8.4,2.2 Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.50(tt,J=8.5,3.9Hz,1H),4.44-4.17(m, 2H),3.02-2.82(m,2H),2.70-2.55(m,2H),2.43-2.30(m,3H),2.16-1.93(m,4H) ,1.78-1.67(m,1H),1.66-1.47(m,1H),1.44-1.31(m,1H),0.99(t,J=7.1Hz,3H).

[0380] Example 3: 3-(5-(((R)-1-isobutylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-7) [ka] Compound I-7 was prepared according to general procedure X starting from 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (61 mg, 0.18 mmol) and isobutanal (0.024 mL, 0.27 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-isobutylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-7 as a white solid. LCMS [M+H] + :400.3. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.54(d,J=8.3Hz,1H),7.11(d,J=2.2Hz,1H),6.97(dd,J=8.3,2.2Hz,1 H),5.00(dd,J=13.3,5.2Hz,1H),4.48-4.37(m,1H),4.31(d,J=17.1Hz,1H),4.18(d,J =17.2Hz,1H),2.89-2.78(m,2H),2.58-2.48(m,2H),2.37-2.25(m,1H),2.06-1.86(m ,6H),1.72-1.60(m,2H),1.55-1.41(m,1H),1.35-1.24(m,1H),0.77(t,J=5.9Hz,6H).

[0381] Example 4: 3-(5-(((R)-1-(oxetan-3-ylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-8) [ka] Compound I-8 was prepared according to general method III starting from 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (72 mg, 0.21 mmol) and oxetane-3-carbaldehyde (27 mg, 0.32 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-(oxetan-3-ylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-8 as a white solid. LCMS [M+H] + :414.3. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.53(d,J=8.4Hz,1H),7.11(d,J=2.2Hz,1H),6.97(dd,J=8.4,2.1Hz,1H),5.00(d d,J=13.4,5.1Hz,1H),4.60-4.49(m,2H),4.44-4.28(m,2H),4.23-4.13(m,3H),3.23-3.21(m,1H ),3.15-3.04(m,1H),2.90-2.78(m,2H),2.62-2.56(m,2H),2.55-2.49(m,1H),2.36-2.28(m,1H) ,2.10-2.02(m,1H),2.00-1.87(m,3H),1.68-1.60(m,1H),1.51-1.38(m,1H),1.34-1.23(m,1H).

[0382] Example 5: 3-(5-(((R)-1-((4,4-difluorocyclohexyl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-9) [ka] Compound I-9 was prepared according to general method III starting from 1-(hydroxymethyl)-3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and 4,4-difluorocyclohexane-1-carbaldehyde (39 mg, 0.26 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-((4,4-difluorocyclohexyl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-9 as a white solid. LCMS [M+H] + :476.4. 1H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.61(d,J=8.3Hz,1H),7.19(d,J=2.2Hz,1H),7.05(dt,J=8.3,2.2H z,1H),5.07(dd,J=13.3,5.1Hz,1H),4.56-4.46(m,1H),4.39(dd,J=17.5,2.4Hz, 1H),4.26(d,J=17.1Hz,1H),2.98-2.86(m,2H),2.66-2.55(m,2H),2.45-2.34(m, 1H),2.20-1.92(m,8H),1.84-1.50(m,7H),1.44-1.33(m,1H),1.15-1.02(m,2H).

[0383] Example 6: 3-(5-(((R)-1-(cyclohexylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-10) [ka] Compound I-10 was prepared according to general method III starting from 1-(hydroxymethyl)-3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and cyclohexanecarboxaldehyde (0.032 mL, 0.26 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-(cyclohexylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-10 as a white solid. LCMS [M+H] + :440.2. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.53(d,J=8.3Hz,1H),7.11(d,J=2.2Hz,1H),6.97(dt,J=8.5,1.6Hz ,1H),5.00(dd,J=13.3,5.2Hz,1H),4.49-4.39(m,1H),4.31(dd,J=17.1,3.4Hz,1H ),4.18(dd,J=17.1,3.0Hz,1H),2.90-2.78(m,2H),2.58-2.48(m,2H),2.38-2.24( m,1H),2.06-1.87(m,6H),1.69-1.25(m,9H),1.17-1.00(m,3H),0.79-0.65(m,2H).

[0384] Example 7: 3-(5-(((R)-1-(cyclobutylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-11) [ka] Compound I-9 was prepared according to general method III starting from 1-(hydroxymethyl)-3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (68 mg, 0.20 mmol) and cyclobutanecarbaldehyde (25 mg, 0.30 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 The material was purified by basic reverse-phase HPLC (5 mM NH as a modifier) ​​to give the product. 4 Further purification was performed by elution with 25-50% ACN in water containing 1,2-dihydro-OH). The test tube contained 3 drops of formic acid before sample collection. Fractions containing the desired product were combined and lyophilized to give the formate salt of 3-(5-(((R)-1-(cyclobutylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-11 as a white solid. LCMS [M+H] + :412.4. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),8.14(s,1H),7.53(d,J=8.5Hz,1H),7.11(d,J=2.2Hz,1H),6.97(dd, J=8.3,2.3Hz,1H),5.00(dd,J=13.3,5.1Hz,1H),4.45-4.35(m,1H),4.31(d,J=17.4 Hz,1H),4.18(d,J=17.1Hz,1H),2.90-2.77(m,2H),2.58-2.47(m,2H),2.41-2.34( m,1H),2.34-2.24(m,3H),2.05-1.84(m,6H),1.82-1.39(m,6H),1.34-1.20(m,1H).

[0385] Example 8: 3-(1-oxo-5-(((R)-1-propylpiperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (I-12) [ka] Compound I-12 was prepared according to general method III starting from 1-(hydroxymethyl)-3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (68 mg, 0.20 mmol) and propanal (0.021 mL, 0.30 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(1-oxo-5-(((R)-1-propylpiperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione I-12 as a white solid. LCMS [M+H] + :386.4. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.54(d,J=8.3Hz,1H),7.12(d,J=2.2Hz,1H),6.97(dd,J=8.3,2.2Hz,1 H),5.00(dd,J=13.3,5.2Hz,1H),4.47-4.36(m,1H),4.31(d,J=17.4Hz,1H),4.18(d,J =17.2Hz,1H),2.93-2.78(m,2H),2.59-2.48(m,2H),2.37-2.16(m,3H),2.07-1.87(m ,4H),1.70-1.61(m,1H),1.54-1.42(m,1H),1.41-1.25(m,3H),0.76(t,J=7.3Hz,3H).

[0386] Example 9: 3-(5-(((R)-1-isopropylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-13) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) was suspended in DMA (1.75 mL). 2 CO 3 (36 mg, 0.26 mmol) was added and the reaction was degassed and back-filled with nitrogen three times. 2-Iodopropane (0.087 mL, 0.87 mmol) was added and the reaction was stirred at 60° C. for 1 h under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give the product 3-(5-(((R)-1-isopropylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-13 as a white solid. LCMS [M+H] + :386.3. 1H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.61(d,J=8.4Hz,1H),7.20(d,J=2.3Hz,1H),7.05(dd,J=8.4,2.3Hz,1H),5.07( dd,J=13.3,5.0Hz,1H),4.56-4.44(m,1H),4.39(d,J=17.1Hz,1H),4.26(d,J=17.1Hz,1H),3.31 -3.27(m,1H),3.01-2.84(m,2H),2.65-2.56(m,1H),2.44-2.35(m,1H),2.31-2.24(m,2H),2.1 8-1.94(m,4H),1.79-1.71(m,1H),1.62-1.52(m,1H),1.49-1.32(m,3H),0.84(t,J=7.3Hz,3H).

[0387] Example 10: 3-(1-oxo-5-(((R)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione (I-14) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and 4-iodotetrahydro-2H-pyran (0.105 mL, 0.874 mmol) were suspended in DMA (1.75 mL). 2 CO 3 (36 mg, 0.26 mmol) was added and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 100° C. for 4 h under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(1-oxo-5-(((R)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione I-14 as a white solid. LCMS [M+H] + :428.4. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.61(d,J=8.3Hz,1H),7.19(d,J=2.4Hz,1H),7.05(dd,J=8.4,2.2Hz,1H),5.07(dd,J= 13.3,5.0Hz,1H),4.53-4.36(m,2H),4.26(d,J=17.5Hz,1H),3.87(dd,J=11.8,3.8Hz,2H),3.30-3.2 1(m,3H),3.14-3.02(m,1H),2.97-2.84(m,1H),2.77-2.71(m,1H),2.64-2.56(m,1H),2.44-2.36(m, 1H),2.31-2.17(m,2H),2.10-1.95(m,2H),1.79-1.70(m,1H),1.68-1.59(m,2H),1.56-1.31(m,4H).

[0388] Example 11: 3-(5-(((R)-1-(2-oxaspiro[3.3]heptan-6-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-15) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and 6-iodo-2-oxaspiro[3.3]heptane (196 mg, 0.87 mmol) were suspended in DMA (1.75 mL). 2 CO 3(36 mg, 0.26 mmol) was added and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 60° C. for 1 h, then at 100° C. for 2 h under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3 The material was purified by reverse-phase basic HPLC (5 mM NH as a modifier) ​​to give the product. 4 Further purification was performed with 15-40% ACN in water containing OH). The tube contained 3 drops of formic acid before sample collection. Pure fractions were combined, concentrated and lyophilized to give the formate salt of 3-(5-(((R)-1-(2-oxaspiro[3.3]heptan-6-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-15 as a white solid. LCMS [M+H] + :440.3. 1 H NMR (400MHz, DMSO-d6) δ 8.25(s,2H),7.54(d,J=8.4Hz,1H),7.11(d,J=2.2Hz,1H),6.97(dd,J=8.4,2 .2Hz,1H),5.00(dd,J=13.3,5.1Hz,1H),4.48(s,2H),4.45-4.27(m,5H),4.1 8(d,J=17.1Hz,1H),2.89-2.72(m,2H),2.56-2.46(m,2H),2.36-2.17(m,3H) ,1.99-1.74(m,6H),1.68-1.61(m,1H),1.48-1.38(m,1H),1.36-1.25(m,1H).

[0389] Example 12: 3-(5-(((R)-1-(oxetan-3-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-16) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and 3-iodooxetane (0.077 mL, 0.87 mmol) were suspended in DMA (1.75 mL). 2 CO 3 (36 mg, 0.26 mmol) was added and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 100° C. for a total of 6 h under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3 The fractions containing the desired product were combined, concentrated, and purified by reverse-phase basic HPLC (5 mM NH as a modifier). 4 H containing OH 2 Further purification was performed by elution with 10-30% ACN in O. The tube contained 3 drops of formic acid before sample collection. Pure fractions were combined and lyophilized to give the formate salt of 3-(5-(((R)-1-(oxetan-3-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-16 as a white solid. LCMS [M+H] + :400.3. 1H NMR(400MHz,DMSO-d6)δ 10.78(s,1H),8.25(s,1H),7.54(d,J=8.4Hz,1H),7.15(d,J=2.3Hz,1H),6.99(dd,J=8.7,2.2Hz ,1H),5.00(dd,J=13.4,5.1Hz,1H),4.51-4.42(m,3H),4.39(td,J=6.0,2.2Hz,1H),4.36-4.27(m ,2H),4.19(dd,J=17.5,2.1Hz,1H),3.39(p,J=6.3Hz,2H),2.90-2.71(m,2H),2.56-2.45(m,1H) ,2.37-2.23(m,1H),2.02-1.84(m,4H),1.72-1.62(m,1H),1.56-1.44(m,1H),1.41-1.29(m,1H).

[0390] Example 13: 3-(5-(((R)-1-(cyclopropylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-17) [ka] To a solution of 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (100 mg, 0.29 mmol) in EtOH (1.5 mL) was added sodium triacetoxyborohydride (123 mg, 0.58 mmol) followed by cyclopropanecarbaldehyde (0.031 mg, 0.44 mmol). The reaction was stirred at room temperature for 1 h. ISOLUTE® (HM-N part number 9800-5000) was added to the reaction and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in DCM). 3 N (v / v / v=75:25:1)) and concentrated. The product was diluted with 1:1 MeCN:water and lyopholized to give 3-(5-(((R)-1-(cyclopropylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-17. LCMS [M+H] + :398.3. 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.60(d,J=8.4Hz,1H),7.19(d,J=2.2Hz,1H),7.05(dd,J=8.4,2.2Hz,1H),5.07(dd,J=13.3,5.1Hz,1H ),4.57-4.44(m,1H),4.43-4.18(m,2H),3.08(d,J=11.0Hz,1H),2.90(ddd,J=17.3,13.6,5.4Hz,1H),2.76(d,J=11. 2Hz,1H),2.63-2.54(m,1H),2.44-2.29(m,1H),2.23(d,J=6.5Hz,2H),2.19-1.92(m,3H),1.77-1.67(m,1H),1.64-1 .48(m,1H),1.36(q,J=11.6,11.0Hz,1H),0.95(m,1H),0.88-0.75(m,1H),0.48-0.38(m,2H),0.05(d,J=4.9Hz,2H).

[0391] Example 14: 3-(5-(((R)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-18) [ka] To a solution of 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (100 mg, 0.29 mmol) in EtOH (1.5 mL) was added sodium triacetoxyborohydride (123 mg, 0.58 mmol) followed by 1-ethyl-1H-pyrazole-4-carbaldehyde (54.2 mg, 0.44 mmol) in EtOH (0.5 mL). The reaction was stirred at room temperature for a total of 48 hours. ISOLUTE® (HM-N part number 9800-5000) was added to the reaction and the reaction was concentrated. The dry loaded crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in DCM). 3N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-((1-ethyl-1H-pyrazol-4-yl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-18 as a colorless oil. LCMS [M+H] + :452.5. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.65-7.54(m,2H),7.29(d,J=1.5Hz,1H),7.17(d,J=2.2Hz,1H),7.03(dd,J=8.3,2. 2Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.50(dt,J=8.8,4.6Hz,1H),4.43-4.18(m,2H),4.06(q,J= 7.3Hz,2H),3.40(s,2H),2.91(ddd,J=17.2,13.6,5.2Hz,2H),2.67-2.55(m,2H),2.46-2.29(m,1H ),2.15-1.92(m,4H),1.72(dt,J=8.5,4.3Hz,1H),1.55(ddt,J=13.5,6.8,3.6Hz,1H),1.32(m,4H).

[0392] Example 15: 3-(5-(((R)-6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-23) [ka] Step 1: (R)-5-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one (21) To a solution of (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one INT-20 (164 mg, 0.63 mmol) in DMF (4.2 mL) was added sodium triacetoxyborohydride (269 mg, 1.3 mmol). Acetaldehyde (54 μL, 0.951 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator, and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3N (v / v / v=75:25:1)) to give (R)-5-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one 21 as a pale yellow oil. LCMS [M+H] + : 288.1. 1H NMR (400MHz, CDCl 3 )δ 7.71(d,J=8.5Hz,1H),6.96(dd,J=8.5,2.2Hz,1H),6.88(d,J=2.0Hz,1H),5.15(s,2H),4.13(s,1H),2.75-2.66(m,1H) ,2.58-2.34(m,5H),1.72-1.43(m,2H),0.99(t,J=7.2Hz,3H),0.68-0.60(m,1H),0.52-0.43(m,1H),0.33-0.24(m,2H).

[0393] Step 2: Ethyl (R)-2-(chloromethyl)-4-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)benzoate (22) To a solution of (R)-5-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one 21 (163 mg, 0.57 mmol) in dichloroethane (2.8 mL) and ethanol (2.8 mL) stirred at 70° C. in a 25 mL two-neck round bottom flask, thionyl chloride (0.50 mL, 6.8 mmol) was added dropwise. The reaction was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with water, and quenched with saturated sodium bicarbonate. The reaction mixture was extracted three times with ethyl acetate. The organic layers were combined, passed through a phase separator, and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane) to give ethyl (R)-2-(chloromethyl)-4-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)benzoate 22 as a pale yellow oil. LCMS [M+H] + :352.2.

[0394] Step 3: 3-(5-(((R)-6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-23). 3-Aminopiperidine-2,6-dione hydrochloride (77 mg, 0.47 mmol) was dissolved in DMF (0.94 mL) in a microwave vial. DIPEA (0.21 mL, 1.2 mmol) was added and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at room temperature for 15 min. Ethyl (R)-2-(chloromethyl)-4-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)benzoate 22 (82.4 mg, 0.23 mmol) dissolved in DMF (1.4 mL) was then added and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 85° C. overnight and then microwaved at 150° C. for 2 h. The reaction was concentrated and the crude material was pushed through a plug of charcoal before arriving at a silica column and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). Pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-23 as a cream solid. LCMS [M+H] + :398.4. 1 H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.52(d,J=8.5Hz,1H),7.09(d,J=2.2Hz,1H),6.96(dd,J=8.4,2.3Hz,1H),4.99(dd,J=1 3.3,5.0Hz,1H),4.30(dd,J=17.2,6.8Hz,1H),4.17(dd,J=17.1,6.8Hz,1H),4.06(s,1H),2.83(ddd,J= 17.2,13.6,5.4Hz,1H),2.68-2.45(m,4H),2.37-2.23(m,4H),1.96-1.86(m,1H),1.84-1.68(m,1H),1. 25-1.12(m,1H),0.87(td,J=7.2,1.7Hz,3H),0.57-0.48(m,1H),0.48-0.38(m,1H),0.31-0.20(m,2H).

[0395] Example 16: 3-(5-(((R)-6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-26) [ka] Step 1: (R)-5-((6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one (24) Compound 24 was prepared according to general method III starting from (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one INT-20 (90 mg, 0.35 mmol) and isobutanal (48 μL, 0.52 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give (R)-5-((6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one 24 as a clear oil. LCMS [M+H] + :316.2.

[0396] Step 2: Ethyl (R)-2-(chloromethyl)-4-((6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)benzoate (25) Compound 25 was made according to general method IV starting from (R)-5-((6-ethyl-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one 24 (114 mg, 0.36 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane) to give (R)-2-(chloromethyl)-4-((6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)benzoate 25 as a light brown oil. LCMS [M+H] + :380.3.

[0397] Step 3: 3-(5-(((R)-6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-26) Compound I-26 was made following general procedure V starting from ethyl (R)-2-(chloromethyl)-4-((6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)benzoate 25 (57.5 mg, 0.15 mmol). The reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3The material was purified by a second silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane (v / v / v=75:25:1)). The pure fractions were combined, concentrated, and lyophilized to give the product. The material was purified by a second silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane (v / v / v=75:25:1)). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-6-isobutyl-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-26 as a white solid. LCMS [M+H] + :426.3. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.60(d,J=8.3Hz,1H),7.15(d,J=2.2Hz,1H),7.03(dd,J=8.7,2.1Hz,1H),5.07(dd,J=13.1, 5.1Hz,1H),4.37(dd,J=17.2,8.9Hz,1H),4.25(dd,J=17.2,9.1Hz,1H),4.14-4.00(m,1H),2.91(ddd,J=17 .4,13.6,5.4Hz,1H),2.73-2.68(m,1H),2.64-2.56(m,1H),2.49-2.29(m,4H),2.10-1.85(m,4H),1.72-1. 59(m,1H),1.27-1.15(m,1H),0.84-0.74(m,6H),0.64-0.57(m,1H),0.54-0.48(m,1H),0.39-0.29(m,2H).

[0398] Example 17: 3-(5-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Step 1: 5-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one (28) Compound 28 was prepared according to general method IX starting from (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one INT-20 (218 mg, 0.84 mmol) and (R)-sec-butyl methanesulfonate INT-27 (192 mg, 1.26 mmol). Additional (R)-sec-butyl methanesulfonate INT-27 (192 mg, 1.26 mmol) and DIPEA (293 μL, 1.68 mmol) were added. The reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 140° C. for 6 hours under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3 N (v / v / v=75:25:1)). Pure fractions were combined, concentrated and lyophilized to give 5-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one 28 as a pale orange oil and recovered starting material (R)-5-((6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one as a pale orange oil. LCMS [M+H] + :316.2. 1 H NMR (400 MHz, CDCl 3 )δ 7.81(d,J=8.5Hz,1H),7.03(d,J=8.7Hz,1H),6.94(s,1H),5.24(s,2H),4.26-4.14(m,1H),2.91-2.76(m,1H),2.72-2.48(m,3H),1.74- 1.43(m,4H),1.28(s,1H),0.97(d,J=6.5Hz,3H),0.89(dt,J=14.1,7.4Hz,3H),0.77-0.72(m,1H),0.58-0.52(m,1H),0.40-0.30(m,2H).

[0399] Step 2: Ethyl 4-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)-2-(chloromethyl)benzoate (29) Compound 29 was made according to general method IV starting from 5-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)isobenzofuran-1(3H)-one 28 (98.8 mg, 0.31 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane) to give ethyl 4-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)-2-(chloromethyl)benzoate 29 as a pale orange oil. LCMS [M+H] + :380.3.

[0400] Step 3: 3-(5-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-30) Compound I-30 was made starting from ethyl 4-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)-2-(chloromethyl)benzoate 29 (88.3 mg, 0.23 mmol) following general procedure V. The reaction was concentrated and the crude material was pushed through a plug of charcoal before arriving at a silica column and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v = 75:25:1)). Fractions containing the desired product were combined and concentrated. The material was purified by basic reversed-phase HPLC (5 mM NH 4 Further purification was performed by elution with 35-60% ACN in water containing OH). The test tube contained 3 drops of formic acid before sample collection. Pure fractions were combined and lyophilized to give the formate salt 3-(5-(((R)-6-((S)-sec-butyl)-6-azaspiro[2.5]octan-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-30 as a white solid. LCMS [M+H] + :426.5. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),8.10(s,1H),7.52(dd,J=8.4,1.9Hz,1H),7.06(d,J=2.2Hz,1H),6.94(dd,J=8.5,2.2Hz,1H),4.9 9(dd,J=13.4,5.2Hz,1H),4.35-4.24(m,1H),4.24-4.12(m,1H),4.09-3.98(m,1H),3.25(s,3H),2.90-2.74(m,1 H),2.70-2.58(m,1H),2.56-2.48(m,2H),2.39-2.23(m,2H),1.95-1.85(m,1H),1.81-1.61(m,1H),1.29-1.08( m,2H),0.84-0.72(m,4H),0.69(td,J=7.4,3.5Hz,2H),0.56-0.48(m,1H),0.46-0.38(m,1H),0.30-0.20(m,2H).

[0401] Example 18: Diastereomeric 3-(5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-35) [ka] Step 1: Single enantiomer of ethyl 2-(chloromethyl)-4-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)benzoate (34) Compound 34 was made following general method IV starting from 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one INT-33 peak 1 (20.88 mg, 0.073 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane) to give ethyl 2-(chloromethyl)-4-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)benzoate 34 as an orange oil. The material was carried on to the next step without purification. LCMS [M+H] + :352.4.

[0402] Step 2: Diastereomeric 3-(5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-35) Compound I-35 was prepared starting from a single enantiomer of ethyl 2-(chloromethyl)-4-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)benzoate 34 (25.7 mg, 0.073 mmol) according to general procedure V. The reaction was concentrated and purified by reversed-phase HPLC (5 mM NH as modifier). 4 The mixture was purified by elution with 15-40% ACN in water containing 1,2-dihydro-OH. The tube contained 3 drops of formic acid before sample collection. The fractions containing the desired product were lyophilized to give the formate salt of diastereomeric 3-(5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-35 as a bluish solid. LCMS [M+H] + :398.4. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),8.26(s,1H),7.61(d,J=8.4Hz,1H),7.19(d,J=2.2Hz,1H),7.03(dd,J=8.4,2.2Hz,1H),5.07( dd,J=13.3,5.0Hz,1H),4.67-4.53(m,1H),4.39(d,J=17.1Hz,1H),4.26(d,J=17.1Hz,1H),3.12(d,J=10.7H) z,1H),2.91(ddd,J=17.4,13.6,5.4Hz,1H),2.64-2.55(m,1H),2.43-2.33(m,3H),2.24(d,J=11.1Hz,1H),2 .12-1.93(m,3H),1.69(dd,J=12.4,9.6Hz,1H),1.57-1.48(m,1H),0.98(t,J=7.1Hz,3H),0.49-0.28(m,4H).

[0403] Example 19: Diastereomeric 3-(5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-37) [ka] Step 1: Single enantiomer of ethyl 2-(chloromethyl)-4-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)benzoate (36) Compound 36 was made according to general method IV starting from 5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)isobenzofuran-1(3H)-one INT-33 peak 2 (18.93 mg, 0.066 mmol) to give a single enantiomer of ethyl 2-(chloromethyl)-4-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)benzoate 36 as an orange oil. The material was carried on to the next step without purification. LCMS [M+H] + :352.3.

[0404] Step 2: Diastereomeric 3-(5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-37) Compound I-37 was prepared starting from the single enantiomer of ethyl 2-(chloromethyl)-4-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)benzoate 36 (23.2 mg, 0.066 mmol) according to general procedure V. The reaction was concentrated and purified by reversed-phase HPLC (5 mM NH 4 The mixture was purified by elution with 15-40% ACN in water containing OH). The tube contained 3 drops of formic acid before sample collection. The fractions containing the desired product were lyophilized to give the formate salt of diastereomeric 3-(5-((5-ethyl-5-azaspiro[2.5]octan-7-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-37 as a bluish solid. LCMS [M+H] + :398.4. 1H NMR(400MHz,DMSO-d6)δ 11.00(s,1H),8.32(s,3H),7.61(d,J=8.4Hz,1H),7.19(d,J=2.2Hz,1H),7.03(dd,J=8.4,2.3Hz,1H), 5.07(dd,J=13.2,5.1Hz,1H),4.66-4.53(m,1H),4.39(d,J=17.1Hz,1H),4.26(d,J=17.2Hz,1H),3.15- 3.10(m,1H),2.96-2.85(m,1H),2.63-2.56(m,1H),2.41-2.32(m,3H),2.24(d,J=11.2Hz,1H),2.11-1 .94(m,3H),1.69(dd,J=12.4,9.6Hz,1H),1.56-1.46(m,1H),0.98(t,J=7.3Hz,3H),0.48-0.25(m,4H).

[0405] Example 20: 3-(5-(((1S * ,5S * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-42) [ka] Step 1: Ethyl 2-(chloromethyl)-4-(((1S * ,5S * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate (41) Compound 41 was prepared by the general procedure IV from 5-(((1S * ,5S * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-40 Prepared starting from peak 1 (86.4 mg, 0.32 mmol), ethyl 2-(chloromethyl)-4-(((1S * ,5S * ,6R * )-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate 41 was obtained as a brown oil. The material was carried to the next step without purification. LCMS [M+H]+ :338.2.

[0406] Step 2: 3-(5-(((1S * ,5S * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-42) Compound I-42 was prepared by the synthesis of ethyl 2-(chloromethyl)-4-(((1S * ,5S * ,6R * This reaction was made starting from 4-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate 41 (107 mg, 0.32 mmol). The reaction was concentrated and the crude material was pushed through a plug of charcoal before arriving at a silica column and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3 N(v / v / v=75:25:1)). The pure fractions were combined, concentrated, and lyophilized to give 3-(5-(((1S * ,5S * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-42 was obtained as a light blue solid. LCMS [M+H] + :384.3. 1 H NMR(400MHz,DMSO-d6)δ 10.90(s,1H),7.58(d,J=8.4Hz,1H),7.13(s,1H),7.06-6.96(m,1H),5.01(dd,J=13.2,5.0Hz,1H),4.51(s,1H),4.33(dd,J=17.2,2.9Hz,1H),4 .20(d,J=17.3Hz,1H),2.90-2.70(m,3H),2.56-2.48(m,1H),2.39-2.19 (m,3H),2.00-1.85(m,2H),1.21-0.83(m,6H),0.59(s,1H),0.39(s,1H).

[0407] Example 21: 3-(5-(((1R * ,5R *,6S * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-44) [ka] Step 1: Ethyl 2-(chloromethyl)-4-(((1R * ,5R * ,6S * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate (43) Compound 43 was prepared by the general procedure IV from 5-(((1R * ,5R * ,6S * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-40 Prepared starting from peak 2 (50.7 mg, 0.19 mmol), ethyl 2-(chloromethyl)-4-(((1R * ,5R * ,6S * )-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate 43 was obtained as a brown oil. The material was carried to the next step without purification. LCMS [M+H] + :338.2.

[0408] Step 2: 3-(5-(((1R * ,5R * ,6S * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-44) Compound I-26 was prepared by the synthesis of ethyl 2-(chloromethyl)-4-(((1R * ,5R * ,6S * The reaction was made starting from 4-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate 43 (62.5 mg, 0.19 mmol). The reaction was concentrated and the crude material was passed through a plug of charcoal before being loaded onto a silica column and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3Pure fractions were combined, concentrated, lyophilized, and purified by reversed-phase HPLC (5 mM NH as a modifier). 4 H containing OH 2 The fractions were further purified by 15-40% ACN in 200. The tubes contained 3 drops of formic acid prior to sample collection. The fractions containing the desired product were combined and lyophilized to give 3-(5-(((1R * ,5R * ,6S * )-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-44 formate salt was obtained. LCMS [M+H] + :384.3. 1 H NMR(400MHz,DMSO-d6)δ 10.66(s,1H),8.22(s,1H),7.57(d,J=8.5Hz,1H),7.12(d,J=2.1Hz,1H),7.01(dd,J=8.7, 2.2Hz,1H),5.00(dd,J=13.4,5.1Hz,1H),4.55-4.45(m,1H),4.33(dd,J=17.1,2.7Hz,1H), 4.20(d,J=17.2Hz,1H),2.91-2.70(m,3H),2.57-2.48(m,1H),2.41-2.14(m,4H),2.00-1. 87(m,2H),1.16-1.07(m,1H),0.99-0.84(m,4H),0.63-0.53(m,1H),0.38(q,J=5.0Hz,1H).

[0409] Example 22 3-(5-(((1S * ,5R * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-49) [ka] Step 1: Ethyl 2-(chloromethyl)-4-(((1S * ,5R * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate (48) Compound 48 was prepared by the general procedure IV from 5-(((1S * ,5R * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)isobenzofuran-1(3H)-one INT-47 Prepared starting from peak 1 (47.2 mg, 0.17 mmol), ethyl 2-(chloromethyl)-4-(((1S * ,5R * ,6R * )-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate 48 was obtained as a brown oil. The material was carried to the next step without purification. LCMS [M+H] + :338.2.

[0410] Step 2: 3-(5-(((1S * ,5R * ,6R * )-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-49) Compound I-49 was prepared by the synthesis of ethyl 2-(chloromethyl)-4-(((1S * ,5R * ,6R * The reaction was made starting from 48 (58.4 mg, 0.17 mmol)-3-ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)benzoate. The reaction was concentrated and the crude material was pushed through a plug of charcoal before arriving at a silica column and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane 3 Pure fractions were combined, concentrated, lyophilized, and purified by reversed-phase HPLC (5 mM NH as a modifier). 4 The fractions were further purified by 15-40% ACN in water containing 1H OH. The tubes contained 3 drops of formic acid prior to sample collection. Pure fractions were combined and lyophilized to give 3-(5-(((1S * ,5R * ,6R *)-3-Ethyl-3-azabicyclo[4.1.0]heptan-5-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-49 was obtained as a white solid. LCMS [M+H] + :384.3. 1 H NMR(400MHz,DMSO-d6)δ 10.49(s,1H),8.23(s,1H),7.53(d,J=8.5Hz,1H),7.15(d,J=2.2Hz,1H),7.01(dd,J=8.3,2.3Hz,1H ),5.00(dd,J=13.3,5.1Hz,1H),4.93-4.83(m,1H),4.31(d,J=17.1Hz,1H),4.18(d,J=17.1Hz,1H), 2.91-2.77(m,1H),2.63(d,J=11.0Hz,1H),2.56-2.46(m,1H),2.40-2.18(m,6H),1.95-1.85(m,1H) ,1.51-1.36(m,1H),1.28-1.13(m,1H),0.89(t,J=7.1Hz,3H),0.64-0.53(m,1H),0.41-0.33(m,1H).

[0411] Example 23: 3-(5-(((3R,6R)-1-ethyl-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-52) [ka] Step 1: tert-Butyl (2R,5R)-5-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpiperidine-1-carboxylate (50) Compound 50 was prepared according to general method VI starting from 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (500 mg, 1.10 mmol) and tert-butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (237 mg, 1.10 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane). Fractions containing the desired product were combined and concentrated to give tert-butyl (2R,5R)-5-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpiperidine-1-carboxylate 50 as an off-white solid. LCMS [MH] - :586.3.

[0412] Step 2: 3-(5-(((3R,6R)-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (51) Compound 51 was prepared according to general method VII starting from tert-butyl (2R,5R)-5-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpiperidine-1-carboxylate 50 (251 mg, 0.43 mmol). The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:TFE. The organic layers were combined and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOH in EtOAc:Et 3 N (v / v=100:1)). Fractions containing the desired product were combined and concentrated to give 3-(5-(((3R,6R)-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 51 as a white solid. LCMS [M+H] + :358.1.

[0413] Step 3: 3-(5-(((3R,6R)-1-ethyl-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-52) To a solution of 3-(5-(((3R,6R)-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 51 (62 mg, 0.17 mmol) and sodium triacetoxyborohydride (55.1 mg, 0.26 mmol) in EtOH (1 mL) was added acetaldehyde (0.015 mL, 0.260 mmol) at 0 °C. The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). Fractions containing the desired product were combined and concentrated to give 3-(5-(((3R,6R)-1-ethyl-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-52 as an off-white solid. LCMS [M+H] + :386.3. 1 H NMR (400MHz, CD 2 Cl 2 )δ 8.19-8.05(m,1H),7.70(d,J=8.3Hz,1H),7.10-6.95(m,2H),5.12(dd,J= 13.4,5.2Hz,1H),4.49(s,1H),4.39-4.26(m,2H),3.25-3.18(m,1H),2.92 -2.75(m,3H),2.61(dq,J=13.8,7.0Hz,1H),2.40-2.12(m,5H),1.81-1.7 5(m,1H),1.52-1.38(m,2H),1.11(d,J=6.2Hz,3H),1.00(t,J=7.1Hz,3H).

[0414] Example 24: 3-(5-(((R)-1-(but-2-yn-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-53) [ka] DIPEA (51 uL, 0.291 mmol) and 1-bromo-2-butyne (17 uL, 0.189 mmol) were added to a solution of 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (50 mg, 0.15 mmol) in ACN (1 mL) in a 2 mL microwave vial. The reaction was stirred at 120° C. for 2 hours under microwave irradiation. The reaction was diluted with acetone and concentrated using ISOLUTE® (HM-N part number 9800-5000). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in DCM). 3 N (v / v / v=75:25:1)) to give the product as a colorless oil that foamed under high vacuum. The product was lyophilized to give 3-(5-(((R)-1-(but-2-yn-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-53. LCMS [M+H] + :396.5. 1 H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.61(d,J=8.4Hz,1H),7.19(s,1H),7.05(d,J=8.4Hz,1H) ,5.07(dd,J=13.3,5.1Hz,1H),4.53(s,1H),4.42-4.17(m,2H),3.25(s, 2H),3.18-2.83(m,2H),2.68-2.53(m,2H),2.43-2.15(m,3H),1.98(d,J =5.0Hz,2H),1.79(d,J=2.3Hz,4H),1.56(s,1H),1.38(d,J=10.2Hz,1H).

[0415] Example 25: 3-(5-(((R)-1-(3-cyclopropylprop-2-yn-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-54) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (73 mg, 0.21 mmol) was added to a 5 mL microwave vial followed by (3-bromoprop-1-yn-1-yl)cyclopropane (44 mg, 0.28 mmol) in ACN (2.1 mL) and DIPEA (74 uL, 0.425 mmol). The reaction was stirred under microwave irradiation at 120° C. for 2 hours. The reaction was diluted with DCM and concentrated using ISOLUTE® (HM-N part number 9800-5000). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in DCM). 3 N (v / v / v=75:25:1)) to give the product. The product material was lyophilized to give 3-(5-(((R)-1-(3-cyclopropylprop-2-yn-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-54 as a fluffy white solid. LCMS [M+H] + :422.4. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.61(dt,J=8.4,3.0Hz,1H),7.20(d,J=3.8Hz,1H),7.11-6.96(m,1H), 5.07(d,J=13.5Hz,1H),4.53(s,1H),4.45-4.15(m,2H),3.23(s,2H),2.91(m,2H),2.5 9(d,J=18.7Hz,2H),2.47-2.13(m,3H),1.97(d,J=11.1Hz,2H),1.74(m,1H),1.55(m, 1H),1.34(d,J=41.6Hz,2H),0.74(dt,J=8.4,3.0Hz,2H),0.54(dq,J=5.8,2.9Hz,2H).

[0416] Example 26: 3-(5-(((R)-1-((1s,3S)-3-ethoxycyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-56) [ka] A 5 mL microwave vial was charged with 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol), (1r,3r)-3-ethoxycyclobutyl methanesulfonate INT-55 (80 mg, 0.35 mmol), DIPEA (0.06 mL, 0.35 mmol) and ACN (0.5 mL). The reaction was stirred at 140° C. for a total of 4 h under microwave irradiation. The reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). Fractions containing the desired product were combined and concentrated to give 3-(5-(((R)-1-((1s,3S)-3-ethoxycyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-56 as a white solid. LCMS [M+H] + :442.3. 1 H NMR (400MHz, CD 2 Cl 2 )δ 8.04(s,1H),7.71(d,J=8.5Hz,1H),7.12-6.95(m,2H),5.19-5.07(m,1 H),4.71-4.43(m,1H),4.43-4.25(m,2H),3.74-3.62(m,1H),3.37(q,J= 7.0Hz,2H),3.07(s,1H),2.94-2.66(m,3H),2.53-2.28(m,4H),2.24-2. 15(m,1H),2.13-1.94(m,3H),1.91-1.74(m,3H),1.14(t,J=7.0Hz,3H).

[0417] Example 27: 3-(5-(((R)-1-(((1r,3R)-3-methoxycyclobutyl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-59) [ka] Compound I-59 was prepared according to general method IX starting from 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and ((1r,3r)-3-methoxycyclobutyl)methyl methanesulfonate INT-58 (51 mg, 0.26 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-1-(((1r,3R)-3-methoxycyclobutyl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-59 as a white solid. LCMS [M+H] + :442.5. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.61(d,J=8.4Hz,1H),7.19(d,J=2.2Hz,1H),7.05(dd,J=8.4,2.3Hz,1H ),5.08(dd,J=13.2,5.1Hz,1H),4.53-4.35(m,2H),4.26(d,J=17.0Hz,1H),3.89(p,J=6 .2Hz,1H),3.30(s,1H),3.09(s,3H),2.97-2.85(m,2H),2.65-2.56(m,2H),2.38(q,J=4 .3Hz,3H),2.14-1.85(m,8H),1.76-1.65(m,1H),1.60-1.46(m,1H),1.42-1.30(m,1H).

[0418] Example 28: 3-(5-(((R)-1-(7-oxaspiro[3.5]nonan-2-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-61) [ka] Compound I-61 was prepared according to general method IX starting from 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (70 mg, 0.20 mmol) and 7-oxaspiro[3.5]nonan-2-yl methanesulfonate INT-60 (79 mg, 0.36 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-1-(7-oxaspiro[3.5]nonan-2-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-61 as a white solid. LCMS [M+H] + :468.5. 1 H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.54(d,J=8.4Hz,1H),7.12(d,J=2.0Hz,1H),6.98(dd,J=8.3,2.3Hz,1H),5.00( dd,J=13.4,5.2Hz,1H),4.49-4.37(m,1H),4.31(dd,J=17.2,2.4Hz,1H),4.25-4.13(m,1H),3. 46-3.39(m,2H),3.39-3.32(m,2H),3.23-3.21(m,1H),2.89-2.76(m,2H),2.69-2.62(m,1H),2 .56-2.48(m,2H),2.37-2.28(m,1H),2.01-1.74(m,6H),1.70-1.62(m,1H),1.52-1.28(m,7H).

[0419] Example 29: 3-(5-(((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-63) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (50 mg, 0.15 mmol) and 3,3-difluorocyclobutyl methanesulfonate INT-62 (54 mg, 0.29 mmol) were added to a 2 mL microwave vial and suspended in ACN (0.73 mL). DIPEA (0.06 mL, 0.34 mmol) was added and the reaction was degassed and back-filled with nitrogen three times. The reaction was stirred at 140° C. for a total of 14 hours under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-1-(3,3-difluorocyclobutyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-63 as a white solid. LCMS [M+H] + :434.2. 1 H NMR (400MHz, DMSO-d6) δ 10.89(s,1H),7.54(d,J=8.4Hz,1H),7.14(d,J=2.1Hz,1H),6.99(dd,J=8.4,2 .2Hz,1H),5.00(dd,J=13.3,5.0Hz,1H),4.50-4.37(m,1H),4.31(dd,J=17.2, 2.6Hz,1H),4.19(dd,J=17.4,2.5Hz,1H),2.90-2.77(m,2H),2.70-2.48(m,5H ),2.39-2.27(m,3H),2.02-1.85(m,4H),1.75-1.63(m,1H),1.57-1.26(m,2H).

[0420] Example 30: 3-(5-(((R)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-65) [ka] Compound I-65 was prepared according to general method IX starting from 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (60 mg, 0.18 mmol) and ((1r,4r)-4-methoxycyclohexyl)methyl methanesulfonate INT-64 (58 mg, 0.26 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-1-(((1r,4R)-4-methoxycyclohexyl)methyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-65 as a white solid. LCMS [M+H] + :470.3. 1 H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.62(d,J=8.4Hz,1H),7.19(d,J=2.2Hz,1H),7.05(dd,J=8.6,2.2Hz,1H),5.08(d d,J=13.2,5.0Hz,1H),4.54-4.46(m,1H),4.39(dd,J=17.2,3.4Hz,1H),4.26(dd,J=17.2,3.2Hz ,1H),3.22(s,3H),3.07-2.96(m,1H),2.96-2.84(m,2H),2.67-2.56(m,2H),2.45-2.33(m,1H), 2.16-1.93(m,8H),1.82-1.67(m,3H),1.61-1.33(m,3H),1.13-0.96(m,2H),0.90-0.78(m,2H).

[0421] Example 31: 3-(5-(((R)-1-(but-3-en-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-67) [ka] 3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (100 mg, 0.29 mmol) and cyclobutyl methanesulfonate INT-66 (66 mg, 0.44 mmol) were added to a 2 mL microwave vial and suspended in ACN (1.5 mL). DIPEA (0.10 mL, 0.58 mmol) was added and the reaction was degassed and backfilled with nitrogen three times. The reaction was stirred at 140° C. for 2 h under microwave irradiation. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated, and lyophilized to give 3-(5-(((R)-1-(but-3-en-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-67 as a white solid and 3-(5-(((R)-1-(cyclopropylmethyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-17 as a white solid.

[0422] 3-(5-(((R)-1-(but-3-en-1-yl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-67): LCMS [M+H] + :398.3. 1H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),7.54(d,J=8.4Hz,1H),7.12(d,J=2.3Hz,1H),6.97(dd,J=8.4,2.3Hz,1H),5.81 -5.63(m,1H),5.08-4.93(m,2H),4.89(dd,J=10.2,2.0Hz,1H),4.47-4.35(m,1H),4.31(d,J=1 7.2Hz,1H),4.19(d,J=17.2Hz,1H),2.98-2.78(m,2H),2.64-2.56(m,1H),2.56-2.47(m,1H),2 .38-2.24(m,3H),2.20-1.85(m,6H),1.71-1.59(m,1H),1.58-1.40(m,1H),1.37-1.23(m,1H).

[0423] Example 32: 3-(5-(((R)-1-((R)-sec-butyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-69) [ka] Compound I-69 was prepared according to general method IX starting from 1-(hydroxymethyl)-3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (100 mg, 0.29 mmol) and (S)-sec-butyl methanesulfonate INT-68 (66 mg, 0.44 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-1-((R)-sec-butyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-69 as a white solid. LCMS [M+H] + :400.3. 1H NMR (400MHz, DMSO-d6) δ 10.89(s,1H),7.54(d,J=8.3Hz,1H),7.10(dd,J=4.6,2.2Hz,1H),6.96(dd, J=8.4,2.3Hz,1H),5.00(dd,J=13.3,5.2Hz,1H),4.46-4.25(m,2H),4.18(d ,J=17.1Hz,1H),2.93-2.74(m,2H),2.58-2.47(m,2H),2.40-2.19(m,3H),2 .15-1.85(m,3H),1.70-1.59(m,1H),1.55-1.11(m,4H),0.86-0.71(m,6H).

[0424] Example 33: 3-(5-(((R)-1-((S)-sec-butyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-70) [ka] Compound I-70 was prepared according to general method IX starting from 1-(hydroxymethyl)-3-(1-oxo-5-(((R)-piperidin-3-yl)oxy)isoindolin-2-yl)piperidine-2,6-dione INT-2 (100 mg, 0.29 mmol) and (R)-sec-butyl methanesulfonate INT-27 (66 mg, 0.44 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). The pure fractions were combined, concentrated and lyophilized to give 3-(5-(((R)-1-((S)-sec-butyl)piperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-70 as a white solid. LCMS [M+H] + :400.4. 1H NMR (400MHz, DMSO-d6) δ 10.89(s,1H),7.53(d,J=8.3Hz,1H),7.10(dd,J=4.6,2.2Hz,1H),6.96(dd, J=8.3,2.1Hz,1H),5.00(dd,J=13.3,5.0Hz,1H),4.45-4.24(m,2H),4.18(d ,J=17.1Hz,1H),2.92-2.79(m,2H),2.58-2.47(m,2H),2.40-2.19(m,3H),2 .14-1.86(m,3H),1.71-1.59(m,1H),1.49-1.10(m,4H),0.87-0.73(m,6H).

[0425] Example 34: rac-3-(5-(((3R,5R)-1-ethyl-5-hydroxypiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-73) [ka] Step 1: rac-tert-butyl (3R,5R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-5-hydroxypiperidine-1-carboxylate (71) 71 was prepared according to general method VI starting from 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (850 mg, 1.88 mmol) rac-tert-butyl (3R,5R)-3,5-dihydroxypiperidine-1-carboxylate (489 mg, 2.25 mmol). The crude material was purified by silica gel chromatography (0-50% acetone in heptane). Fractions containing the desired product were combined and concentrated to give rac-tert-butyl (3R,5R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-5-hydroxypiperidine-1-carboxylate 71 as a pale yellow solid. LCMS [MH] - :588.3.

[0426] Step 2: rac-3-(5-(((3R,5R)-5-hydroxypiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72) 72 was made starting from 71 (453 mg, 0.77 mmol) following general procedure VII. The reaction was diluted with saturated NaHCO 3Quenched with aqueous solution and extracted 3 times with 4:1 DCM:EtOH. The organic layers were combined and concentrated to give rac-3-(5-(((3R,5R)-5-hydroxypiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 72 (276 mg, 0.768 mmol). The material was used directly in the next reaction. LCMS [M+H] + :360.2.

[0427] Step 3: rac-3-(5-(((3R,5R)-1-ethyl-5-hydroxypiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-73) To a solution of rac-3-(5-(((3R,5R)-5-hydroxypiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 72 (276 mg, 0.77 mmol) and sodium triacetoxyborohydride (1.30 g, 6.14 mmol) in EtOH (5.0 mL) was added acetaldehyde (0.34 mL, 6.14 mmol) at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). Fractions containing the desired product were combined and concentrated to give rac-3-(5-(((3R,5R)-1-ethyl-5-hydroxypiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-73 as a white solid. LCMS [M+H] + :388.4. 1 H NMR(400MHz, heavy water)δ 8.43(s,1H),7.74(d,J=8.5Hz,1H),7.23-7.20(m,1H),7.15(dd,J=8.5,2.3Hz,1 H),5.17(s,1H),5.10(dd,J=13.3,5.2Hz,1H),4.56-4.41(m,2H),4.32(s,1H),3 .92-3.44(m,2H),3.32(q,J=7.3Hz,2H),2.98-2.79(m,3H),2.49(qd,J=12.9,5. 5Hz,2H),2.23(dtd,J=13.0,5.2,2.7Hz,1H),1.78(s,1H),1.34(t,J=7.3Hz,3H).

[0428] Example 34a: tert-Butyl (3R,5R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-5-hydroxypiperidine-1-carboxylate (71a) [ka] Example 34a was synthesized by analogy with the previous Example 34 starting from tert-butyl (3R,5R)-3,5-dihydroxypiperidine-1-carboxylate. LCMS [MH] - :588.3.

[0429] Example 35: rac-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-76); (R)-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (R)-3-(5-(((3S,4R)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(5-(((3S,4R)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, and (S)-3-(5-(((3S,4R)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Step 1: rac-tert-butyl (3R,4S)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpiperidine-1-carboxylate (74) 74 was prepared according to general method VI starting from 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (1.85 g, 4.08 mmol) and rac-tert-butyl (3R,4S)-3-hydroxy-4-methylpiperidine-1-carboxylate (966 mg, 4.49 mmol). The reaction mixture was filtered and concentrated to give rac-tert-butyl (3R,4S)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpiperidine-1-carboxylate 74 as a yellow oil. The material was carried on to the next step without purification. LCMS [MH] - :586.7

[0430] Step 2: rac-3-(5-(((3R,4S)-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (75) 75 was made according to general method VII starting from rac-tert-butyl (3R,4S)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-4-methylpiperidine-1-carboxylate 74 (2.4 g, 4.08 mmol). The reaction was diluted with saturated NaHCO 3The organic layers were combined, concentrated, and the crude material purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1). Fractions containing the desired product were combined and concentrated to give rac-3-(5-(((3R,4S)-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 75 as a white solid. LCMS [M+H] + :358.4.

[0431] Step 3: rac-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-76), (R)-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (S)-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(5-(((3S,4R)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, (R)-3-(5-(((3S,4R)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, and (S)-3-(5-(((3S,4R)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a solution of rac-3-(5-(((3R,4S)-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 75 (350 mg, 0.979 mmol) and sodium triacetoxyborohydride (311 mg, 1.469 mmol) in EtOH (5 mL) at 0 °C was added acetaldehyde (64.7 mg, 1.469 mmol). The reaction was stirred at room temperature for 2 h. The reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)). Fractions containing the desired product were combined and concentrated to give rac-3-(5-(((3R,4S)-1-ethyl-4-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-76 as a white solid. LCMS [M+H] + :386.3. 1 H NMR (400MHz, CD 2 Cl 2)δ 7.69(d,J=8.4Hz,1H),7.10(s,1H),7.03(ddd,J=8.5,3.9,2.2Hz,1H),5.12(ddd,J=13 .4,5.2,3.5Hz,1H),4.41-4.19(m,2H),4.07(qd,J=9.4,4.2Hz,1H),3.31-3.12(m,1H) ,2.98-2.73(m,3H),2.53-2.37(m,2H),2.37-2.23(m,1H),2.20-2.10(m,1H),2.07-1. 87(m,2H),1.84-1.75(m,1H),1.73-1.61(m,1H),1.47-1.36(m,1H),1.09-0.96(m,6H).

[0432] The diastereomeric mixture of isomers was analyzed by chiral SFC [column 20 × 250 mm ES Chrome Chiral CC4;CO 2 Co-solvent 55% ethanol / ACN (1:3) containing 0.25% triethylamine; 80 g / min, 100 bar, 25° C. to give four stereoisomers: peak 1 (Example 35A) as a white solid, Rt=1.74 min; peak 2 (Example 35B) as a white solid, Rt=1.56 min. The two stereoisomers were separated by chiral SFC [column 30×250 mm RegisPack from Regis Technologies; CO 2 Further separation with co-solvent 35% isopropanol containing 0.25% triethylamine; 80 g / min at 100 bar at 25° C. was required to give two single stereoisomers: peak 3 (Example 35C), obtained as a white solid, Rt=2.98 min; peak 4 (Example 35D), obtained as a white solid, Rt=. The absolute stereochemistry of the four stereoisomers corresponding to the four product peaks was not determined.

[0433] Example 36: 3-(5-(((R)-1-ethylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-79) [ka] Step 1: tert-Butyl (3R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)azepane-1-carboxylate (77) Compound 77 was made according to general method VI starting from 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (200 mg, 0.44 mmol) and tert-butyl (3R)-3-hydroxyazepane-1-carboxylate (104 mg, 0.49 mmol). The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (3R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)azepane-1-carboxylate 77 as a yellow oil. LCMS[M+H-156.34] + :432.4.

[0434] Step 2: 3-(5-(((R)-azepan-3-yl)oxy)-1-oxoisoindolin-2-yl)-1-(hydroxymethyl)piperidine-2,6-dione (78) To tert-butyl (3R)-3-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)azepane-1-carboxylate 77 (44.4 mg, 0.076 mmol) dissolved in ACN (1.0 mL) was added methanesulfonic acid (0.1 mL, 1.54 mmol). The reaction was stirred at room temperature for 2 h. The reaction was cooled to 0° C. and triethylamine (0.43 mL, 3.1 mmol) was added followed by N1,N2-dimethylethane-1,2-diamine (0.016 mL, 0.15 mmol). The reaction was stirred at room temperature for 96 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated to give 3-(5-(((R)-azepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 78 as a yellow solid. LCMS [M+H] + :358.2.

[0435] Step 3: 3-(5-(((R)-1-ethylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-79) To a solution of 3-(5-(((R)-azepan-3-yl)oxy)-1-oxoisoindolin-2-yl)-1-(hydroxymethyl)piperidine-2,6-dione 78 (28 mg, 0.078 mmol) in DMF (0.522 mL) was added sodium triacetoxyborohydride (50 mg, 0.24 mmol) followed by acetaldehyde (0.01 mL, 0.18 mmol). The reaction was stirred at room temperature for 18 h. The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated on CELITE®. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 The product was purified by reversed-phase HPLC (5 mM NH as a modifier). 4 H containing OH 2 Further purification was performed by elution with 25-50% ACN in O. The tube contained 3 drops of formic acid before sample collection. The fractions containing the pure product were combined and lyophilized to give the formate salt 3-(5-(((R)-1-ethylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-79 as a white solid. LCMS [M+H] + :386.4. 1 H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),8.17(s,1H),7.54(d,J=8.3Hz,1H),7.06(d,J=2.2Hz,1H),6.94(dd ,J=8.4,2.2Hz,1H),5.00(dd,J=13.3,5.1Hz,1H),4.59-4.43(m,1H),4.31(dd,J=1 7.1,1.9Hz,1H),4.18(d,J=17.1Hz,1H),2.89-2.77(m,2H),2.67-2.45(m,6H),2.3 7-2.23(m,1H),2.01-1.86(m,2H),1.70-1.39(m,5H),0.88(td,J=7.0,1.7Hz,3H).

[0436] Example 37: 3-(5-(((S)-1-ethylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-84) [ka] Step 1: tert-Butyl (S)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)azepane-1-carboxylate (80) In a 40 mL vial, add 5-bromoisobenzofuranone (100 mg, 0.47 mmol), (S)-3-hydroxy-1-N-Boc-azepane (101 mg, 0.47 mmol), dtbbpy (12.6 mg, 0.047 mmol), NiCl 2 (glyme) (10.3 mg, 0.047 mmol), and Ir[dF(CF 3 )ppy) 2 dtbbpy]PF 6 (13.1 mg, 0.012 mmol) was added. ACN (1.6 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-tetramethylpiperidine (84 μL, 0.49 mmol) was then added. The reaction was placed in a PennOC ml 450 nm photoreactor under blue LED light at room temperature for 18 hours. The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% ethyl acetate in heptane) to give tert-butyl (S)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)azepane-1-carboxylate 80 as a yellow solid. LCMS [M+H-tert-butyl] + :292.1.

[0437] Step 2: (S)-5-(azepan-3-yloxy)isobenzofuran-1(3H)-one (81) tert-Butyl (S)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)azepane-1-carboxylate 80 (104 mg, 0.30 mmol) was suspended in dioxane (3.0 mL). 4M HCl in dioxane (449 μL, 1.8 mmol) was added and the reaction was stirred at room temperature for 5 h. The reaction was concentrated to give (S)-5-(azepan-3-yloxy)isobenzofuran-1(3H)-one 81 as a brown semi-solid. The material was used directly in the next reaction. LCMS [M+H] + :248.2.

[0438] Step 3: (S)-5-((1-ethylazepan-3-yl)oxy)isobenzofuran-1(3H)-one (82) Compound 82 was prepared according to general procedure X starting from (S)-5-(azepan-3-yloxy)isobenzofuran-1(3H)-one 81 (74 mg, 0.30 mmol) and acetaldehyde (25 μL, 0.45 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give (S)-5-((1-ethylazepan-3-yl)oxy)isobenzofuran-1(3H)-one 82 as a brown oil. LCMS [M+H] + :276.2

[0439] Step 4: Ethyl (S)-2-(chloromethyl)-4-((1-ethylazepan-3-yl)oxy)benzoate (83) Compound 83 was made according to general method IV starting from (S)-5-((1-ethylazepan-3-yl)oxy)isobenzofuran-1(3H)-one 82 (7 mg, 0.025 mmol) to give ethyl (S)-2-(chloromethyl)-4-((1-ethylazepan-3-yl)oxy)benzoate 83 as a brown oil. The material was carried on to the next step without purification. LCMS [M+H] + :340.4.

[0440] Step 5: 3-(5-(((S)-1-ethylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-84) Compound I-84 was prepared according to general procedure V starting from ethyl (S)-2-(chloromethyl)-4-((1-ethylazepan-3-yl)oxy)benzoate 83 (20 mg, 0.059 mmol). The reaction was concentrated and purified by basic reversed-phase HPLC (5 mM NH 4 The material was purified by basic reverse-phase HPLC (15-40% ACN in water containing 5 mM NH as a modifier). The test tube contained 3 drops of formic acid prior to sample collection. Fractions containing the desired product were combined and concentrated to give the product as a deep blue solid. The material was purified by basic reverse-phase HPLC (5 mM NH as a modifier). 4Further purification was performed by elution with 15-40% ACN in water containing 1,2-dichlorophenyl OH). The tube contained 3 drops of formic acid before sample collection. Fractions containing the desired product were combined and concentrated to give 3-(5-(((S)-1-ethylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-84 as a clear oil. LCMS [M+H] + :386.4. 1 H NMR(400MHz,Acetonitrile-d3)δ 8.84(s,1H),7.69(d,J=8.3Hz,1H),7.20(d,J=6.6Hz,1H),7.11(dt,J=8.4,2.3Hz,1H),5.07(dd,J=13. 4,5.1Hz,1H),4.92(dd,J=7.0,3.6Hz,1H),4.44-4.27(m,2H),3.89(p,J=6.1Hz,3H),3.32(dd,J=13.8,3 .0Hz,2H),3.26-3.19(m,2H),3.11(t,J=6.0Hz,2H),2.99(q,J=7.2Hz,2H),2.86-2.79(m,1H),2.74(ddd ,J=17.6,4.8,2.6Hz,1H),2.43(qd,J=13.2,4.9Hz,1H),2.18-2.06(m,2H),1.21(td,J=7.2,1.2Hz,3H).

[0441] Example 38: 3-(5-(((R)-1-isobutylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-89) [ka] Step 1: tert-Butyl (R)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)azepane-1-carboxylate (85) Compound 85 was made according to general method I starting from 5-bromoisobenzofuran-1(3H)-one (250 mg, 1.17 mmol) and tert-butyl (3R)-3-hydroxyazepane-1-carboxylate (278 mg, 1.29 mmol). The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (R)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)azepane-1-carboxylate 85 as a clear oil. LCMS [M+H-tert-butyl] + :292.3.

[0442] Step 2: (R)-5-(azepan-3-yloxy)isobenzofuran-1(3H)-one (86) tert-Butyl (R)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)azepane-1-carboxylate 85 (305 mg, 0.88 mmol) was suspended in dioxane (4.4 mL). 4M HCl in dioxane (1.3 mL, 5.3 mmol) was added and the reaction was stirred at room temperature for 72 h. The reaction was concentrated to give (R)-5-(azepan-3-yloxy)isobenzofuran-1(3H)-one 86 as a clear oil. The material was used directly in the next reaction. LCMS [M+H] + :248.3.

[0443] Step 3: (R)-5-((1-isobutylazepan-3-yl)oxy)isobenzofuran-1(3H)-one (87) Compound 87 was prepared according to general method III starting from (R)-5-(azepan-3-yloxy)isobenzofuran-1(3H)-one 86 (64 mg, 0.26 mmol) and isobutanal (0.04 mL, 0.44 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give (R)-5-((1-isobutylazepan-3-yl)oxy)isobenzofuran-1(3H)-one 87 as a clear oil. LCMS [M+H] + :304.2.

[0444] Step 4: Ethyl (R)-2-(chloromethyl)-4-((1-isobutylazepan-3-yl)oxy)benzoate (88) Compound 88 was made according to general method IV starting from (R)-5-((1-isobutylazepan-3-yl)oxy)isobenzofuran-1(3H)-one 87 (30.3 mg, 0.10 mmol) to give ethyl (R)-2-(chloromethyl)-4-((1-isobutylazepan-3-yl)oxy)benzoate 88 as a brown oil. The material was carried on to the next step without purification. LCMS [M+H] + :368.5.

[0445] Step 5: 3-(5-(((R)-1-isobutylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-89) Compound I-89 was made starting from ethyl (R)-2-(chloromethyl)-4-((1-isobutylazepan-3-yl)oxy)benzoate 88 (36.8 mg, 0.10 mmol) following general procedure V. The reaction was concentrated onto CELITE®. A dry loading tube was first packed with ½ inch activated charcoal, then a filter pad, CELITE® residue, and a second filter pad. The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((R)-1-isobutylazepan-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-89 as a white solid. LCMS [M+H] + :414.4. 1H NMR(400MHz,DMSO-d6)δ 10.97(s,1H),7.61(d,J=8.4Hz,1H),7.12(d,J=2.3Hz,1H),7.00(dd,J=8.4,2.2Hz,1H),5.07 (dd,J=13.2,5.0Hz,1H),4.68-4.51(m,1H),4.38(dd,J=17.2,3.3Hz,1H),4.26(dd,J=17.1,2 .0Hz,1H),2.96-2.85(m,2H),2.75(dd,J=13.9,6.6Hz,1H),2.66-2.56(m,3H),2.45-2.36(m, 1H),2.24(d,J=7.2Hz,2H),2.12-1.94(m,2H),1.81-1.48(m,6H),0.86(dd,J=6.4,2.8Hz,6H).

[0446] Example 39: 3-(5-(((R)-1-ethylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-94) [ka] Step 1: tert-Butyl (R)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)pyrrolidine-1-carboxylate (90) Compound 90 was made according to general method I starting from 5-bromoisobenzofuran-1(3H)-one (100 mg, 0.47 mmol) and (R)-1-N-Boc-3-hydroxy-pyrrolidine (97 mg, 0.52 mmol). The reaction was concentrated on CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (R)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)pyrrolidine-1-carboxylate 90 as a yellow oil. LCMS [M+H-tert-butyl] + :264.1.

[0447] Step 2: (R)-5-(pyrrolidin-3-yloxy)isobenzofuran-1(3H)-one (91) tert-Butyl (R)-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)oxy)pyrrolidine-1-carboxylate 90 (98 mg, 0.31 mmol) was suspended in dioxane (3.1 mL). 4M HCl in dioxane (0.46 mL, 1.84 mmol) was added and the reaction was stirred at room temperature for 2 h. Trifluoroethanol (1 mL) was added followed by additional 4M HCl in dioxane (0.46 mL, 1.84 mmol). The reaction was stirred at room temperature for 72 h. The reaction was concentrated to give (R)-5-(pyrrolidin-3-yloxy)isobenzofuran-1(3H)-one 91 as a white solid. The material was used directly in the next reaction. LCMS [M+H] + :220.1.

[0448] Step 3: (R)-5-((1-ethylpyrrolidin-3-yl)oxy)isobenzofuran-1(3H)-one (92) Compound 92 was prepared according to general procedure X starting from (R)-5-(pyrrolidin-3-yloxy)isobenzofuran-1(3H)-one 91 (67.3 mg, 0.31 mmol) and acetaldehyde (26 μL, 0.46 mmol). The crude material was purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give (R)-5-((1-ethylpyrrolidin-3-yl)oxy)isobenzofuran-1(3H)-one 92 as a brown oil. LCMS [M+H] + :248.2. 1 H NMR (400 MHz, CDCl 3 )δ 7.74(d,J=8.5Hz,1H),6.92(dd,J=8.5,2.1Hz,1H),6.78(d,J=2.1Hz,1H),5.17(s,2H),4.87-4.78(m,1H),2.84- 2.76(m,3H),2.53-2.43(m,2H),2.35-2.26(m,1H),2.00-1.90(m,1H),1.74-1.65(m,1H),1.08(t,J=7.2Hz,3H).

[0449] Step 4: Ethyl (R)-2-(chloromethyl)-4-((1-ethylpyrrolidin-3-yl)oxy)benzoate (93) Compound 93 was made according to general method IV starting from (R)-5-((1-ethylpyrrolidin-3-yl)oxy)isobenzofuran-1(3H)-one 92 (17.5 mg, 0.071 mmol) to give ethyl (R)-2-(chloromethyl)-4-((1-ethylpyrrolidin-3-yl)oxy)benzoate 93 as a brown oil. The material was carried on to the next step without purification. LCMS [M+H] + :312.3.

[0450] Step 5: 3-(5-(((R)-1-ethylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-94) Compound I-94 was prepared starting from ethyl (R)-2-(chloromethyl)-4-((1-ethylpyrrolidin-3-yl)oxy)benzoate 93 (22 mg, 0.071 mmol) according to general procedure V. The reaction was concentrated and purified by reverse-phase HPLC (5 mM NH 4 The mixture was purified by elution with 10-30% ACN in water containing 1,2-dihydro-OH. The tube contained 3 drops of formic acid before sample collection. Fractions containing the desired product were combined and lyophilized to give the formate salt of 3-(5-(((R)-1-ethylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-94 as a white solid. LCMS [M+H] + :358.2. 1 H NMR(400MHz,DMSO-d6)δ 10.89(s,1H),8.17(s,1H),7.54(d,J=8.4Hz,1H),7.04(d,J=2.2Hz,1H),6.93(dd,J =8.3,2.4Hz,1H),5.00(dd,J=13.4,5.1Hz,1H),4.93-4.85(m,1H),4.32(d,J=17.1H) z,1H),4.19(d,J=17.2Hz,1H),2.89-2.72(m,2H),2.68-2.58(m,1H),2.56-2.49(m, 1H),2.39-2.20(m,6H),1.95-1.86(m,1H),1.75-1.62(m,1H),0.96(t,J=7.2Hz,3H).

[0451] Example 40: 3-(5-(((S)-1-ethylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-99) [ka] Compound I-99 was made according to the previous Example 39, except that step 1 utilized (S)-1-N-boc-3-hydroxy-pyrrolidine. In the final step 5, the reaction was concentrated and purified by silica gel chromatography (0-100% EtOAc:EtOH:Et in heptane). 3 N (v / v / v=75:25:1)) to give 3-(5-(((S)-1-ethylpyrrolidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione I-99 as a black solid. LCMS [M+H] + :358.1. 1 H NMR (400 MHz, CDCl 3 )δ 7.71(d,J=8.5Hz,1H),6.89(dd,J=8.4,2.2Hz,1H),6.82(d,J=2.2Hz,1H),5.13(dd, J=13.2,5.2Hz,1H),4.86(q,J=4.8,3.0Hz,1H),4.36(dd,J=15.9,4.7Hz,1H),4.21( d,J=15.9Hz,1H),3.38(q,J=7.3Hz,1H),3.04(dt,J=14.1,7.1Hz,1H),2.84-2.74(m ,5H),2.58(ddt,J=11.4,8.1,3.5Hz,3H),2.34-2.24(m,2H),1.11(t,J=7.2Hz,3H).

[0452] Example 41: 3-(5-(((3R,6S)-1-ethyl-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-102) [ka] Step 1: tert-Butyl (2S,5R)-5-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpiperidine-1-carboxylate (100) In a 40 mL vial, 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione INT-1 (527 mg, 1.16 mmol), dtbbpy (16 mg, 0.058 mmol), NiCl 2 (glyme) (13 mg, 0.058 mmol), and Ir[(dF(CF 3 )ppy)2 dtbbpy]PF 6 (13 mg, 0.012 mmol) was added. tert-Butyl (2S,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (250 mg, 1.16 mmol) in ACN (6.0 mL) was added and the reaction was flushed with nitrogen for 5-10 minutes to ensure the reaction turned green. 2,2,6,6-tetramethylpiperidine (0.206 mL, 1.2 mmol) was then added. The reaction was placed in a PennOC ml 450 nm photoreactor under blue LED light at room temperature for 72 hours. The reaction was concentrated onto CELITE® and purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl (2S,5R)-5-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpiperidine-1-carboxylate 100 as a yellow foam. LCMS [MH] - :586.1.

[0453] Step 2: 3-(5-(((3R,6S)-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (101) Compound 101 was made according to general method VII starting from tert-butyl (2S,5R)-5-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)-2-methylpiperidine-1-carboxylate 100 (525 mg, 0.89 mmol). The reaction was quenched with 50% saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM:iPrOH. The organic layers were combined, passed through a phase separator and concentrated to remove DCM. A white solid crashed out of solution leaving iPrOH behind. The solid was filtered to give 3-(5-(((3R,6S)-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 101 as a white powder. LCMS [M+H] + :358.1. 1H NMR(400MHz,DMSO-d6)δ 10.96(s,1H),7.61(d,J=8.4Hz,1H),7.17(d,J=2.2Hz,1H),7.07(dd,J=8 .4,2.2Hz,1H),5.07(dd,J=13.3,5.1Hz,1H),4.59-4.17(m,4H),3.32(s,3 H),3.09(d,J=13.7Hz,1H),2.95-2.72(m,2H),2.65-2.54(m,2H),2.43-2 .26(m,1H),2.01-1.89(m,2H),1.70(t,J=13.9Hz,1H),1.46-1.22(m,2H).

[0454] Step 3: 3-(5-(((3R,6S)-1-ethyl-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-102) To a vial containing 3-(5-(((3R,6S)-6-methylpiperidin-3-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 101 (200 mg, 0.56 mmol) and ACN (4.0 mL) was added sodium triacetoxyborohydride (356 mg, 1.68 mmol) followed by acetaldehyde (63 uL, 1.12 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted three times with 4:1 DCM / iPrOH. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified by basic reverse ...

Claims

Claim 1 A compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (wherein 【Chemical 1】 Each R １ is hydrogen, C １ ~C ６ Alkyl, hydroxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, １ together with the same carbon atom to which they are attached, C ３ ~C ８ or two R on adjacent carbon atoms form a cycloalkyl; １ together with the adjacent carbon atoms to which they are attached, ３ ~C ８ or two R on non-adjacent carbon atoms form a cycloalkyl; １ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ is independently selected from hydrogen, C ３ to C １１ a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from cycloalkyl, N, O, and S, C １ to C ６ haloalkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C １０ alkyl, -SO ２ R ６ , -C(=O)-R ２ａ , -C(=O)-O-R ２ａ , and -C(=O)NR ２ｂ R ２ｃ and is selected from Here, the C ３ to C １１ cycloalkyl, 4- to 11-membered heterocyclyl, C ２ to C ６ alkynyl, and C １ to C １０ alkyl is each independently substituted by R ３ which appears 0 to 5 times; R ２ａ is selected from C １ -C ６ alkyl, and 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; R ２ｂ and R ２ｃ are each independently selected from hydrogen and C １ ~C ６ alkyl; Each R ３ is independently selected from C １ to C ６ alkoxyl, halo, C ６ to C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C ３ to C ８ cycloalkyl, where each of said C ６ to C １０ aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C ３ to C ８ cycloalkyl is independently substituted 0 to 4 times by R ４ ; Each R ４ is independently selected from C １ to C １０ alkyl, C １ to C ６ alkoxyl, halo, and C ３ to C ８ cycloalkyl, where the C ３ to C ８ cycloalkyl appears 0 to 3 times and is substituted by R ５ ; Each R ５ is independently selected from -CN, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, hydroxyl, and C １ ~C ６ haloalkyl; R ６ is selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected therefrom, and C ６ to C １０ aryl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, or 2; provided that the compound of formula (I') does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione). Claim 2 A compound of formula (I'') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (wherein 【Chemical Formula 2】 Each R １ is hydrogen, C １ ~C ６ Alkyl, hydroxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, １ together with the same carbon atom to which they are attached, C ３ ~C ８ or two R on adjacent carbon atoms form a cycloalkyl; １ together with the adjacent carbon atoms to which they are attached, ３ ~C ８ or two R on non-adjacent carbon atoms form a cycloalkyl; １ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ is independently selected from hydrogen, C ３ to C １１ a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from cycloalkyl, N, O, and S, C １ to C ６ haloalkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C １０ alkyl, -SO ２ R ６ , -C(=O)-R ２ａ , -C(=O)-O-R ２ａ , and -C(=O)NR ２ｂ R ２ｃ and is selected from Here, the C ３ to C １１ cycloalkyl, 4- to 11-membered heterocyclyl, C ２ to C ６ alkynyl, and C １ to C １０ alkyl is each independently substituted by R ３ which appears 0 to 5 times; R ２ａ is selected from C １ -C ６ alkyl, and 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S; R ２ｂ and R ２ｃ are each independently selected from hydrogen and C １ to C ６ alkyl; Each R ３ is independently selected from C １ to C ６ alkoxyl, halo, C ６ to C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C ３ to C ８ cycloalkyl, where each of the C ６ to C １０ aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C ３ to C ８ cycloalkyl is independently substituted by 0 to 4 occurrences of R ４ ; Each R ４ is C １ ~C １０ Alkyl, C １ ~C ６ Alkoxyl, halo, and C ３ ~C ８ cycloalkyl, wherein said C ３ ~C ８ Cycloalkyl may occur 0 to 3 times. ５ is replaced by; Each R ５ is independently selected from -CN, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, hydroxyl, and C １ ~C ６ haloalkyl; R ６ is selected from C ３ to C ８ cycloalkyl, C １ to C ６ alkyl, N, O, and S, a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected therefrom, and C ６ to C １０ aryl; n is 0, 1, 2, 3, 4, or 5; and m is 1 or 2). Claim 3 A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof (wherein 【Chemical Formula 3】 Each R １ is hydrogen, C １ ~C ６ Alkyl, hydroxyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxyl and C １ ~C ６ or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, １ together with the same carbon atom to which they are attached, C ３ ~C ８ or two R on adjacent carbon atoms form a cycloalkyl; １ together with the adjacent carbon atoms to which they are attached, ３ ~C ８ or two R on non-adjacent carbon atoms form a cycloalkyl; １ form a bridged ring together with the non-adjacent carbon atoms to which they are attached; R ２ is independently selected from hydrogen, C ３ -C １１ -cycloalkyl, N, O, and S, a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected therefrom, C １ -C ６ -haloalkyl, C ２ -C ６ -alkenyl, C ２ -C ６ -alkynyl, and C １ -C １０ -alkyl, and is selected from Here, the C ３ to C １１ cycloalkyl, 4- to 11-membered heterocyclyl, C ２ to C ６ alkynyl, and C １ to C １０ alkyl is each independently substituted by 0 to 5 occurrences of R ３ ; Each R ３ is independently selected from C １ to C ６ alkoxyl, halo, C ６ to C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C ３ to C ８ cycloalkyl, where the C ６ to C １０ aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C ３ to C ８ cycloalkyl are each independently substituted by 0 to 4 occurrences of R ４ ; Each R ４ is independently selected from C １ to C １０ alkyl, C １ to C ６ alkoxyl, halo, and C ３ to C ８ cycloalkyl, where the C ３ to C ８ cycloalkyl appears 0 to 3 times and is substituted by R ５ ; Each R ５ is independently selected from -CN, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, hydroxyl, and C １ ~C ６ haloalkyl; n is 0, 1, 2, 3, or 4; and m is 0, 1, or 2; provided that the compound of formula (I) does not include 3-(1-oxo-5-(pyrrolidin-3-yloxy)isoindolin-2-yl)piperidine-2,6-dione). Claim 4 R ２ is selected from C ３ -C １１ cycloalkyl, N, O, and S, a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected therefrom, C １ -C ６ haloalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, and C １ -C １０ alkyl, wherein said C ３ -C １１ cycloalkyl, 4- to 11-membered heterocyclyl, C ２ -C ６ alkynyl, and C １ -C １０ alkyl are each independently substituted by 0 to 5 occurrences of R ３ ; Each R ３ is independently selected from C １ to C ６ alkoxyl, halo, C ６ to C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, O, and S, 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C ３ to C ８ cycloalkyl, where the C ６ to C １０ aryl, 5- to 10-membered heteroaryl, 4- to 11-membered heterocyclyl, and C ３ to C ８ cycloalkyl are each independently substituted 0 to 4 times by R ４ ; Each R ４ is independently selected from C １ to C １０ alkyl, C １ to C ６ alkoxyl, halo, and C ３ to C ８ cycloalkyl, where the C ３ to C ８ cycloalkyl appears 0 to 3 times and is substituted by R ５ ; Each R ５ is independently selected from -CN, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, hydroxyl, and C １ ~C ６ haloalkyl; n is 0, 1, 2, 3, or 4; and m is 0, 1, or 2, for example, m is 1 or 2, the compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Claim 5 Each R １ is hydrogen, C １ ~C ６ Alkyl, hydroxyl, halo, and C １ ~C ６ or two R on the same carbon atom are independently selected from the group consisting of alkoxyl, １ together with the same carbon atom to which they are attached, C ３ ~C ６ or two R on adjacent carbon atoms form a cycloalkyl; １ together with the adjacent carbon atoms to which they are attached, C ３ ~C ６ or two R on non-adjacent carbon atoms form a cycloalkyl; １ together with the non-adjacent carbon atoms to which they are attached, １ ~C ３ forming an alkylene bridge ring; R ２ is selected from hydrogen, C ３ to C １１ cycloalkyl, C １ to C ６ haloalkyl, N, O, and S, and is a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected therefrom, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, and C １ to C １０ alkyl, and is selected from Here, the C ３ to C １１ cycloalkyl, C ２ to C ６ alkynyl, and C １ to C １０ alkyl are each independently substituted by R ３ which appears 0 to 5 times; Each R ３ is independently selected from C １ to C ６ alkoxyl, halo, N, O, and S, a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected therefrom, and C ３ to C ８ cycloalkyl, wherein the 4- to 11-membered heterocyclyl and C ３ to C ８ cycloalkyl are each independently substituted by R ４ which appears 0 to 3 times; Each R ４ is independently selected from C １ to C １０ alkyl, C １ to C ６ alkoxyl, halo, and C ３ to C ８ cycloalkyl; n is 0, 1, 2, 3, or 4; and m is 0, 1, or 2, for example, m is 1 or 2, the compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Claim 6 Each R １ is independently selected from hydrogen, C １ ~C ６ alkyl, hydroxyl, fluoro, and C １ ~C ６ alkoxyl; or two Rs on the same carbon atom, together with the same carbon atom to which they are attached, form C １ ~C ３ cycloalkyl; or two Rs on adjacent carbon atoms, together with the adjacent carbon atoms to which they are attached, form C ６ ~C １ cycloalkyl; or two Rs on non-adjacent carbon atoms, together with the non-adjacent carbon atoms to which they are attached, form C ３ ~C ６ cycloalkyl; or two Rs on non-adjacent carbon atoms, together with the non-adjacent carbon atoms to which they are attached, form C １ ~C １ ~C ２ an alkylene-bridged ring; R ２ is selected independently from hydrogen, C ３ -C １１ - a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms selected independently from cycloalkyl, N, O, and S, C ２ -C ６ - alkynyl, and C １ -C ６ - alkyl, and Here, the C ３ ~C １１ The cycloalkyl appears 0 to 3 times in R ３ and is substituted by １ ~C ６ The alkyl appears 0 to 1 time in R ３ａ and is substituted by ２ ~C ６ The alkynyl appears 0 to 1 time in R ３ｂ and is substituted by; Each R ３ is independently selected from C １ to C ６ alkoxyl, and fluoro; R ３ａ is a 4- to 11-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and C ３ -C ８ -cycloalkyl, wherein the 4- to 11-membered heterocyclyl and C ３ -C ８ -cycloalkyl are each independently substituted by R ４ which appears 0 to 3 times; R ３ｂ is C ３ to C ８ is cycloalkyl; Each R ４ is independently selected from C １ to C ６ alkyl, C １ to C ６ alkoxyl, fluoro, and C ３ to C ８ cycloalkyl; n is 0, 1, 2, or 3; and m is 1, the compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Claim 7 Each R １ is independently selected from hydrogen, C １ to C ６ alkyl, hydroxyl, fluoro, and C １ to C ６ alkoxyl; or two Rs on the same carbon atom, together with the same carbon atom to which they are attached, form C １ to C ３ cycloalkyl; ６ ​ R ２ is selected from C ３ to C ８ a 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from cycloalkyl, N, O, and S, C ２ to C ６ alkynyl, and C １ to C ６ alkyl, and is selected from Here, the C ３ ~C ８ The cycloalkyl appears 0 to 3 times in R ３ which is substituted, and the C １ ~C ６ The alkyl appears 0 to 1 time in R ３ａ which is substituted, and the C ２ ~C ６ The alkynyl appears 0 to 1 time in R ３ｂ which is substituted; Each R ３ is independently selected from C １ to C ６ alkoxyl, and fluoro; R ３ａ is C ３ to C ８ cycloalkyl, where the C ３ to C ８ cycloalkyl appears 0 to 3 times and R ４ is substituted by; R ３ｂ is C ３ to C ８ is cycloalkyl; Each R ４ is selected independently from C １ to C ６ alkyl, C １ to C ６ alkoxyl, fluoro, and C ３ to C ８ cycloalkyl; n is 0, 1, 2, or 3; and m is 1, the compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Claim 8 R ２ is unsubstituted C １ ~C ６ alkyl or -(CH ２ )-R ３ wherein R ３ is as defined in claim 1, a compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Claim 9 R ２ is unsubstituted C １ ~C ６ alkyl, 【Chemical Formula 6】 The compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from Claim 10 R １ is C １ -C ６ alkyl, hydroxyl, halo, and C １ -C ６ alkoxyl; or two Rs on the same carbon atom, together with the same carbon atom to which they are attached, form C １ -C ３ -C ８ cycloalkyl, a compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Claim 11 The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, represented by formula (IC-i), formula (IC-ii), formula (ID-i), or formula (ID-ii): 【Chemical Formula 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical Formula 19】 。

12. The compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from the following: 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical 24】 【Chemical Formula 25】 【Chemical 26】 【Chemical 27】 。

13. The compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the absolute configuration of the glutarimide stereocenter is S.

14. The compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein the absolute configuration of the glutarimide stereocenter is R.

15. The compound of formula (I') according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, selected from the following: 【Chemical 28】 【Chemical Formula 29】 。

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or excipient.

17. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use as a medicament.

18. The compound according to any one of claims 1 to 15, or a pharmaceutically 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.

19. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disorder affected by a decrease in the level of WIZ protein in a subject in need thereof.

20. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating hemoglobin abnormalities in a subject in need thereof.

21. A pharmaceutical combination comprising the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one or more additional therapeutic agents.

22. A compound of formula (Y) 【Chemical 31】 (wherein each R １ is independently selected from hydrogen, C １ -C ６ alkyl, hydroxyl, halo, C １ -C ６ haloalkyl, C １ -C ６ haloalkoxyl, and C １ -C ６ alkoxyl; or two Rs on the same carbon atom １ together with the same carbon atom to which they are attached form C ３ -C ８ cycloalkyl; or two Rs on adjacent carbon atoms １ together with the adjacent carbon atoms to which they are attached form C ３ -C ８ cycloalkyl; or two Rs on non-adjacent carbon atoms １ together with the non-adjacent carbon atoms to which they are attached form a bridged ring; n is 0, 1, 2, 3, 4, or 5; m is 0, 1 or 2; and PG １ and PG ２ each of which is independently a nitrogen protecting group).

23. PG ２ is a base-labile protecting group, and PG １ is an acid-labile protecting group, the compound according to claim 22.

24. PG ２ is an SEM protecting group (trimethylsilylethoxymethyl), and PG １ is a BOC protecting group (tert-butyloxycarbonyl), the compound according to claim 22 or 23.

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