Compounds for the treatment of hemoglobinopathies and their uses

Abstract

Disclosed herein are compounds and methods for preventing and / or treating hemoglobinopathies. Also provided herein are such compounds for use in such methods. Also disclosed herein are pharmaceutical compositions comprising such compounds for use in such methods of preventing or treating hemoglobinopathies.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 422,847, filed November 4, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] Field Disclosed herein are compounds and methods for preventing and / or treating hemoglobinopathies. Also provided herein are such compounds for use in such methods. Also disclosed herein are pharmaceutical compositions comprising such compounds for use in such methods of preventing or treating hemoglobinopathies. [Background technology]

[0003] Hemoglobin is an iron-containing metalloprotein present in red blood cells (RBCs). Hemoglobin transports oxygen to various tissues throughout the body. Fetal hemoglobin (HbF) is present in fetal RBCs and is responsible for transporting oxygen from the mother to the fetus. After birth, a "fetal switch" occurs, during which erythroid progenitor cells switch from producing predominantly fetal hemoglobin to predominantly adult hemoglobin. Adult and fetal hemoglobin are tetramers containing two alpha globin subunits and two beta globin subunits (α2β2) or two alpha globin subunits and two gamma globin subunits (α2γ2), respectively. Fetal hemoglobin binds oxygen more strongly than adult hemoglobin.

[0004] Hemoglobinopathies can occur, for example, when there is an abnormal expression of adult hemoglobin or a structural abnormality in the adult hemoglobin protein. For example, sickle cell disease, such as sickle cell anemia, occurs when a point mutation in the beta globin gene results in the formation of hemoglobin S (HbS), which is composed of two normal alpha globin chains and two beta globin variant chains. The presence of HbS causes red blood cells to have an abnormal shape, and when the amount of oxygen decreases, they take on a sickle shape, which can impede blood flow and cause hemolysis. Patients with sickle cell disease suffer from a variety of symptoms, including pain, anemia, bacterial infections, increased risk of stroke, and reduced life expectancy.

[0005] Another example of a hemoglobinopathy is beta-thalassemia. Beta-thalassemia occurs when the beta chain of hemoglobin is reduced or absent. If left untreated, people with severe forms of beta-thalassemia can suffer from numerous health complications, including growth retardation, skeletal abnormalities, and heart failure. People with beta-thalassemia may be treated with blood transfusions, but transfusions carry the risk of iron overload and resulting complications with the spleen, liver, and heart.

[0006] Reactivation of HbF functional expression in adult hematopoietic cells could be clinically very useful for patients with hemoglobin disorders such as sickle cell disease and beta-thalassemia. Hydroxyurea, the current standard treatment for sickle cell disease, works by inducing fetal hemoglobin, but is limited by variable clinical response, bone marrow toxicity, and carcinogenic risk. Therefore, alternative, more effective therapies for hemoglobinopathies are needed. Summary of the Invention

[0007] Compounds of formula (I): [ka] [In the formula, A 1 , A 2 , A 3 , Q, and R 3 is as defined herein] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof are provided herein.

[0008] Compounds of formula (II): [ka] [Wherein, Y, Q', R 7 , and R 8 is as defined herein] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof are provided herein.

[0009] Compounds of formula (III): [ka] [Wherein Q″ and R 12 is as defined herein] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof are provided herein.

[0010] In one embodiment, provided herein are compounds as described in the present disclosure, such as compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or compounds in Table 1.

[0011] In one aspect, provided herein is a pharmaceutical composition comprising an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1, as described herein, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0012] In one embodiment, provided herein is a method for treating a subject having a hemoglobinopathy. In another embodiment, provided herein is a use of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1 for treating or preventing a hemoglobinopathy, comprising administering to a subject suffering from a hemoglobinopathy an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1 as described herein.

[0013] In certain embodiments, the methods described herein comprise administering to a subject a therapeutically effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0014] In one embodiment, provided herein is a use of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1 for treating or preventing a hemoglobinopathy, comprising administering to a subject affected with a hemoglobinopathy an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1 as described herein.

[0015] In one aspect, provided herein is a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1 for use as a medicament. In certain embodiments, provided herein is a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1 for use in a method for treating or preventing a hemoglobinopathy, comprising administering to a subject an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1.

[0016] In another aspect, provided herein are methods for preparing a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or a compound of Table 1, as described herein.

[0017] A more detailed understanding of the present embodiments can be obtained by reference to the detailed description and examples, which are intended as non-limiting examples of embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0018] definition As used herein, the terms "comprising" and "including" may be used interchangeably. The terms "comprising" and "including" should be interpreted as specifying that the described features or components are present exactly as stated, but do not exclude the presence or addition of one or more features, components, or groups thereof. Furthermore, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0019] The term "consisting of" means that the invention has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make it up. In another embodiment, the term "consisting of" excludes from any succeeding description any other features or components, except those that are not essential to the technical effect to be achieved.

[0020] The term "or" as used herein should be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition occur only when combinations of elements, features, steps, or acts are inherently mutually exclusive in some way.

[0021] Unless otherwise specified, an "alkyl" group, as used herein, is a saturated, partially saturated, or unsaturated, straight-chain or branched, acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbons, or in some embodiments, 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyl groups include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. An "alkenyl" group is an alkyl group containing one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted.When an alkyl group described herein is referred to as "substituted," it means any and all substituents found in the representative compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino , heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2. In some embodiments, one or more hydrogens in the alkyl group, for example, 1, 2, 3, 4, or 5 hydrogens, may be substituted with a halogen.

[0022] Unless otherwise indicated, a "cycloalkyl" group, as used herein, refers to a saturated or partially saturated cyclic alkyl group of 3 to 10 carbon atoms having a single ring or multiple fused or bridged rings, which may be optionally substituted. In some embodiments, a cycloalkyl group has 3 to 8 ring atoms, while in other embodiments, the number of ring carbon atoms is 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring or bridged ring structures, such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of unsaturated cycloalkyl groups include, inter alia, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0023] Unless otherwise specified, an "aryl" group, as used herein, is an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In some embodiments, an aryl group contains 6 to 14 carbons, and in other embodiments, 6 to 12 or 6 to 10 carbon atoms in the ring portion of the group. Particular aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0024] Unless otherwise specified, a "heteroaryl" group, as used herein, is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remaining atoms being carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in other embodiments, 6 to 9 or 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-onyl), isoindolin-1-onyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), azabenzimidazolyl, Heteroaryl groups include, but are not limited to, groups such as aryl, imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinolin-1(2H)-onyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be substituted or unsubstituted.

[0025] Unless otherwise specified, as used herein, a "heterocyclyl" refers to an aromatic ring system (also referred to as heteroaryl) or a non-aromatic cycloalkyl (also referred to as heterocycloalkyl) in which 1 to 4 of the ring carbon atoms are independently replaced with a heteroatom. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, a heterocyclyl group contains 3 to 10 ring atoms, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring atoms. A heterocyclyl can also be attached to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated, and saturated ring systems, such as, for example, imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl) groups. The term heterocyclyl includes fused ring species, such as those containing fused aromatic and non-aromatic groups, such as 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The term also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-oxo- nyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithionyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indol-2-onyl), isoindolin-1-onyl, indolinyl, iso indolyl, isoindolinyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiyl nyl, benzothiazinyl, benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), azabenzimidazolyl, imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,Representative non-aromatic heterocyclyl groups include, but are not limited to, 4-dihydroisoquinolin-1(2H)-onyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups exclude fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups can be mono- or multiply substituted (e.g., pyridyl or morpholinyl groups that are di-, tri-, tetra-, penta-, or hexa-substituted or di-substituted with various substituents, including, but not limited to, those described below).

[0026] Unless otherwise specified, a "cycloalkylalkyl" group as used herein is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, the cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl, and the like.

[0027] Unless otherwise specified, an "aralkyl" group, as used herein, is a radical of the formula: -alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups can be substituted on the alkyl portion, the aryl portion, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups, and aralkyl groups in which the aryl group is fused to a cycloalkyl group, such as indan-4-ylethyl.

[0028] Unless otherwise specified, as used herein, a "heterocyclylalkyl" group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. A "heteroarylalkyl" group is a radical of the formula: -alkyl-heteroaryl, where alkyl and heteroaryl are defined above. A "heterocycloalkylalkyl" group is a radical of the formula: -alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. Substituted heterocyclylalkyl groups may be substituted on the alkyl, the heterocyclyl, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-ylethyl, morpholin-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0029] Unless otherwise specified, "halogen" as used herein is fluorine, chlorine, bromine, or iodine.

[0030] Unless otherwise specified, a "hydroxyalkyl" group as used herein is an alkyl group, as described above, substituted with one or more hydroxy groups.

[0031] Unless otherwise specified, as used herein, an "alkoxy" group is -O-(alkyl), where alkyl is defined above. An "alkylthio" group is -S-(alkyl), where alkyl is defined above.

[0032] Unless otherwise specified, an "alkoxyalkyl" group as used herein is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0033] As used herein, unless otherwise noted, a "cycloalkyloxy" group is -O-(cycloalkyl), where cycloalkyl is defined above.

[0034] Unless otherwise indicated, an "aryloxy" group as used herein is --O-(aryl), where aryl is defined above.

[0035] Unless otherwise specified, as used herein, a "heterocyclyloxy" group is -O-(heterocyclyl), where heterocyclyl is defined above. A "heteroaryloxy" group is -O-(heteroaryl), where heteroaryl is defined above. A "heterocycloalkyloxy" group is -O-(heterocycloalkyl), where heterocycloalkyl is defined above.

[0036] Unless otherwise specified, as used herein, an "amino" group is a group of the formula: -NH, -NH(R # ), or -N(R # )2, where R # are each independently an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) group as defined above, each of which is independently substituted or unsubstituted.

[0037] In one embodiment, an "amino" group is an "alkylamino" group which is a radical of the formula: -NH-alkyl or -N(alkyl), where each alkyl is independently defined above. The terms "cycloalkylamino," "arylamino," "heterocyclylamino," "heteroarylamino," "heterocycloalkylamino," or the like are explained similarly as above for "alkylamino," where the term "alkyl" is replaced by, respectively, "cycloalkyl," "aryl," "heterocyclyl," "heteroaryl," "heterocycloalkyl," or the like.

[0038] Unless otherwise specified, a "carboxy" group as used herein is a radical of the formula: --C(O)OH.

[0039] Unless otherwise specified, as used herein, an "acyl" group is a group of the formula: -C(O)(R # ) or a radical of —C(O)H, where R # is defined above. A "formyl" group is a radical of the formula: -C(O)H.

[0040] Unless otherwise specified, as used herein, an "amide" group is a group of the formula: -C(O)-NH, -C(O)-NH(R # ), -C(O)-N(R # )2, -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H, or -N(R # )-C(O)-(R # ) radical, where R # are each independently defined above.

[0041] In one embodiment, an "amide" group has the formula: -C(O)-NH, -C(O)-NH(R # ), -C(O)-N(R # )2, where R # are each independently defined above.

[0042] In one embodiment, an "amide" group has the formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H, or -N(R # )-C(O)-(R # ) where R # are each independently defined above.

[0043] Unless otherwise indicated, as used herein, a "sulfonylamino" group is a group of the formula: -NHSO(R # ) or -N(R # )SO2(R # ) radical, where each R # is defined above.

[0044] Unless otherwise specified, as used herein, an "ester" group is an ester of the formula: -C(O)-O-(R # ) or -OC(O)-(R # ) radical, where R # is defined above.

[0045] In one embodiment, an "ester" group is an "alkoxycarbonyl" group which is a radical of the formula: -C(O)-O-(alkyl), where alkyl is defined above. The terms "cycloalkyloxycarbonyl", "aryloxycarbonyl", "heterocyclyloxycarbonyl", "heteroaryloxycarbonyl", "heterocycloalkyloxycarbonyl" or the like are explained similarly as above for "alkoxycarbonyl", where the term "alkoxy" is replaced by "cycloalkyloxy", "aryloxy", "heterocyclyloxy", "heteroaryloxy", "heterocycloalkyloxy", or the like, respectively.

[0046] Unless otherwise specified, as used herein, a "carbamate" group is a group of the formula: -OC(O)-NH, -OC(O)-NH(R # ), -OC(O)-N(R # )2, -NH-C(O)-O-(R # ), or -N(R # )-C(O)-O-(R # ) radical, where R # are each independently defined above.

[0047] Unless otherwise specified, as used herein, a "urea" group refers to a group of the formula: -NH(CO)NH, -NHC(O)NH(R # ), -NHC(O)N(R # )2, -N(R # )C(O)NH2, -N(R # )C(O)NH(R # ), or -N(R # )C(O)N(R #)2, where R # are each independently defined above.

[0048] Unless otherwise indicated, as used herein, a "sulfinyl" group is a group of the formula: -S(O)R # where R # is defined above.

[0049] Unless otherwise indicated, as used herein, a "sulfonyl" group is a group of the formula: -S(O)R # where R # is defined above.

[0050] Unless otherwise indicated, as used herein, an "aminosulfonyl" group is a group of the formula: -SO2NH2, -SO2NH(R # ), or -SO2N(R # )2, where R # are each independently defined above.

[0051] Except in the case of alkyl groups, when a group described herein is said to be "substituted," it can be substituted with any suitable substituent. Illustrative examples of substituents include those found in the representative compounds and embodiments disclosed herein, as well as halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, heterocycloalkylalkyl (which are optionally further substituted); hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); oxide ( For example, a nitrogen atom substituted with oxide is referred to as N-oxide); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazide; hydrazono; azide; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2. In some embodiments, one or more hydrogens in a substituent, for example, 1, 2, 3, 4, or 5 hydrogens, may be replaced with a halogen. In some embodiments, the substitution replaces a hydrogen atom with alkyl, alkoxy, aryloxy, halogen, or haloalkyl.

[0052] As used herein, the term "hemoglobinopathy" means any disease or disorder that affects red blood cells. Hemoglobinopathies include, but are not limited to, sickle cell disease and anemia.

[0053] As used herein, the term "HbF" means fetal hemoglobin.

[0054] As used herein, the term "gene therapy" refers to the treatment of a disease or condition by the introduction or contacting of genetic material into cells.

[0055] As used herein, the term "CRISPR" means clustered regularly interspaced short palindromic repeats.

[0056] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of the compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), and Table 1 include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine), and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, specific examples of salts include hydrochloride and mesylate. Others are known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0057] Unless otherwise specified, the term "stereoisomer" or "stereoisomerically pure," as used herein, means one stereoisomer of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomers, including mixtures thereof, are included within the scope of the embodiments disclosed herein.

[0058] The use of stereomerically pure forms of such compounds set forth in Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), and Table 1, as well as the use of mixtures of such forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0059] It should also be noted that the compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may include E and Z isomers, or mixtures thereof, and cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either E or Z isomers. In other embodiments, the compounds are mixtures of E and Z isomers. In certain embodiments, the compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 are isolated as either E or Z isomers. In other embodiments, the compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 are mixtures of E and Z isomers.

[0060] "Tautomers" refer to isomers of a compound that are in equilibrium with each other due to proton migration. The concentrations of isomers depend on the environment in which the compound is found, and may vary depending on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomers, which are called tautomers of each other: [ka]

[0061] As will be readily understood by one of ordinary skill in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 are within the scope of this disclosure.

[0062] It should also be noted that the compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may contain unnatural proportions of atomic isotopes at at least one of the atoms. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I), sulfur 35( 35 S), or carbon-14 ( 14They may be radiolabeled with carbon-13 (e.g., C) or 13 C) or nitrogen-15( 15 A compound may be isotopically enriched, such as with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, In some embodiments, isotopologues of compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 are provided, e.g., isotopologues are compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 enriched at carbon-13 or nitrogen-15. As used herein, "deuterated" means that at least one hydrogen (H) is replaced with a deuterium (D or 2 H), meaning that the compound is enriched with deuterium at at least one position. Note that if there is a discrepancy between the drawn structure and the name of that structure, the drawn structure should be given more weight.

[0063] As used herein, "treating" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting further progression or worsening of those symptoms, or reducing or eradicating the cause of the disorder, disease, or condition itself. In one embodiment, the disorder, disorder, or condition is a hemoglobinopathy.

[0064] As used herein, "preventing" refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition; a method of preventing a subject from acquiring a disorder, disease, or condition; or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder, disorder, or condition is a hemoglobinopathy.

[0065] The term "effective amount" in reference to a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, means an amount capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof. In one embodiment, the disorder, disease, or condition is a hemoglobinopathy.

[0066] The term "subject" or "patient" includes humans.

[0067] The term "combination" or "administration in combination" includes administration as a mixture, simultaneous administration in separate formulations, and sequential administration in any order.

[0068] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0069] compound The following formula (I): [ka] [In the formula, [ka] is a single or double bond; A 1 is NR 1 , O, CH(R 2 ), or C(R 2 )2; A 2 is NR 1 , C=O, CH(R 2 ), or C(R 2 )2; A 3 is NR 1 , O, CH(R 2 ), or C(R 2 )2; R 1 are each independently absent, H, substituted or unsubstituted alkyl, substituted or unsubstituted cyclylalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heterocyclylalkyl; R 2 are each independently absent, H, an amine, or a substituted or unsubstituted alkyl; R 3 are each independently H, substituted or unsubstituted cycloalkyl, -OR 4 , CH2-R', substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or substituted 3,4-dihydro-2(1H)-quinolinone; R 4 is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R' is cycloalkyl; Q is H or CH3. Provided herein are compounds of the formula:

[0070] The following formula (I'): [ka] [In the formula, [ka] is a single or double bond; A 1’ is NR 1’ , O, or CH(R 2’ ) and; A 2’ is NR 1’ , C=O, CR 2’ , or CH(R 2’ ) and; A 3’ is NR 1’ , O, C.R. 2’ , or CH(R 2’ ) and; R 1’ are each independently absent, H, substituted or unsubstituted alkyl, substituted or unsubstituted cyclylalkyl, or substituted or unsubstituted heterocyclylalkyl; R 2’ are each independently H, an amine, or a substituted or unsubstituted alkyl; R 3’ are each independently H, substituted or unsubstituted cycloalkyl, -OR 4’ , CH2-R*, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted 3,4-dihydro-2(1H)-quinolinone; R 4’ is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R* is cycloalkyl; Q* is H or CH3] Provided herein are compounds of formula (I) represented by the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0071] In one embodiment, [ka] is a single bond.

[0072] In one embodiment, [ka] is a double bond.

[0073] In one embodiment, A 1’ is NR 1 In one embodiment, A 1 is NR 1 is.

[0074] In one embodiment, A 2’ is NR 1 In one embodiment, A 2 is NR 1 is.

[0075] In one embodiment, A 3’ is NR 1 In one embodiment, A 3 is NR 1 is.

[0076] In one embodiment, R 1’ is CH3. In one embodiment, R 1 is CH3.

[0077] In one embodiment, A 2’ is CR 2’ In one embodiment, A 2 is CR 2’ is.

[0078] In one embodiment, R 2’ is H. In one embodiment, R 2 is H.

[0079] In one embodiment, R 2’ is CH3. In one embodiment, R 2 is CH3.

[0080] In one embodiment, R3’ is CH2-R*, where R* is C1-C6 substituted or unsubstituted alkyl or C3-C6 substituted or unsubstituted cycloalkyl. 3 is CH2-R', where R' is C1-C6 substituted or unsubstituted alkyl or C3-C6 substituted or unsubstituted cycloalkyl.

[0081] In one embodiment, R 3 teeth, [ka] is.

[0082] In some embodiments, R* is cyclopropyl. In some embodiments, R' is cyclopropyl.

[0083] In one embodiment, R 3’ teeth [ka] where: R 5’ is H, substituted or unsubstituted alkyl, or alkoxy; R 6’ is H, halogen, or substituted or unsubstituted alkyl.

[0084] In one embodiment, R 3 teeth, [ka] where: R 5 is H, substituted or unsubstituted alkyl, or alkoxy; R 6 is H, halogen, or substituted or unsubstituted alkyl.

[0085] In one embodiment, R 5’ is CH3. In one embodiment, R 5 is CH3.

[0086] In one embodiment, R 6’ is haloalkyl. In some embodiments, R 6 is haloalkyl.

[0087] In one embodiment, [ka]

[0088] Provided herein are compounds of formula (I) or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0089] The following formula (II): [ka] [In the formula, Q' is H or CH3; Y is CR 13 , CH, or N; R 7 H, OR 9 , substituted or unsubstituted aryl, or substituted or unsubstituted alkyl; R 8 H, OR 10 or substituted or unsubstituted aryl; R 9 is a substituted or unsubstituted alkyl, aryl, CH2CH2N(CH3)2, or CH2CH2-R 11 and; R 10 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R 11 is piperidinyl; R 13 is a substituted or unsubstituted alkyl] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0090] The following formula (II'): [ka] [In the formula, Q** is H or CH3; Y' is CH or N; R 7’ H, OR 9’ , substituted or unsubstituted aryl, or substituted or unsubstituted alkyl; R 8’ H, OR 10’ or substituted or unsubstituted aryl; R9’ is a substituted or unsubstituted alkyl, aryl, CH2CH2N(CH3)2, or CH2CH2-R 11’ and; R 10’ is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R 11’ is piperidinyl] Provided herein are compounds of formula (II) represented by the formula: and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0091] In some embodiments, Y is CH. In some embodiments, Y' is CH.

[0092] In some embodiments, Y is N. In some embodiments, Y' is N.

[0093] In one embodiment, R 7 is CH3. In one embodiment, R 7’ is CH3.

[0094] In one embodiment, R 10 is CH3. In one embodiment, R 10’ is CH3.

[0095] In one embodiment, R 10 is aryl. In some embodiments, R 10’ is aryl.

[0096] In one embodiment, R 10 is phenyl. In one embodiment, R 10’ is phenyl.

[0097] In one embodiment, R 10 is substituted phenyl. In some embodiments, R 10’ is a substituted phenyl.

[0098] In one embodiment, R13 is C1-C6 alkyl substituted with aryloxy.

[0099] Provided herein are compounds of formula (II) selected from the following, or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof: [ka] [ka]

[0100] The following formula (III): [ka] [In the formula, Q" is H or CH3; R 12 is substituted or unsubstituted pyridyl, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C3-C6 cycloalkyl] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0101] In some embodiments, Q″ is H.

[0102] In some embodiments, Q" is CH3.

[0103] In one embodiment, R 12 is CH3.

[0104] In one embodiment, R 12 is cyclopropyl.

[0105] In one embodiment, R 12 is selected from substituted or unsubstituted thiazole or substituted or unsubstituted pyrazole.

[0106] In one embodiment, R 12 teeth, [ka] where: Q 3 is selected from H, Cl, or F; Q 4 is selected from H, CH3, or CH(F)2; Q 5 is selected from H, CH3, or OCH3; Q 6 is selected from H or F.

[0107] In one embodiment, Q 3 is F.

[0108] In one embodiment, Q 5 is OCH3.

[0109] In one embodiment, Q 5 is CH3.

[0110] In one embodiment, Q 3 is H and Q 4 is H and Q 5 is CH3 and Q 6 is H.

[0111] In one embodiment, Q 3 is H and Q 4 is CH(F)2 and Q 5 is H and Q 6 is H.

[0112] In one embodiment, Q 3 is F and Q 4 is CH3 and Q 5 is H and Q 6 is H.

[0113] In one embodiment, Q 3 is F and Q 4 is H and Q5 is CH3 and Q 6 is H.

[0114] In one embodiment, Q 3 is Cl and Q 4 is CH3 and Q 5 is H and Q 6 is H.

[0115] In one embodiment, Q 3 is H and Q 4 is CH3 and Q 5 is CH3 and Q 6 is H.

[0116] In one embodiment, Q 3 is H and Q 4 is CH3 and Q 5 is OCH3 and Q 6 is H.

[0117] In one embodiment, Q 3 is F and Q 4 is H and Q 5 is OCH3 and Q 6 is H.

[0118] In one embodiment, Q 3 is F and Q 4 is OCH33, and Q 5 is H and Q 6 is H.

[0119] Provided herein are compounds of formula (III) selected from the following, or pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof: [ka] [ka] [ka] [ka] [ka] [ka]

[0120] In some embodiments, the compound is selected from the following: 4-((1,2-dimethyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((1-cyclopropyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazol-4-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-5-(2-methylpyridin-4-yl)-1H-indazol-6-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((3-methyl-6-(2-methylpyridin-4-yl)benzo[d]isoxazol-5-yl)amino)isoindoline-1,3-dione; 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((2-methoxy-4-(2-(piperidin-1-yl)ethoxy)phenyl)amino)isoindoline-1,3-dione; 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-4-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-phenoxy-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-methyl-4-phenoxypyridin-3-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 4-((1,2-dimethyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(6-methylpyridazin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 4-((6-(3-chlorophenoxy)-1-methyl-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-5-((4-methylpyrimidin-5-yl)oxy)-1H-indazol-4-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-5-phenoxy-1H-indazol-6-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(3-(trifluoromethyl)phenyl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 4-((6-(2,3-dimethylpyridin-4-yl)-1-methyl-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-methoxy-4-phenylpyridin-3-yl)amino)isoindoline-1,3-dione; 4-((3-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)-2-((S)-3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 4-((1,6-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-cyclopropyl-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (S)-4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; (S)-4-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (S)-4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(4-methylthiazol-2-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; (S)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (S)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 2-((S)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-2-methylpyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(5-fluoro-2-methylpyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 4-((6-(3-chloro-2-methylpyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; 4-((6-(2,6-dimethylpyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; (S)-2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methoxy-6-methylpyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-2-methoxypyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-4-((6-(5-fluoro-2-methoxypyridin-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 2-((R)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione; (R)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione; 2-(3-methyl-2,6-dioxopiperidin-3-yl)-4-((3-(phenoxymethyl)phenyl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0121] In certain embodiments, the compound is 4-((1,2-dimethyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0122] In certain embodiments, the compound is 4-((1-cyclopropyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0123] In certain embodiments, the compound is 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0124] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0125] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0126] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazol-4-yl)amino)isoindoline-1,3-dione.

[0127] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-5-(2-methylpyridin-4-yl)-1H-indazol-6-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0128] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((3-methyl-6-(2-methylpyridin-4-yl)benzo[d]isoxazol-5-yl)amino)isoindoline-1,3-dione.

[0129] In certain embodiments, the compound is 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0130] In certain embodiments, the compound is 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0131] In certain embodiments, the compound is 4-((6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0132] In certain embodiments, the compound is 2,6-dioxopiperidin-3-yl)-4-((2-methoxy-4-(2-(piperidin-1-yl)ethoxy)phenyl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0133] In certain embodiments, the compound is 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-4-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0134] In certain embodiments, the compound is 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-4-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0135] In certain embodiments, the compound is (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione.

[0136] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt, tautomer, isotopologue, and / or stereoisomer thereof.

[0137] In certain embodiments, the compound is 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione.

[0138] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0139] Representative compounds of formula (I), formula (I'), formula (II), formula (II'), and formula (III) are set forth in Table 1.

[0140] How to use In some embodiments, the disclosure provides a method of inducing HbF expression in a cell, the method comprising contacting the cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0141] In some embodiments, the disclosure provides a method of reducing WIZ expression in a cell, comprising contacting the cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0142] In some embodiments, the disclosure provides a method for reducing ZBTB7A expression in a cell, comprising contacting the cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof.

[0143] In some embodiments, the present disclosure provides a method for inducing HbF expression in a cell, and / or decreasing ZBTB7A expression in a cell, and / or decreasing WIZ expression in a cell, comprising contacting a cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0144] In some embodiments, the disclosure provides a method of treating a hemoglobinopathy, comprising administering to a subject in need thereof a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

[0145] In some embodiments, the present disclosure provides the use of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, for the treatment of a hemoglobinopathy.

[0146] In some embodiments, the hemoglobinopathy is anemia. In some embodiments, the hemoglobinopathy is sickle cell disease. In some embodiments, the hemoglobinopathy is thalassemia. In some embodiments, the hemoglobinopathy is alpha thalassemia. In some embodiments, the hemoglobinopathy is beta thalassemia.

[0147] In certain embodiments, provided herein are pharmaceutical compositions comprising an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0148] In certain embodiments, provided herein is a method of inducing HbF expression in a cell, the method comprising contacting the cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0149] In one embodiment, provided herein is a method of decreasing expression of WIZ, a regulator of G9a / GLP histone methyltransferase, in a cell, comprising contacting the cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0150] In one embodiment, provided herein is a method for reducing ZBTB7A expression in a cell, the method comprising contacting the cell with a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0151] In certain embodiments, provided herein is a method of treating a hemoglobinopathy, comprising administering to a subject in need thereof a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or a pharmaceutical composition of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0152] In certain embodiments, the hemoglobinopathy is anemia.

[0153] In certain embodiments, the hemoglobinopathy is sickle cell disease.

[0154] In certain embodiments, the hemoglobinopathy is sickle cell anemia.

[0155] In certain embodiments, the hemoglobinopathy is thalassemia.

[0156] In certain embodiments, the hemoglobinopathy is alpha thalassemia.

[0157] In certain embodiments, the hemoglobinopathy is beta thalassemia.

[0158] In certain embodiments, provided herein are methods for treating hemoglobinopathies, comprising administering to a subject in need thereof a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or a pharmaceutical composition of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, in combination with a second active agent and / or a second therapy. In certain embodiments, the second active agent is luspatercept. In certain embodiments, the second active agent is voxerotol. In certain embodiments, the second active agent is crizanlizumab-tmca. In certain embodiments, the second active agent is hydroxyurea. In certain embodiments, the second active agent is L-glutamine. In certain embodiments, the second active agent is etabopibat. In certain embodiments, the second active agent is mitapivat. In certain embodiments, the second active agent is cybelotol. In some embodiments, the second active agent is inlacumab. In some embodiments, the second therapy is a blood transfusion. In some embodiments, the second therapy is a stem cell transplant. In some embodiments, the second therapy is a bone marrow transplant. In some embodiments, the second therapy is gene therapy. In some embodiments, the gene therapy is CRISPR therapy. In some embodiments, the hemoglobinopathy is anemia. In some embodiments, the hemoglobinopathy is sickle cell disease. In some embodiments, the hemoglobinopathy is thalassemia. In some embodiments, the hemoglobinopathy is alpha thalassemia. In some embodiments, the hemoglobinopathy is beta thalassemia.

[0159] The compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 have utility as pharmaceuticals for treating, preventing, or ameliorating hemoglobinopathies. The compounds provided herein are useful for treating or preventing any of the diseases, disorders, or conditions disclosed herein.

[0160] In one aspect, provided herein are methods for treating diseases caused by hemoglobinopathies. In certain embodiments, the compounds described herein are used in human medical therapy, particularly for the treatment of hemoglobinopathies.

[0161] In one aspect, provided herein are methods for treating diseases caused by hemoglobinopathies. In some embodiments, the compounds described herein are used in human medical therapy, particularly for the treatment of hemoglobinopathies. In some embodiments, the method comprises administering a therapeutically effective amount of a compound described herein to a subject having a disease caused by hemoglobinopathies.

[0162] In one aspect, provided herein is a method for treating or preventing a hemoglobinopathy, comprising administering to a subject an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof. In some embodiments, the hemoglobinopathy is anemia. In some embodiments, the hemoglobinopathy is sickle cell disease. In some embodiments, the hemoglobinopathy is sickle cell anemia.

[0163] In another aspect, methods for preventing diseases caused by hemoglobinopathies are also provided herein. In one embodiment, a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, is used in human medical therapy, particularly for the prevention of hemoglobinopathies. In one embodiment, the method comprises administering to a subject a therapeutically effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, to prevent diseases caused by hemoglobinopathies.

[0164] Second Active Agent and Second Therapy In one embodiment, the second active agent used in the methods provided herein is selected from the group consisting of luspatercept, voxerotol, crizanlizumab-tmca, hydroxyurea, L-glutamine, etabopivat, mitapivat, ocybelotol, and inlacumab.

[0165] In one embodiment, the second therapy used in the methods provided herein is selected from the group consisting of blood transfusion, stem cell transplant and / or bone marrow transplant, and / or gene therapy. In one embodiment, the gene therapy is CRISPR therapy.

[0166] Treatment and / or prevention methods In one embodiment, provided herein is a method of treating a hemoglobinopathy comprising administering to a patient a therapeutically effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or an enantiomer, mixture of enantiomers, tautomer, isotope, or pharmaceutically acceptable salt thereof, in combination with a second active agent, wherein the second active agent is selected from the group consisting of luspatercept, voxerotol, crizanlizumab-tmca, hydroxyurea, L-glutamine, etabopivat, mitapivat, ocivelotol, and inlacumab.

[0167] In one embodiment, provided herein is a method of treating a hemoglobinopathy, comprising administering to a patient a therapeutically effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with a second therapy, wherein the second therapy is selected from the group consisting of blood transfusion, stem cell and / or bone marrow transplant, and / or gene therapy. In one embodiment, the gene therapy is CRISPR therapy.

[0168] Pharmaceutical Compositions and Routes of Administration Provided herein are pharmaceutical compositions comprising an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, as described herein, and a pharmaceutically acceptable carrier, excipient, or vehicle. The compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 can be administered to a subject enterally (e.g., orally, rectally), topically, or parenterally (e.g., intravenously, intramuscularly, subcutaneously) in conventional dosage forms (e.g., capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, emulsions, and the like).Suitable formulations may contain conventional organic or inorganic additives, such as fillers (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or citrate), or the like. The formulations can be prepared by commonly used methods using additives such as cellulose acetate, cellulose acetate stearate ... The effective amount of the compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 in the pharmaceutical composition may be at a level that exerts a desired effect, for example, about 0.005 mg / kg (body weight of the subject) to about 20 mg / kg (body weight of the subject) for both oral and parenteral administration unit doses.

[0169] The dosage of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 to be administered to a subject may vary considerably and be subject to the judgment of a healthcare practitioner. Generally, a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may be administered at a dosage of about 0.5 mg / kg (subject's body weight) to about 20 mg / kg (subject's body weight) once to four times daily, although the dosage may vary appropriately depending on the subject's age, body weight, and medical condition, as well as the type of administration. In one embodiment, the dosage is about 0.1 mg / kg (subject's body weight) to about 3 mg / kg (subject's body weight), about 0.5 mg / kg (subject's body weight) to about 2 mg / kg (subject's body weight), about 1 mg / kg (subject's body weight) to about 2 mg / kg (subject's body weight), or about 1.5 mg / kg (subject's body weight) to about 2 mg / kg (subject's body weight). In one embodiment, the dosage is about 1 mg / kg (subject's body weight) to about 3 mg / kg (subject's body weight). In one embodiment, the dosage is about 0.5 mg / kg (subject's body weight) to about 1 mg / kg (subject's body weight). In one embodiment, the dosage is about 1 mg / kg (subject's body weight) to about 2 mg / kg (subject's body weight). In one embodiment, the dosage is about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mg / kg (subject's body weight). In one embodiment, one dosage is given per day. In any given case, the amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 administered will depend on factors such as the solubility of the active ingredient, the formulation used, and the route of administration. In one embodiment, the application of a local concentration results in an intracellular exposure or concentration of about 0.01-10 μM.

[0170] In another embodiment, provided herein is a method for treating or preventing a disease or disorder, comprising administering from about 1 mg / day to about 1200 mg / day of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 to a subject afflicted with a hemoglobinopathy. In another embodiment, provided herein is a method for treating or preventing a disease or disorder, comprising administering from about 0.375 mg / day to about 750 mg / day, from about 0.75 mg / day to about 375 mg / day, from about 3.75 mg / day to about 75 mg / day, from about 7.5 mg / day to about 55 mg / day, or from about 18 mg / day to about 37 mg / day of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 to a subject afflicted with a hemoglobinopathy. In one embodiment, a method for treating a disease or disorder comprises administering to a subject suffering from a hemoglobinopathy from about 0.375 mg / day to about 750 mg / day of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, a method for treating a disease or disorder comprises administering to a subject suffering from a hemoglobinopathy from about 3.75 mg / day to about 75 mg / day of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0171] In another embodiment, provided herein are unit dose formulations comprising about 1 mg to 200 mg, about 35 mg to about 1400 mg, about 125 mg to about 1000 mg, about 250 mg to about 1000 mg, or about 500 mg to about 1000 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises about 1 mg to 200 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises about 35 mg to about 1400 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation contains from about 125 mg to about 1000 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation contains from about 250 mg to about 1000 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation contains from about 500 mg to about 1000 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0172] In certain embodiments, provided herein are unit dose formulations comprising about 100 mg or 400 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0173] In another embodiment, provided herein is a unit dose formulation comprising 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 40 mg, 50 mg, 70 mg, 100 mg, 125 mg, 130 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 1 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 5 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 10 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 15 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 20 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 25 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 30 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 35 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 40 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 50 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 70 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.In one embodiment, the unit dose formulation comprises 100 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 125 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 130 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 140 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 175 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 200 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 250 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 280 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 350 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 500 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 560 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 700 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 750 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1. In one embodiment, the unit dose formulation comprises 1000 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.In one embodiment, the unit dose formulation comprises 1400 mg of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1.

[0174] A compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, can be administered once, twice, three times, four or more times daily. In certain embodiments, doses of 600 mg or less are administered as a single daily dose, and doses greater than 600 mg are administered twice daily in an amount equal to half the total daily dose.

[0175] A compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may be administered orally for convenience. In one embodiment, when administered orally, a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 is administered with food and water. In another embodiment, a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.

[0176] A compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin, or topically to the eye (i.e., subconjunctivally, intravitreal, retrobulbar, intracameral). The method of administration is left to the discretion of the healthcare practitioner and may depend in part on the site of the disease.

[0177] In one embodiment, provided herein is a capsule comprising a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, without any additional carrier, excipient, or vehicle.

[0178] In another embodiment, provided herein are compositions comprising an effective amount of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1, and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may include an excipient, diluent, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0179] The compositions may be in the form of tablets, chewable tablets, capsules, solutions, injectable solutions, troches, suppositories, suspensions, gels, intraruminal devices (e.g., for prolonged prophylaxis or controlled release), implants, topical pour-ons, transdermal delivery gels, spot-ons, implants (including devices, gels, liquids (e.g., PLGA)), and the like. The compositions may be formulated to contain a daily dose or an appropriate fraction of a daily dose in a dosage unit, which may be a tablet, a capsule, or a suitable amount of liquid. In one embodiment, solutions are prepared from water-soluble salts, such as hydrochloride salts. Generally, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules may be prepared by mixing a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 with a suitable carrier or diluent and filling the appropriate amount of the mixture into capsules. Typical carriers and diluents include, but are not limited to, inert powdered substances (such as various types of starch), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol, and sucrose), flours and similar edible powders.

[0180] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually incorporate diluents, binders, lubricants, and disintegrants, as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars (such as lactose, fructose, glucose, and the like). Natural and synthetic gums are also useful, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0181] Lubricants may be necessary in tablet formulations to prevent the tablet and punch from sticking in the dye. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wet, causing the tablet to disintegrate and release the compound. These include starch, clay, cellulose, algin, and gums. More specifically, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, and sodium lauryl sulfate may be used. Tablets may be coated with sugar as a flavor and filler or with a film-forming protecting agent to modify the tablet's dissolution characteristics. The composition may also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0182] The effects of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 can be delayed or prolonged by appropriate formulation. For example, slowly dissolving pellets of a compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 can be prepared and incorporated into tablets or capsules or as sustained-release implantable devices. Techniques include creating pellets with different dissolution rates and filling capsules with a mixture of pellets. Tablets or capsules can be coated with a membrane that resists dissolution for a predictable period of time. Even parenteral formulations can be made long-acting by dissolving or suspending the compound of Formula (I), Formula (I'), Formula (II), Formula (II'), Formula (III), or Table 1 in an oily or emulsifying vehicle that allows it to slowly disperse in serum, or by adding an amount of PLGA.

[0183] Embodiments of the present disclosure include the following. 1. Formula (I): [ka] [In the formula, [ka] is a single or double bond; A1 is NR1, O, or CR2; A2 is NR1, C=O, or CR2; A3 is NR1, O, or CR2; Each R1 is independently absent, H, substituted or unsubstituted alkyl, substituted or unsubstituted cyclylalkyl, or substituted or unsubstituted heterocyclylalkyl; Each R2 is independently H, an amine, or a substituted or unsubstituted alkyl; Each R3 is independently H, substituted or unsubstituted alkyl, cycloalkyl, -O-R4, CH2-R', substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted 3,4-dihydro-2(1H)-quinolinone; R4 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R' is cycloalkyl; Q is H or CH3. and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0184] 2. [ka] is a single bond.

[0185] 3. [ka] is a double bond.

[0186] 4. The compound of any one of embodiments 1-3, wherein A1 is NR1.

[0187] 5. The compound of any one of embodiments 1-4, wherein A2 is NR1.

[0188] 6. The compound of any one of embodiments 1-5, wherein A3 is NR1.

[0189] 7. The compound of any one of embodiments 1-6, wherein R1 is CH3.

[0190] 8. The compound of any one of embodiments 1-6, wherein A2 is CR2.

[0191] 9. The compound according to any one of embodiments 1-8, wherein R2 is H.

[0192] 10. The compound of any one of embodiments 1-8, wherein R2 is CH3.

[0193] 11. The compound of any one of embodiments 1-10, wherein R3 is CH2-R', and R' is C1-C6 substituted or unsubstituted alkyl or C3-C6 substituted or unsubstituted cycloalkyl.

[0194] 12. The compound according to embodiment 11, wherein R' is cyclopropyl.

[0195] 13.R 3 but, [ka] where: R5 is H, substituted or unsubstituted alkyl, or alkoxy; R6 is H, halogen, or substituted or unsubstituted alkyl; A compound according to any one of embodiments 1 to 12.

[0196] 14. The compound according to embodiment 13, wherein R5 is CH3.

[0197] 15. The compound according to any one of embodiments 13-14, wherein R6 is haloalkyl.

[0198] 16.Formula (II): [ka] [In the formula, Q' is H or CH3; Y is CH or N; R7 is H, O-R9, substituted or unsubstituted aryl, or substituted or unsubstituted alkyl; R8 is H, OR 10 or substituted or unsubstituted aryl; R9 is a substituted or unsubstituted alkyl, aryl, CH2CH2N(CH3)2, or CH2CH2-R 11 and; R 10 is substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R 11 is piperidinyl] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0199] 17. The compound according to embodiment 16, wherein Y is CH.

[0200] 18. The compound according to embodiment 16, wherein Y is N.

[0201] 19. The compound according to any one of embodiments 16-18, wherein R7 is CH3.

[0202] 20.R 10 The compound of any one of embodiments 16-18, wherein is CH3.

[0203] 21.R 10 The compound of any one of embodiments 16-18, wherein is aryl.

[0204] 22.R 10 The compound of any one of embodiments 16-18, wherein is phenyl.

[0205] 23.R 10 The compound of any one of embodiments 16-18, wherein is substituted phenyl.

[0206] 24.Formula (III): [ka] [In the formula, Q" is H or CH3; R 12is substituted or unsubstituted pyridyl, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C3-C6 cycloalkyl] and pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers thereof.

[0207] 25. The compound of embodiment 24, wherein Q″ is H.

[0208] 26. The compound of embodiment 24, wherein Q" is CH3.

[0209] 27.R 12 The compound of any one of embodiments 24-26, wherein is CH3.

[0210] 28.R 12 The compound of any one of embodiments 24-26, wherein is cyclopropyl.

[0211] 29.R 12 The compound of any one of embodiments 24-26, wherein is selected from substituted or unsubstituted thiazole, or substituted or unsubstituted pyrazole.

[0212] 30.R 12 but, [ka] where: Q3 is selected from H, Cl, or F; Q4 is selected from H, CH3, or CH(F)2; Q5 is selected from H, CH3, or OCH3; Q6 is selected from H or F; A compound according to any one of embodiments 24 to 26.

[0213] 31. The compound according to embodiment 30, wherein Q3 is F.

[0214] 32. The compound according to any one of embodiments 30-31, wherein Q5 is OCH3.

[0215] 33. The compound according to any one of embodiments 30-31, wherein Q5 is CH3.

[0216] 34. The compound according to embodiment 30, wherein Q3 is H, Q4 is H, Q5 is CH3, and Q6 is H.

[0217] 35. The compound according to embodiment 30, wherein Q3 is H, Q4 is CH(F)2, Q5 is H, and Q6 is H.

[0218] 36. The compound according to embodiment 30, wherein Q3 is F, Q4 is CH3, Q5 is H, and Q6 is H.

[0219] 37. The compound according to embodiment 30, wherein Q3 is F, Q4 is H, Q5 is CH3, and Q6 is H.

[0220] 38. The compound according to embodiment 30, wherein Q3 is Cl, Q4 is CH3, Q5 is H, and Q6 is H.

[0221] 39. The compound according to embodiment 30, wherein Q3 is H, Q4 is CH3, Q5 is CH3, and Q6 is H.

[0222] 40. The compound according to embodiment 30, wherein Q3 is H, Q4 is CH3, Q5 is OCH3, and Q6 is H.

[0223] 41. The compound according to embodiment 30, wherein Q3 is F, Q4 is H, Q5 is OCH3, and Q6 is H.

[0224] 42. The compound according to embodiment 30, wherein Q3 is F, Q4 is OCH3, Q5 is H, and Q6 is H.

[0225] 43. A pharmaceutical composition comprising an effective amount of a compound according to any one of embodiments 1-42, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0226] 44. A method for inducing HbF expression in a cell, the method comprising contacting the cell with a compound or pharmaceutical composition according to any one of embodiments 1 to 43.

[0227] 45. A method for reducing WIZ expression in a cell, comprising contacting the cell with a compound or pharmaceutical composition according to any one of embodiments 1-43.

[0228] 46. ​​A method for reducing ZBTB7A expression in a cell, comprising contacting the cell with a compound or pharmaceutical composition according to any one of embodiments 1-43.

[0229] 47. A method for inducing HbF expression in a cell, and / or decreasing ZBTB7A expression in a cell, and / or decreasing WIZ expression in a cell, comprising contacting the cell with a compound or pharmaceutical composition according to any one of embodiments 1 to 43.

[0230] 48. A method for treating a hemoglobinopathy, comprising administering to a subject in need thereof a compound or pharmaceutical composition according to any one of embodiments 1-43.

[0231] 49. The method of embodiment 48, wherein the hemoglobinopathy is anemia.

[0232] 50. The method of embodiment 48, wherein the hemoglobinopathy is sickle cell disease.

[0233] 51. The method of embodiment 48, wherein the hemoglobinopathy is thalassemia.

[0234] 52. The method of embodiment 48, wherein the hemoglobinopathy is alpha thalassemia.

[0235] 53. The method of embodiment 48, wherein the hemoglobinopathy is beta-thalassemia.

[0236] 54. Use of a compound or pharmaceutical composition according to any one of embodiments 1 to 43 for the treatment of hemoglobinopathies.

[0237] 55. The use according to embodiment 54, wherein the hemoglobinopathy is anemia.

[0238] 56. The use according to embodiment 54, wherein the hemoglobinopathy is sickle cell disease.

[0239] 57. The use according to embodiment 54, wherein the hemoglobinopathy is thalassemia.

[0240] 58. The use according to embodiment 54, wherein the hemoglobinopathy is alpha thalassemia.

[0241] 59. The use according to embodiment 54, wherein the hemoglobinopathy is beta-thalassemia. [Example]

[0242] The following examples are presented by way of illustration and not by way of limitation. Compounds are named using the automatic name generation tool provided in Chemdraw Ultra 20.1 (Cambridgesoft), which generates systematic names for chemical structures while following the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art can modify the procedures described in the illustrative examples to achieve their goals.

[0243] Provided herein are compounds of Formula (I), Formula (II), and Formula (III), as set forth in the table below.

[0244] [Table 1] Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24 Table 25 Table 26 Table 27 Table 28

[0245] The compounds disclosed herein can be made using conventional organic synthesis and commercially available starting materials. Certain compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) are prepared as described in the Examples below.

[0246] Example 1: 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-phenoxy-1H-indazol-5yl)amino)isoindoline-1,3-dione [ka]

[0247] 6-Bromo-1-methyl-5-nitro-1H-indazole [ka] To a solution of 4-bromo-2-fluoro-5-nitrobenzaldehyde (0.500 g, 2.02 mmol) in propan-2-ol (2 mL) / water (1 mL) was added potassium carbonate (0.420 g, 3.04 mmol). The mixture was stirred at 41°C for 1 hour, and methylhydrazine (0.350 g, 3.04 mmol) (40% purity) was added dropwise. The resulting mixture was heated to 77°C and stirred for 6 hours. The mixture was cooled to 20°C, and water (8 mL) was added. The mixture was stirred for 1 hour and filtered. The separated solid was rinsed with water (2 mL) and filtered. The separated solid was mixed with water (20 mL) and lyophilized to give 6-bromo-1-methyl-5-nitro-1H-indazole (0.470 g, 1.84 mmol, 91.045% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.32 (d, J = 1.2 Hz, 2H), 4.11 (s, 3H)

[0248] 1-Methyl-5-nitro-6-phenoxy-1H-indazole [ka] To a solution of 6-bromo-1-methyl-5-nitro-1H-indazole (0.470 g, 1.84 mmol) in N,N-dimethylformamide (5 mL) was added phenol (0.180 g, 1.91 mmol) and cesium carbonate (1.492 g, 4.59 mmol). The resulting mixture was stirred at 100 °C for 36 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated brine (20 mL × 3), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 1-methyl-5-nitro-6-phenoxy-1H-indazole (0.330 g, 1.22 mmol, 66% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.33 (s, 1H), 7.55 (s, 1H), 7.42 - 7.38 (m, 2H), 7.18 - 7.14 (m, 1H), 7.04 (dd, J = 0.8 Hz, 7.6 Hz, 2H), 4.02 (s, 3H); MS (ESI) m / z: 270.0 [M+1] +

[0249] 1-Methyl-6-phenoxy-1H-indazol-5-amine [ka] To a solution of 1-methyl-5-nitro-6-phenoxy-1H-indazole (0.260 g, 0.97 mmol) in methanol (50 mL) was added dry palladium on carbon (0.070 g, 0.66 mmol). The resulting mixture was stirred under 15 psi of hydrogen at 20°C for 3 hours. The mixture was diluted with methanol (50 mL) and filtered. The filtrate was concentrated under water-pump vacuum. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 1-methyl-6-phenoxy-1H-indazol-5-amine (0.200 g, 0.84 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 0.8 Hz, 1H), 7.37 - 7.35 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 7.07 (s, 1H), 7.00 (d, J = 0.8 Hz, 1H), 6.98 (d, J = 7.6 Hz, 2H), 4.69 (s, 2H), 3.85 (s, 3H); MS (ESI) m / z: 240.1 [M+1] +

[0250] 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-phenoxy-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of 1-methyl-6-phenoxy-1H-indazol-5-amine (0.120 g, 0.50 mmol) in 1,4-dioxane (5 mL) was added 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.205 g, 0.61 mmol), XPhos-Pd-G2 (0.040 g, 0.05 mmol), and potassium carbonate (0.208 g, 1.51 mmol). The resulting mixture was stirred under nitrogen at 110 °C for 12 hours. The mixture was diluted with dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give the crude product (0.100 g). The crude product was dissolved in N,N-dimethylformamide (2 mL) and filtered. The mixture was purified by preparative HPLC (ACN / water) to give 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-phenoxy-1H-indazol-5-yl)amino)isoindoline-1,3-dione (44.6 mg, 0.090 mmol, 17% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.94 (s, 1H), 7.60 (dd, J = 7.2 Hz, 8.4 Hz, 1H), 7.35 - 7.31 (m, 3H), 7.29 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.98 - 6.96 (m, 2H), 5.08 (dd, J = 5.2 Hz, 12.8 Hz, 1H), 3.97 (s, 3H), 2.88 - 2.85 (m, 1H), 2.62 - 2.57 (m, 1H), 2.47 - 2.46 (m, 1H), 2.05 - 2.02 (m, 1H); MS (ESI) m / z: 496.2 [M+1] +

[0251] Example 2: 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione

change

[0252] 6-(4-フルオロフェノキシ)-1-メチル-5-ニトロ-1H-インダゾール

change

[0253] 6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-amine [ka] To a solution of 6-(4-fluorophenoxy)-1-methyl-5-nitro-1H-indazole (0.150 g, 0.52 mmol) in acetic acid (1 mL) and water (1 mL) was added iron (0.117 g, 2.09 mmol). The mixture was stirred at 40° C. for 12 hours. The mixture was filtered and concentrated. The residue was purified by silica gel preparative TLC (petroleum ether:ethyl acetate) to give 6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-amine (0.080 g, 0.31 mmol, 59% yield). 1 H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.06 (m, 7.08-7.05, 5H), 6.70 (s, 1H), 3.90 (s, 3H);MS (ESI) m / z: 258.1 [M+1] +

[0254] 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.060 g, 0.18 mmol) and 6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-amine (0.046 g, 0.18 mmol) in 1,4-dioxane (1 mL) was added potassium carbonate (0.074 g, 0.53 mmol) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.014 g, 0.02 mmol). The mixture was stirred at 110° C. for 12 hours under nitrogen. The mixture was filtered and concentrated. The residue was purified by preparative HPLC. The organic solvent was removed and the separated liquid phase was lyophilized to give 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.050 g, 0.10 mmol, 54% yield). The crude residue was dissolved in dichloromethane (5 mL) and purified by preparative TLC (petroleum ether:ethyl acetate). The mixture was filtered and concentrated. The solid was dissolved in acetonitrile (10 mL) and water (15 mL). The separated liquid phase was lyophilized to give 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione (28 mg, 0.054 mmol, 55% yield) and 2-(2,6-dioxopiperidin-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione (2.4 mg, 0.004 mmol, 4% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.20 (s, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.91 (s, 1H), 7.58 (dd, J = 7.6 Hz, 8.8 Hz, 1H), 7.27 - 7.23 (m, 2H), 7.20 - 7.14 (m, 3H), 7.03 - 7.00 (m, 2H), 5.11 - 5.06 (m, 1H), 3.96 (s, 3H), 2.93 - 2.84 (m, 1H), 2.61 - 2.54 (m, 2H), 2.07 - 1.99 (m, 1H); MS (ESI) m / z: 514.2 [M+1] +

[0255] Example 3: 2-(2,6-dioxopiperidin-3-yl)-4-((6-methoxy-4-phenylpyridin-3-yl)amino)isoindoline-1,3-dione [ka]

[0256] 2-chloro-5-nitro-4-phenylpyridine [ka] To a deoxygenated solution of 2,4-dichloro-5-nitropyridine (0.40 g, 2.07 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added phenylboronic acid (0.252 g, 2.07 mmol), potassium carbonate (0.858 g, 6.22 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.169 g, 0.2100 mmol). The resulting mixture was heated at 60 °C under nitrogen for 18 hours. The mixture was cooled and partitioned with water (50 mL) and ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to give 2-chloro-5-nitro-4-phenylpyridine (350 mg, 1.49 mmol, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.53 - 7.51 (m, 3H), 7.47 (s, 1H), 7.37 - 7.35 (m, 2H); MS (ESI) m / z: 235.4 [M+1] +

[0257] 2-Methoxy-5-nitro-4-phenylpyridine [ka] To a solution of 2-chloro-5-nitro-4-phenylpyridine (0.20 g, 0.8500 mmol) in methanol (10 mL) was added sodium methoxide (0.13 g, 2.56 mmol). The solution was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (8:1 to 4:1 petroleum ether:ethyl acetate) to give 2-methoxy-5-nitro-4-phenylpyridine (150 mg, 0.651 mmol, 76% yield). 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.80 - 7.45 (m, 3H), 7.32 - 7.31 (m, 2H), 6.74 (s, 1H), 4.06 (s, 3H); MS (ESI) m / z: 231.0 [M+1] +

[0258] 6-Methoxy-4-phenylpyridin-3-amine [ka] To a solution of 2-methoxy-5-nitro-4-phenylpyridine (0.150 g, 0.6500 mmol) in methanol (10 mL) was added wet palladium active carbonate (0.03 g). The suspension was degassed with nitrogen. The solution was stirred at 25 °C under hydrogen (15 psi) for 12 h. The suspension was filtered and the filtrate was concentrated to give 6-methoxy-4-phenylpyridin-3-amine (130 mg, 0.64 mmol, 99% yield). MS (ESI) m / z: 269.5 [M+1] +

[0259] 2-(2,6-dioxopiperidin-3-yl)-4-((6-methoxy-4-phenylpyridin-3-yl)amino)isoindoline-1,3-dione [ka] To a solution of 6-methoxy-4-phenylpyridin-3-amine (0.10 g, 0.50 mmol) and 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.168 g, 0.500 mmol) in 1,4-dioxane (5 mL), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.019 g, 0.020 mmol) and potassium carbonate (0.206 g, 1.500 mmol) were added under nitrogen. The suspension was degassed under vacuum and purged with nitrogen several times. The reaction mixture was stirred at 110 °C for 12 h. The suspension was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC. The resulting solution was then lyophilized and the crude product was purified by preparative TLC to give 2-(2,6-dioxo-3-piperidyl)-4-[(6-methoxy-4-phenyl-3-pyridyl)amino]isoindoline-1,3-dione (150 mg, 0.330 mmol, 66% yield). 1H NMR (400 MHz,DMSO-d6) δ 11.10 (s, 1 H), 8.23 ​​(s, 1 H), 8.19 (s, 1 H), 7.53 -7.52 (m, 1 H), 7.51 - 7.34(m, 4 H), 7.04 (d, J = 6.8 Hz, 1 H), 6.91 (s, 1 H), 6.67 (d, J = 6.8 Hz, 1 H), 5.08 - 5.04 (m, 1 H), 3.93 (s, 3 H), 2.91 - 2.90 (m, 1 H), 2.60 - 2.58 (m, 2 H), 2.08 - 2.04 (m, 1 H); MS (ESI) m / z: 457.2 [M+1] +

[0260] Example 4: 2-(2,6-dioxopiperidin-3-yl)-4-((6-methyl-4-phenoxypyridin-3-yl)amino)isoindoline-1,3-dione [ka]

[0261] 5-Bromo-2-methyl-4-phenoxypyridine [ka] To a solution of phenol (0.040 g, 0.43 mmol) in N-methylpyrrolidone (1.5 mL) were added cesium carbonate (0.345 g, 1.06 mmol) and 5-bromo-4-chloro-2-methylpyridine (0.105 g, 0.51 mmol). The mixture was stirred at 90 °C for 4 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (12 mL × 3). The combined organic layer was washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel preparative TLC (petroleum ether:ethyl acetate) to give 5-bromo-2-methyl-4-phenoxypyridine (0.080 g, 0.30 mmol, 71% yield). 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.52 - 7.48 (m, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 6.53 (s, 1H), 2.53 (s, 3H); MS (ESI) m / z: 264.0 [M+1] +

[0262] 2-(2,6-dioxo-3-piperidyl)-4-[(6-methyl-4-phenoxy-3-pyridyl)amino]isoindoline-1,3-dione [ka] To a solution of 5-bromo-2-methyl-4-phenoxypyridine (0.060 g, 0.23 mmol) and 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.062 g, 0.23 mmol) in 1,4-dioxane (1 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.018 g, 0.02 mmol) and potassium carbonate (0.031 g, 0.23 mmol). The mixture was stirred at 110 °C for 12 hours under nitrogen. The mixture was filtered and concentrated. The residue was purified by silica gel preparative TLC (petroleum ether:ethyl acetate) to give 2-(2,6-dioxo-3-piperidyl)-4-[(6-methyl-4-phenoxy-3-pyridyl)amino]isoindoline-1,3-dione (29 mg, 0.06 mmol, 27% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.78 (s, 1H), 8.73 (s, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.40 - 7.36 (m, 3H), 7.27 (d, J = 8.4 Hz, 2H), 6.98 (s, 1H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.62 - 2.56 (m, 2H), 2.55 (s, 3H), 2.07 - 2.03 (m, 1H); MS (ESI) m / z: 456.9 [M+1] +

[0263] Example 5: 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0264] 2-((4-chloro-5-nitropyridin-2-yl)oxy)-N,N-dimethylethanamine [ka] To a solution of 4-chloro-5-nitropyridin-2-ol (1.50 g, 8.59 mmol) in tetrahydrofuran (30 mL) was added 2-chloro-N,N-dimethylethanamine hydrochloride (1.857 g, 12.89 mmol) and silver carbonate (7.11 g, 25.78 mmol). The mixture was stirred at 15 °C for 12 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and dichloromethane (50 mL), and the mixture was filtered. The organic layer of the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((4-chloro-5-nitropyridin-2-yl)oxy)-N,N-dimethylethanamine (0.10 g, 0.41 mmol, 5% yield). 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 6.67 (s, 1H), 4.09 - 4.02 (m, 2H), 2.69 - 2.60 (m, 2H), 2.29 (s, 6H); MS (ESI) m / z 246.1 [M+1] +

[0265] N,N-Dimethyl-2-((5-nitro-4-phenoxypyridin-2-yl)oxy)ethanamine [ka] To a solution of 2-((4-chloro-5-nitropyridin-2-yl)oxy)-N,N-dimethylethanamine (0.090 g, 0.37 mmol) in N,N-dimethylformamide (1 mL) was added dropwise a solution of phenoxysodium (0.064 g, 0.55 mmol) in N,N-dimethylformamide (1 mL) at 0 °C. The mixture was stirred at 15 °C for 2 h. The mixture was filtered, and the filtrate was purified by preparative HPLC. The mixture was evaporated to remove the organic phase, and the aqueous phase was lyophilized to give N,N-dimethyl-2-[(5-nitro-4-phenoxy-2-pyridyl)oxy]ethanamine (0.013 g, 0.04 mmol, 12% yield). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.50 - 7.45 (m, 2H), 7.36 - 7.31 (m, 1H), 7.17 - 7.13 (m, 2H), 6.11 (s, 1H), 4.72 - 4.34 (m, 2H), 3.10 - 2.59 (m, 2H), 2.57 - 2.18 (m, 6H); MS (ESI) m / z 304.1[M+1] +

[0266] 6-(2-(dimethylamino)ethoxy)-4-phenoxypyridin-3-amine [ka] To a solution of N,N-dimethyl-2-[(5-nitro-4-phenoxy-2-pyridyl)oxy]ethanamine (0.013 g, 0.04 mmol) in methanol (5 mL) was added palladium-activated carbon catalyst (0.010 g, 0.05 mmol) under nitrogen. The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 15 °C for 12 h under hydrogen (15 Psi). The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without purification. 6-[2-(dimethylamino)ethoxy]-4-phenoxypyridin-3-amine (0.01 g, 0.04 mmol, 85% yield). MS (ESI) m / z 274.1 [M+1] +

[0267] 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of 6-[2-(dimethylamino)ethoxy]-4-phenoxypyridin-3-amine (0.010 g, 0.04 mmol) in 1,4-dioxane (3 mL), 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (15 mg g, 0.04 mmol), potassium carbonate (15 mg, 0.11 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (3 mg) were added. The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 110 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3.41 mg, 0.006 mmol, 17% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.08 - 9.87 (m, 1H), 8.23 ​​(s, 2H), 7.61 (dd, J = 7.4, 8.4 Hz, 1H), 7.52 - 7.44 (m, 2H), 7.33 - 7.27 (m, 1H), 7.24 - 7.19 (m, 1H), 7.19 - 7.13 (m, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.04 (s, 1H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.61 - 4.50 (m, 2H), 3.48 - 3.44 (m, 2H), 2.95 - 2.86 (m, 1H), 2.79 (s, 6H), 2.64 - 2.57 (m, 2H), 2.09 - 2.01 (m, 1H); MS (ESI) m / z 530.3 [M+1] +

[0268] Example 6: 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0269] 6-Fluoro-5-nitro-1H-indazole [ka] To a solution of 6-fluoro-1H-indazole (10.000 g, 73.50 mmol) in concentrated sulfuric acid (220 mL) was added potassium nitrate (7.4 g, 7.35 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 12 h. The mixture was added dropwise to ice water (1000 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This was purified by silica gel column chromatography (40-50% ethyl acetate in petroleum ether) to give 6-fluoro-5-nitro-1H-indazole (3.0 g, 16.56 mmol, 22% yield). NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 7.2 Hz, 1H), 8.38 (s, 1H), 7.68 (d, J = 12.0 Hz, 1H)

[0270] 6-Fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ka] To a solution of 6-fluoro-5-nitro-1H-indazole (3.00 g, 16.56 mmol) in N,N-dimethylformamide (30 mL) was added sodium hydride (6.34 g, 26.50 mmol) at 0 °C, and the mixture was stirred for 0.5 h. Subsequently, (2-(chloromethoxy)ethyl)trimethylsilane (4.3 mL, 24.29 mmol) was added to the mixture. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography (20-25% ethyl acetate in petroleum ether) to give 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.00 g, 3.21 mmol, 14% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 7.2 Hz, 1H), 8.45 (s, 1H), 8.04 (d, J = 12.0 Hz, 1H), 5.80 (s, 2H), 3.55 (t, J = 8.0 Hz, 2H), 3.32 (s, 3H), 0.05 (s, 2H), 0.09 (s, 1H), 0.10 (s, 6H)

[0271] 6-(3-fluorophenoxy)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole [ka] To a solution of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.00 g, 3.20 mmol) in N,N-dimethylformamide (10 mL) was added 3-fluorophenol (0.432 g, 0.39 mmol) and potassium carbonate (0.668 g, 0.48 mmol). The resulting mixture was stirred at 110° C. for 12 hours. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography (20-25% ethyl acetate in petroleum ether) to give 6-(3-fluorophenoxy)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.70 g, 1.73 mmol, 54% yield). 1 HNMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.75 (s, 1H), 8.43 (s, 1H), 7.73 (s, 1H), 7.43 (d, J = 1.6, 6.8 Hz, 1H), 7.17 (s, 1H), 7.01 - 6.95 (m, 1H), 6.93 (m, 1H), 6.88 (t, J = 2.0 Hz, 1H), 6.55 (m, 2H), 5.76 (s, 2H), 3.51 (t, J = 8.0, 2H ), 0.14 (s, 9H)

[0272] 6-(3-fluorophenoxy)-5-nitro-1H-indazole [ka] To a solution of 6-(3-fluorophenoxy)-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.700 g, 1.70 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL, 0.10 mmol), and the mixture was stirred at 25 °C for 12 h. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to give 6-(3-fluorophenoxy)-5-nitro-1H-indazole (0.50 g, 1.83 mmol, 61% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.68 (s, 1H), 7.33 (s, 1H), 7.02 - 6.99 (m, 2H), 6.98 - 6.88 (m, 2H)

[0273] 6-(3-fluorophenoxy)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To a solution of 6-(3-fluorophenoxy)-5-nitro-1H-indazole (0.10 g, 0.37 mmol) in dimethylformamide (2 mL) was added 4-iodotetrahydro-2H-pyran (0.093 g, 0.44 mmol) and potassium carbonate (0.151 g, 1.10 mmol). The mixture was stirred at 110 °C for 12 hours. The mixture was filtered. The filtrate was purified by preparative HPLC to give 6-(3-fluorophenoxy)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.02 g, 0.042 mmol, 11% yield). MS (ESI) m / z: 538.2 [M+1]+

[0274] 6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine [ka] To a solution of 6-(3-fluorophenoxy)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.015 g, 0.04 mmol) in ethanol (1.5 mL) and water (0.50 mL) was added iron powder (0.007 g, 0.13 mmol) and ammonium chloride (0.022 g, 0.42 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine (0.008 g, 0.024 mmol, 58% yield). MS (ESI) m / z: 328.1 [M+1] +

[0275] 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of 6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine (0.008 g, 0.03 mmol) in 1,4-dioxane (2 mL), 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.018 g, 0.05 mmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.036 g, 0.01 mmol), and potassium carbonate (0.006 g, 0.05 mmol) were added. The mixture was stirred at 110° C. for 12 hours under nitrogen. The solution was filtered, concentrated, and purified by preparative HPLC to give 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (7.82 mg, 0.013 mmol, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.12-11.04 (m, 1H), 8.11 (d, J = 7.2 Hz, 2H), 7.95 (s, 1H), 7.67 (s, 1H), 7.56-7.32 (m, 1H), 7.30 (m, 1H), 7.24-7.22 (m, 2H), 7.19 - 7.17 (m, 1H), 6.78-6.74 (m, 2H), 5.07 (dd, J = 4.8, 12.4, 1H), 4.86 (s, 1H), 4.00 - 3.96 (m, 2H), 3.53 (t, J = 12.8 Hz, 2H), 2.61 (m, 1H), 2.60 (m, 2H), 2.12 - 2.04 (m, 2H), 1.90 - 1.86 (m, 2H), 1.24 (s, 1H); MS (ESI) m / z: 584.2 [M+1] +

[0276] Example 7: 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0277] 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole [ka] To a solution of 6-bromo-1-methyl-5-nitro-1H-indazole (0.300 g, 1.17 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.282 g, 1.29 mmol) in 1,4-dioxane (3 mL) was added cesium carbonate (1.14 g, 3.51 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) (0.096 g, 0.120 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole (0.250 mg, 0.931 mmol, 79% yield). 1 H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 5.6 Hz, 1H), 8.67 (s, 1H), 8.23 ​​(s, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.46 (s, 1H), 7.19 (s, 1H), 4.12 (s, 3H), 2.83 (s, 3H); MS (ESI) m / z: 268.8[M-100] +

[0278] 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine [ka] To a solution of 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole (0.250 g, 0.930 mmol) in ethanol (3 mL) and water (1 mL) was added ammonium chloride (0.503 g, 9.32 mmol) and iron(II) powder (0.520 g, 9.32 mmol). The resulting mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate) to give 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (0.145 g, 0.638 mmol, 96% yield). MS (ESI) m / z: 239.1 [M+1] +

[0279] 2-(2,6-Dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione. [ka] To a solution of 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (0.070 g, 0.290 mmol) and 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.099 g, 0.290 mmol) in 1,4-dioxane (2 mL), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.024 g, 0.030 mmol) and potassium carbonate (0.122 g, 0.880 mmol) were added. The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure using a water pump. The residue was purified by preparative HPLC to give 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (93 mg, 0.188 mmol, 64% yield).1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.73 (d, J = 6.4 Hz, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.40 (dd, J = 7.2, 8.4 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 4.16 (s, 3H), 2.91 - 2.88 (m, 1H), 2.67 (s, 3H), 2.58 (d, J = 12.8 Hz, 2H), 2.08 - 2.05 (m, 1H); MS (ESI) m / z: 495.1 [M+1] +

[0280] Example 8: 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-4-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0281] 5-Fluoro-4-nitro-1H-indazole [ka] A solution of 5-fluoro-1H-indazole (10 g, 73.46 mmol) in concentrated sulfuric acid (200 mL, 73.46 mmol) was cooled to 0° C. Fuming nitric acid (10.00 mL, 224.29 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 hour. The reaction mixture was poured onto ice water (1000 mL) and the precipitate was collected by filtration, washed with water (300 mL) and dried under reduced pressure to give crude 5-fluoro-4-nitro-1H-indazole (8 g, yield: 60%). 1H NMR (400 MHz, DMSO-d6) δ 11.29 - 11.20 (m, 1H), 8.33 (d, J = 0.8 Hz, 1H), 7.95 (dd, J = 0.8, 8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H)

[0282] 2-[(5-fluoro-4-nitro-indazol-1-yl)methoxy]ethyltrimethylsilane [ka] To a solution of 5-fluoro-4-nitro-1H-indazole (8.0 g, 44.1 mmol) in dimethylformamide (80 mL) was added sodium hydride (1.9 g, 48.59 mmol) at 0° C. and stirred for 0.5 hours. (2-(chloromethoxy)ethyl)trimethylsilane (8.8 g, 53.0 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with lithium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the product 2-[(5-fluoro-4-nitroindazol-1-yl)methoxy]ethyltrimethylsilane (3.0 g, yield: 21%). 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 9.2 Hz, 1H), 5.46 (s, 2H), 3.55 - 3.49 (m, 2H), 0.82 - 0.79 (m, 2H), -0.12 (s, 9H)

[0283] 2-[[5-(2-chlorophenoxy)-4-nitroindazol-1-yl]methoxy]ethyltrimethylsilane [ka] To a solution of 2-chlorophenol (0.136 g, 1.06 mmol) in dimethylformamide (4 mL) was added cesium carbonate (0.626 g, 1.93 mmol) and 2-[(5-fluoro-4-nitroindazol-1-yl)methoxy]ethyltrimethylsilane (0.300 g, 0.96 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate (20 mL x 2). The combined organic layers were washed with lithium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (ethyl acetate) to give the product 2-[[5-(2-chlorophenoxy)-4-nitroindazol-1-yl]methoxy]ethyltrimethylsilane (0.370 g, yield: 91%). MS (ESI) m / z: 421.2[M+1] +

[0284] 5-(2-chlorophenoxy)-4-nitro-1H-indazole [ka] To a solution of 2-[[5-(2-chlorophenoxy)-4-nitroindazol-1-yl]methoxy]ethyltrimethylsilane (0.370 g, 0.88 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL, 26.12 mmol). The mixture was stirred at 25 °C for 3 hours. The mixture was evaporated, and the resulting residue was purified by preparative TLC (ethyl acetate) to give 5-(2-chlorophenoxy)-4-nitro-1H-indazole (0.110 g, yield: 43%). 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.81 - 7.78 (m, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.30 - 7.29 (m, 1H), 7.19 - 7.17 (m, 1H), 7.12 - 7.11 (m, 1H), 6.99 - 6.97 (m, 1H); MS (ESI) m / z: 290.2 [M+1] +

[0285] 5-(2-chlorophenoxy)-4-nitro-1-tetrahydropyran-4-yl-indazole [ka] To a solution of 5-(2-chlorophenoxy)-4-nitro-1H-indazole (0.050 g, 0.17 mmol) and 4-iodotetrahydropyran (0.044 g, 0.21 mmol) in dimethylformamide (1 mL) was added potassium carbonate (0.048 g, 0.35 mmol). The mixture was stirred at 85 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure using a water pump to obtain a residue. The residue was purified by preparative HPLC to obtain the product, 5-(2-chlorophenoxy)-4-nitro-1-tetrahydropyran-4-yl-indazole (0.010 g, yield: 15%). 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.51 (dd, J = 1.6, 8.0 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.16 - 7.12 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 1.2, 8.0 Hz, 1H), 4.71 - 4.63 (m, 1H), 4.23 - 4.19 (m, 2H), 3.67 - 3.61 (m, 2H), 2.50 - 2.39 (m, 2H), 2.04 - 2.00 (m, 2H); MS (ESI) m / z: 374.1 [M+1] +

[0286] 5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-amine [ka] To a solution of 5-(2-chlorophenoxy)-4-nitro-1-tetrahydropyran-4-yl-indazole (0.023 g, 0.06 mmol) in ethanol (1 mL) and water (0.30 mL) was added ammonia hydrochloride (0.033 g, 0.62 mmol) and iron powder (0.017 g, 0.31 mmol). The mixture was stirred at 80° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (100% ethyl acetate) to give the product 5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-amine (0.013 g, yield: 61%). 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.45 (dd, J = 1.6, 8.0 Hz, 1H), 7.13 - 7.08 (m, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.99 - 6.95 (m, 1H), 6.82 (d, J = 9.2 Hz, 1H), 6.74 (dd, J = 1.2, 8.4 Hz, 1H), 4.62 - 4.54 (m, 1H), 4.20 - 4.16 (m, 2H), 3.65 - 3.59 (m, 2H), 2.46 -2.35(m, 2H), 2.03 - 1.99 (m, 2H); MS (ESI) m / z: 344.1 [M+1] +

[0287] Dimethyl 3-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-yl]amino]benzene-1,2-dicarboxylate [ka] To a solution of 5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-amine (0.013 g, 0.04 mmol) and dimethyl 3-bromobenzene-1,2-dicarboxylate (0.011 g, 0.04 mmol) in 1,4-dioxane (1 mL) was added potassium carbonate (0.016 g, 0.11 mmol) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.003 g) under nitrogen. The suspension was degassed under vacuum and purged with nitrogen several times. The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (ethyl acetate) to give the product dimethyl 3-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-yl]amino]benzene-1,2-dicarboxylate (0.020 g, 98%). MS (ESI) m / z: 536.1 [M+1] +

[0288] 4-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ka] To a solution of dimethyl 3-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-yl]amino]benzene-1,2-dicarboxylate (0.020 g, 0.04 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.007 g, 0.04 mmol) in pyridine (1 mL) was added lithium iodide (0.01 mL, 0.11 mmol). The suspension was degassed under vacuum and purged with nitrogen several times. The reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give the product 4-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazol-4-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (10 mg, 40%). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.29 (s, 1H), 7.97 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.44 (dd, J = 1.6, 8.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.20 - 7.15 (m, 2H), 7.05 - 6.97 (m, 2H), 6.83 (dd, J = 1.2, 8.4 Hz, 1H), 5.10 - 5.06 (m, 1H), 4.99 - 4.91 (m, 1H), 4.04 - 3.97 (m, 2H), 3.61 - 3.55 (m, 2H), 2.93 - 2.83 (m, 1H), 2.62 - 2.54 (m, 2H), 2.18 - 2.12 (m, 2H), 2.04 - 2.00 (m, 1H), 1.96 - 1.92 (m, 2H); MS (ESI) m / z: 600.2 [M+1] +

[0289] Example 9: 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0290] 6-Bromo-1-methyl-5-nitro-1H-indazole [ka] A 250 mL three-neck flask was charged with 4-bromo-2-fluoro-5-nitrobenzaldehyde (15 g, 60.48 mmol), potassium carbonate (12.6 g, 91.3 mmol), isopropyl alcohol (120 mL), and water (60 mL). The mixture was stirred at 41 °C for 1 hour. Methylhydrazine (10.5 g, 91.17 mmol) was then added dropwise. The resulting mixture was stirred at 77 °C for 6 hours. The mixture was cooled to 20 °C, and water (240 mL) was added. The mixture was stirred for 1 hour and filtered. The separated solid was rinsed with water (20 mL × 3) and filtered. The solid was dried under reduced pressure to give 6-bromo-1-methyl-5-nitro-1H-indazole (7.0 g, 27.3 mmol, 45% yield). 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 4.04 (s, 3H)

[0291] 6-(3-fluoro-4-methoxyphenyl)-1-methyl-5-nitro-1H-indazole [ka] To a solution of 6-bromo-1-methyl-5-nitro-1H-indazole (0.300 g, 1.17 mmol) and (3-fluoro-4-methoxyphenyl)boronic acid (0.209 g, 1.23 mmol) in dioxane (3 mL) was added cesium carbonate (1.146 g, 3.52 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct (0.096 g, 0.120 mmol). The resulting mixture was stirred at 110 °C for 12 h under nitrogen. The reaction was filtered, and the filtrate was concentrated under water-pump vacuum. The residue was purified by preparative HPLC to give 6-(3-fluoro-4-methoxyphenyl)-1-methyl-5-nitro-1H-indazole (0.100 g, 0.332 mmol, 28% yield). 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.10 (s, 1H), 7.25 (s, 1H), 7.07 (dd, J = 2.0, 11.6 Hz, 1H), 7.01 - 6.92 (m, 2H), 4.06 (s, 3H), 3.88 (s, 3H); MS (ESI) m / z: 301.8[M+1] +

[0292] 6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-amine [ka] To a solution of 6-(3-fluoro-4-methoxyphenyl)-1-methyl-5-nitro-1H-indazole (0.080 g, 0.270 mmol) in ethanol (0.6 mL) and water (0.2 mL) was added ammonium chloride (0.143 g, 2.66 mmol) and iron(II) powder (0.148 g, 2.66 mmol). The resulting mixture was stirred at 70° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-amine (0.070 g, 0.258 mmol, 97% yield). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 0.8 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.18 - 7.15 (m, 1H), 7.06 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H); MS (ESI) m / z: 272.4[M+1] +

[0293] 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of 6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-amine (0.070 g, 0.260 mmol) and 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.091 g, 0.270 mmol) in dioxane (2 mL) was added potassium carbonate (0.107 mg, 0.770 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.020 g, 0.030 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and preparative TLC (petroleum ether:ethyl acetate 1:1) to give 2-(2,6-dioxopiperidin-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazol-5-yl)amino)isoindoline-1,3-dione (53 mg, 0.098 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.46 (dd, J = 2.4, 4.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.23 - 7.18 (m, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.14 (dd, J = 5.2, 12.8 Hz, 1H), 4.16 (s, 3H), 3.87 (s, MS (ESI) m / z: 528.1 [M+1] +

[0294] Example 10: 2-(2,6-dioxopiperidin-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazol-4-yl)amino)isoindoline-1,3-dione [ka]

[0295] 5-(2-fluoro-6-methylphenoxy)-1-methyl-4-nitro-1H-indazole [ka] To a solution of 2-fluoro-6-methylphenol (0.1 g, 0.79 mmol) in N,N-dimethylformamide (3 mL) were added 5-fluoro-1-methyl-4-nitroindazole (0.154 g, 0.79 mmol) and cesium carbonate (0.515 g, 1.59 mmol), and the mixture was stirred at 90 °C for 12 hours. The mixture was diluted with water and extracted with ethyl acetate (10 mL × 3). The separated organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The organic layer was filtered, and the filtrate was concentrated to give crude 5-(2-fluoro-6-methylphenoxy)-1-methyl-4-nitroindazole (190 mg, 0.630 mmol, 79% yield). MS (ESI) m / z: 301.8 [M+1] +

[0296] 5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazol-4-amine [ka] To a solution of 5-(2-fluoro-6-methylphenoxy)-1-methyl-4-nitroindazole (0.19 g, 0.63 mmol) in ethanol (3 mL) and water (1 mL) was added iron (0.176 g, 3.15 mmol) and ammonium chloride (0.34 g, 6.31 mmol), and the mixture was stirred at 80 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (40% ethyl acetate in petroleum ether) to give 5-(2-fluoro-6-methylphenoxy)-1-methylindazol-4-amine (50 mg, 0.184 mmol, 29% yield).

[0297] 2-(2,6-dioxopiperidin-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazol-4-yl)amino)isoindoline-1,3-dione [ka] To a solution of 5-(2-fluoro-6-methylphenoxy)-1-methylindazol-4-amine (0.05 g, 0.18 mmol) in 1,4-dioxane (3 mL) was added 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.062 g, 0.18 mmol), potassium carbonate (0.05 g, 0.37 mmol), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.014 g, 0.02 mmol), and the mixture was stirred under nitrogen at 110° C. for 12 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 2-(2,6-dioxo-3-piperidyl)-4-[[5-(2-fluoro-6-methylphenoxy)-1-methylindazol-4-yl]amino]isoindoline-1,3-dione (13 mg, 0.025 mmol, 13% yield) and 2-(2,6-dioxo-3-piperidyl)-4-[[5-(2-fluoro-6-methylphenoxy)-1-methylindazol-4-yl]amino]isoindoline-1,3-dione (3 mg, 0.005 mmol, 3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.38 (s, 1H), 7.83 (s, 1H), 7.60 - 7.46 (m, 2H), 7.30 - 7.27 (m, 1H), 7.15 - 7.13 (m, 3H), 6.96 - 6.86 (m, 2H), 5.16 - 5.11 (m, 1H), 4.05 (s, 3H), 2.90 - 2.80 (m, 1H), 2.63 - 2.58 (m, 2H), 2.18 (s, 3H), 2.08 - 2.00 (m, 1H); MS (ESI) m / z: 528.2 [M+1] +

[0298] Example 11: 2-(2,6-dioxopiperidin-3-yl)-4-((4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0299] 5-Bromo-4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To a solution of 5-bromo-4-methyl-1H-indazole (0.2 g, 0.95 mmol) in N,N-dimethylformamide (5 mL) were added cesium carbonate (0.924 g, 2.84 mmol) and 4-iodotetrahydropyran (0.6 g, 2.84 mmol), and the mixture was stirred at 135°C for 24 hours. The mixture was diluted with 20 ml of water and extracted with ethyl acetate (20 ml x 3). The combined organic layer was washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel preparative TLC (50% ethyl acetate in petroleum ether) to give 5-bromo-4-methyl-1-tetrahydropyran-4-yl-indazole (100 mg, 0.338 mmol, 35% yield). 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.44 - 7.37 (m, 2H), 4.68 - 4.64 (m, 1H), 4.19 - 4.16 (m, 2H), 3.64 - 3.58 (m, 2H), 2.57 (s, 3H), 2.27 - 2.23 (m, 4H); MS (ESI) m / z: 295.1 [M+1] +

[0300] 2-(2,6-dioxopiperidin-3-yl)-4-((4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of 5-bromo-4-methyl-1-tetrahydropyran-4-yl-indazole (0.1 g, 0.34 mmol) in 1,4-dioxane (3 mL) was added 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.101 g, 0.37 mmol), potassium carbonate (0.09 g, 0.68 mmol), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.026 g, 0.03 mmol). The mixture was stirred under nitrogen at 110° C. for 12 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 2-(2,6-dioxo-3-piperidyl)-4-[(4-methyl-1-tetrahydropyran-4-yl-indazol-5-yl)amino]isoindoline-1,3-dione (65 mg, 0.134 mmol, 39% yield) and 2-(2,6-dioxo-3-piperidyl)-4-[(4-methyl-1-tetrahydropyran-4-yl-indazol-5-yl)amino]isoindoline-1,3-dione (3 mg, 0.006 mmol, 2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.20 - 8.19 (m, 2H), 7.66 - 7.64 (m, 1H), 7.50 - 7.46 (m, 1H), 7.30 - 7.28 (m, 1H), 7.14 - 7.12 (m, 1H), 6.64 - 6.62 (m, 1H), 5.15 - 5.10 (m, 1H), 4.92 - 4.88 (m, 1H), 4.04 - 4.00 (m, 2H), 3.60 - 3.55 (m, 2H), 2.90 - 2.85 (m, 1H), 2.60 - 2.55 (m, MS (ESI) m / z: 488.3 [M+1] +

[0301] Example 12: 2-(2,6-dioxopiperidin-3-yl)-4-((6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0302] 5-Bromo-6-methoxy-1-tetrahydropyran-4-yl-indazole TIFF2025537152000131.tif4247 To a solution of 5-bromo-6-methoxy-1H-indazole (0.3 g, 1.32 mmol) in dimethylformamide (4 mL) was added 4-iodotetrahydropyran (0.56 g, 2.64 mmol) and cesium carbonate (1.2 g, 3.96 mmol). The mixture was stirred at 135 °C for 24 hours. The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by preparative TLC (petroleum ether:ethyl acetate 3:1) to give 5-bromo-6-methoxy-1-tetrahydropyran-4-yl-indazole (60 mg, 0.192 mmol, 15% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.94 (s, 1H), 7.38 (s, 1H), 4.91 - 4.85 (m, 1H), 4.05 - 3.99 (m, 2H), 3.94 (s, 3H), 3.59 - 3.52 (m, 2H), 2.14 - 2.04 (m, 2H), 1.88 - 1.84 (m, 2H); MS (ESI) m / z: 313.3 [M+1] +

[0303] 2-(2,6-Dioxo-3-piperidyl)-4-[(6-methoxy-1-tetrahydropyran-4-yl-indazol-5-yl)amino]isoindoline-1,3-dione [ka] To a solution of 5-bromo-6-methoxy-1-tetrahydropyran-4-yl-indazole (0.06 g, 0.19 mmol) in 1,4-dioxane (2 mL), potassium carbonate (0.09 g, 0.57 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.02 g, 0.02 mmol), and 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.08 g, 0.29 mmol) were added. The mixture was stirred at 110°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-(2,6-dioxo-3-piperidyl)-4-[(6-methoxy-1-tetrahydropyran-4-yl-indazol-5-yl)amino]isoindoline-1,3-dione (52 mg, 0.103 mmol, 53% yield). 1 HNMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.3 (d, J = 8.4 Hz, 1H), 7.2 (d, J = 8 Hz, 1H), 5.15 - 5.10 (m, 1H), 4.92 - 4.87 (m, 1H), 4.04 - 4.01 (m, 2H), 3.94 (s, 3H), 3.61 - 3.55 (m, 2H), 2.95 - 2.86 (m, 1H), 2.66 - 2.55 (m, 2H), 2.18 - 2.05 (m, 3H), 1.90 - 1.87 (m, 2H); MS (ESI) m / z: 504.3 [M+1] +

[0304] Example 13: 2-(2,6-dioxo-3-piperidyl)-4-[[1-methyl-5-(2-methyl-4-pyridyl)indazol-6-yl]amino]isoindoline-1,3-dione [ka]

[0305] 5-Bromo-1-methyl-6-nitroindazole [ka] To a solution of 5-bromo-6-nitro-1H-indazole (2.0 g, 8.26 mmol) in DMF (20 mL) was added sodium hydride (0.363 g, 9.09 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hours. To the mixture was added iodomethane (1.17 g, 8.26 mmol). The mixture was stirred at 25° C. for 12 hours. The mixture was added to water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by semi-preparative reverse-phase HPLC to give 5-bromo-1-methyl-6-nitroindazole (1.20 g, 4.69 mmol, 57% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.56 (s, 1H), 8.32 (s, 1H), 8.21 (d, J = 0.8 Hz, 1H), 4.12 (s, 3H); MS (ESI) m / z: 256.1[M+1] +

[0306] 1-Methyl-5-(2-methyl-4-pyridyl)-6-nitroindazole [ka] To a solution of 5-bromo-1-methyl-6-nitroindazole (0.300 g, 1.17 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.385 g, 1.76 mmol), potassium carbonate (0.485 g, 3.51 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.096 g, 0.12 mmol). The mixture was stirred at 100°C under nitrogen for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in petroleum ether) to give 1-methyl-5-(2-methyl-4-pyridyl)-6-nitroindazole (0.290 g, 1.08 mmol, 92% yield). MS (ESI) m / z: 269.1 [M+1] +

[0307] 1-Methyl-5-(2-methyl-4-pyridyl)indazol-6-amine [ka] To a solution of 1-methyl-5-(2-methyl-4-pyridyl)-6-nitroindazole (0.290 g, 1.08 mmol) in ethanol (3 mL) and water (1.5 mL) was added iron powder (0.182 g, 3.24 mmol) and ammonium chloride (0.286 g, 5.41 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (100% ethyl acetate) to give 1-methyl-5-(2-methyl-4-pyridyl)indazol-6-amine (0.130 g, 0.54 mmol, 50% yield). 1HNMR (400MHz, DMSO-d6) δ 8.46 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.39 (s, 1H), 7.32 (s, 1H), 7.25 (d, J = 5.2 Hz, 1H), 6.70 (s, 1H), 5.09 (s, 2H), 3.85 (s, 3H), 2.50 (s, 3H); MS (ESI) m / z: 239.2[M+1] +

[0308] Dimethyl 3-[[1-methyl-5-(2-methyl-4-pyridyl)indazol-6-yl]amino]benzene-1,2-dicarboxylate [ka] To a solution of 1-methyl-5-(2-methyl-4-pyridyl)indazol-6-amine (0.120 g, 0.50 mmol) in 1,4-dioxane (2 mL) was added dimethyl 3-bromobenzene-1,2-dicarboxylate (0.165 g, 0.60 mmol), potassium carbonate (0.208 g, 1.51 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.043 g, 0.05 mmol). The mixture was stirred at 110 °C under nitrogen for 12 hours. The mixture was filtered and concentrated. The residue was purified by semi-preparative reverse-phase HPLC to give dimethyl 3-[[1-methyl-5-(2-methyl-4-pyridyl)indazol-6-yl]amino]benzene-1,2-dicarboxylate (0.200 g, 0.46 mmol, 92% yield). MS (ESI) m / z: 431.2 [M+1] +

[0309] 2-(2,6-Dioxo-3-piperidyl)-4-[[1-methyl-5-(2-methyl-4-pyridyl)indazol-6-yl]amino]isoindoline-1,3-dione [ka] To a solution of dimethyl 3-[[1-methyl-5-(2-methyl-4-pyridyl)indazol-6-yl]amino]benzene-1,2-dicarboxylate (0.100 g, 0.23 mmol) in pyridine (1 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (0.042 g, 0.26 mmol) and lithium iodide (0.091 g, 0.70 mmol). The mixture was stirred at 120 °C for 12 hours. The mixture was concentrated under reduced pressure. The resulting residue was purified by semi-preparative reverse-phase HPLC to give the product, 2-(2,6-dioxo-3-piperidyl)-4-[[1-methyl-5-(2-methyl-4-pyridyl)indazol-6-yl]amino]isoindoline-1,3-dione (52 mg, 0.104 mmol, 45% yield). 1 H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 8.41 - 8.35 (m, 2H), 8.12 (s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.52 - 7.45 (m, 1H), 7.39 (s, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.17 - 7.09 (m, 2H), 5.10 - 5.03 (m, 1H), 4.06 (s, 3H), 2.90 - 2.82 (m, 1H), 2.61 - 2.57 (m, 2H), 2.43 (s, 3H), 2.07 - 1.99 (m, 1H); MS (ESI) m / z: 495.1[M+1] +

[0310] Example 14: 2-(2,6-dioxopiperidin-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)isoindoline-1,3-dione [ka]

[0311] 5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-nitro-1H-benzo[d]imidazole [ka] To a solution of 5-bromo-1-methyl-6-nitro-1H-benzo[d]imidazole (0.060 g, 0.23 mmol) and (3-fluoro-4-methoxyphenyl)boronic acid (0.048 g, 0.28 mmol) in dioxane (0.5000 mL) was added potassium carbonate (0.096 g, 0.70 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) (0.018 g, 0.03 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 1:2) to give 5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-nitro-1H-benzo[d]imidazole (0.054 g, 0.18 mmol, 76% yield). MS (ESI) m / z: 302.1 [M+1] +

[0312] 5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-amine [ka] To a solution of 5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-nitro-1H-benzo[d]imidazole (0.050 g, 0.17 mmol) in ethanol (0.3 mL) and water (0.1 mL) was added iron(II) powder (0.050 g, 0.90 mmol) and ammonium chloride (0.090 g, 1.67 mmol). The resulting mixture was stirred at 70 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-amine (0.051 g, 0.188 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1 H), 7.19 (s, 1 H), 7.14 - 7.01 (m, 3 H), 6.74 (s, 1 H), 5.00 - 5.52 (m, 2 H), 3.92 (s, 3 H), 3.89 (s, 3H); MS (ESI) m / z: 272.1[M+1] +

[0313] Dimethyl 3-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)phthalate [ka] To a solution of 5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-amine (0.041 g, 0.15 mmol) and dimethyl 3-bromophthalate (0.045 g, 0.16 mmol) in dioxane (2 mL) was added methanesulfonate (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.012 g, 0.01 mmol) and cesium carbonate (0.148 g, 0.46 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 1:1) to give dimethyl 3-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)phthalate (0.041 g, 0.088 mmol, 58% yield). MS (ESI) m / z: 464.2 [M+1] +

[0314] 2-(2,6-Dioxopiperidin-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)isoindoline-1,3-dione [ka] To a solution of dimethyl 3-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)phthalate (0.035 g, 0.08 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (0.035 g, 0.21 mmol) in pyridine (1.5 mL) was added lithium iodide (0.049 mg, 0.38 mmol). The resulting mixture was stirred at 130° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 2-(2,6-dioxopiperidin-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-6-yl)amino)isoindoline-1,3-dione (33 mg, 0.063 mmol, 84% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.94 - 8.90 (m, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.49 - 7.40 (m, 1H), 7.39 - 7.37 (m, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.28 (d, J = 2.4 Hz, 1H), 5.08 (dd, J = 5.6, 13.2 Hz, 1H), 3.96 (s, 3H), 3.82 (s, 3H), 2.92 - 2.89 (m, 1H), 2.86 - 2.84 (m, 2H), 2.10 - 2.01 (m, 1H); MS (ESI) m / z: 528.0 [M+1] +

[0315] Example 15: 2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0316] 6-Bromo-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To a solution of 6-bromo-5-nitro-1H-indazole (1.0 g, 4.13 mmol) in N,N-dimethylacetamide (10 mL) were added potassium carbonate (1.7 g, 12.4 mmol) and 4-iodotetrahydropyran (1.05 g, 4.96 mmol). The solution was stirred at 135 °C for 1 hour. The suspension was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 2:1) to give 6-bromo-5-nitro-1-tetrahydropyran-4-yl-indazole (200 mg, 0.613 mmol, 14% yield). 1 H NMR (400 MHz,CDCl3) δ 8.41 (s, 1H), 8.09 (s, 1H), 7.59 (s, 1H), 4.56 - 4.53 (m, 1H), 4.14 - 4.10 (m, 2H), 3.60 - 3.53 (m, 2H), 2.36 - 2.32 (m, 2H), 1.94 - 1.90 (m, 2H); MS (ESI) m / z 326.2 [M+1] +

[0317] 6-(2-methylpyridin-4-yl)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To a solution of 6-bromo-5-nitro-1-tetrahydropyran-4-yl-indazole (0.220 g, 0.670 mmol) in 1,4-dioxane (10 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.177 g, 0.810 mmol), potassium carbonate (0.279 g, 2.02 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (0.055 g, 0.070 mmol). The mixture was stirred at 110 °C under nitrogen for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 3:1) to give 6-(2-methyl-4-pyridyl)-5-nitro-1-tetrahydropyran-4-yl-indazole (160 mg, 0.472 mmol, 70% yield). 1 H NMR (400 MHz,CDCl3) δ 8.79 (d, J = 6.0 Hz, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 4.65 - 4.63 (m, 1H), 4.14 - 4.10 (m, 2H), 3.58 - 3.52 (m, 2H), 2.58 (s, 3H), 2.40 - 2.36 (m, 2H), 1.95 - 1.92 (m, 2H); MS (ESI) m / z 339.2 [M+1] +

[0318] 6-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine [ka] To a solution of 6-(2-methyl-4-pyridyl)-5-nitro-1-tetrahydropyran-4-yl-indazole (0.160 g, 0.4700 mmol) in ethanol (10 mL) was added iron powder (0.265 g, 4.73 mmol) and ammonium chloride (0.255 g, 4.73 mmol) in water (2 mL). The solution was stirred at 90°C for 2 hours. The suspension was filtered, and the filtrate was extracted with dichloromethane (100 ml x 2). The combined organic phase was washed with saturated brine (50 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated to give 6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-yl-indazol-5-amine (100 mg, 0.324 mmol, 68% yield). MS (ESI) m / z 309.4 [M+1] +

[0319] Dimethyl-3-((6-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)phthalate [ka] To a solution of 6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-yl-indazol-5-amine (0.10 g, 0.320 mmol) in 1,4-dioxane (5 mL) was added dimethyl 3-bromobenzene-1,2-dicarboxylate (0.106 g, 0.390 mmol), potassium carbonate (0.134 g, 0.970 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.027 g, 0.030 mmol). The mixture was stirred at 110 °C under nitrogen for 12 h. The solution was concentrated and the residue was purified by preparative HPLC to give dimethyl 3-[[6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-yl-indazol-5-yl]amino]benzene-1,2-dicarboxylate (100 mg, 0.199 mmol, 61% yield). 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.71 (brs, 2H), 7.58 (brs, 1H),7.24 - 7.20 (m, 1H), 7.01 - 6.99 (m,1H), 6.83 (d, J = 8.4 Hz, 1H), 4.75 - 4.72 (m, 2H), 4.22 - 4.20 (m, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.70 - 3.65 (m, 2H), 2.65 (s, 3H), 2.49 - 2.47 (m, 2H), 2.07 - 2.04 (m, 2H); MS (ESI) m / z 501.3 [M+1] +

[0320] 2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of dimethyl 3-[[6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-yl-indazol-5-yl]amino]benzene-1,2-dicarboxylate (0.10 g, 0.200 mmol) in pyridine (2 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (0.036 g, 0.220 mmol) and lithium iodide (0.053 g, 0.400 mmol). The mixture was stirred at 120° C. for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by semi-preparative reverse-phase HPLC to give 2-(2,6-dioxo-3-piperidyl)-4-[[6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-yl-indazol-5-yl]amino]isoindoline-1,3-dione (45 mg, 0.073 mmol, 36% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.85 (brs, 1H), 7.76 - 7.74 (m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.10 - 5.03 (m, 2H), 4.06 - 4.02 (m, 2H), 3.60 - 3.55 (m, MS (ESI) m / z 565.3 [M+1] +

[0321] Example 16: 4-((1-cyclopropyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0322] 6-Bromo-5-nitro-1H-benzimidazole [ka] To a solution of 5-bromo-1H-benzimidazole (10.0 g, 50.75 mmol) in sulfuric acid (50 mL, 2967.60 mmol) was added potassium nitrate (5.18 g, 60.90 mmol) in several portions at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction mixture was poured into 500 mL of ice water, and the pH of the combined aqueous layer was adjusted to pH 7 by the addition of 6 N aqueous sodium hydroxide. The resulting precipitated solid was collected by filtration and purified by preparative HPLC to give 5-bromo-6-nitro-1H-benzimidazole (5.10 g, 21.07 mmol, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H); MS (ESI) m / z: 244.0 [M] +

[0323] 5-Bromo-1-cyclopropyl-6-nitro-1H-benzimidazole [ka] To a solution of 6-bromo-5-nitro-1H-benzimidazole (0.600 g, 2.48 mmol) in dichloroethane (20 mL) was added cyclopropylboronic acid (0.430 g, 4.96 mmol), 2-(2-pyridyl)pyridine (0.388 g, 2.48 mmol), copper diacetate (0.394 g, 2.48 mmol), and sodium carbonate (0.525 g, 4.96 mmol). The mixture was stirred at 70 °C under air for 12 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel preparative TLC (50% ethyl acetate in petroleum ether) to give 6-bromo-1-cyclopropyl-5-nitrobenzimidazole (0.290 g, 1.02 mmol, 41% yield). MS (ESI) m / z: 283.3 [M+1] +

[0324] 1-Cyclopropyl-5-(2-methylpyridin-4-yl)-6-nitro-1H-benzimidazole [ka] To a solution of 6-bromo-1-cyclopropyl-5-nitrobenzimidazole (0.280 g, 0.99 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.217 g, 0.99 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.080 g, 0.10 mmol), and potassium carbonate (0.274 g, 1.99 mmol). The mixture was stirred under nitrogen at 100°C for 12 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel preparative TLC (80% ethyl acetate in petroleum ether) to give 1-cyclopropyl-6-(2-methyl-4-pyridyl)-5-nitrobenzimidazole (0.200 g, 0.679 mmol, 68% yield). MS (ESI) m / z: 295.1 [M+1] +

[0325] 1-Cyclopropyl-5-(2-methylpyridin-4-yl)-1H-benzimidazol-6-amine [ka] To a solution of 1-cyclopropyl-5-(2-methyl-4-pyridyl)-6-nitrobenzimidazole (0.200 g, 0.68 mmol) in ethanol (6 mL) and water (2 mL) was added iron (0.189 g, 3.40 mmol) and ammonium chloride (0.367 g, 6.80 mmol). The mixture was stirred at 80 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC to give 3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazol-5-amine (0.070 g, 0.264 mmol, 38% yield). MS (ESI) m / z: 265.1 [M+1] +

[0326] Dimethyl 3-((1-cyclopropyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)phthalate [ka] To a solution of 3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazol-5-amine (0.050 g, 0.19 mmol) in 1,4-dioxane (4 mL) was added dimethyl 3-bromobenzene-1,2-dicarboxylate (0.057 g, 0.21 mmol), potassium carbonate (0.078 g, 0.57 mmol), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (0.015 g, 0.02 mmol). The mixture was stirred under nitrogen at 110 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give dimethyl 3-[[3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazol-5-yl]amino]benzene-1,2-dicarboxylate (0.030 g, 0.065 mmol, 34% yield). 1 H NMR (400 MHz, MeOD-d4) δ 9.12 (brs, 1H), 8.59 - 8.58 (m, 1H), 8.08 - 8.01 (m, 1H), 8.00 - 7.98 (m, 2H), 7.82 (s, 1H), 7.28 - 7.20 (m, MS (ESI) m / z: 457.2 [M+1] +

[0327] 4-((1-cyclopropyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of dimethyl 3-[[3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazol-5-yl]amino]benzene-1,2-dicarboxylate (0.030 g, 0.07 mmol) in pyridine (2 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (0.016 g, 0.10 mmol) and lithium iodide (0.044 g, 0.33 mmol). The solution was stirred at 120 °C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-[[3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazol-5-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (9.96 mg, 0.018 mmol, 28% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.37 - 8.33 (m, 4H), 7.75 - 7.72 (m, 2H), 7.42 - 7.40 (m, 1H), 7.36 (s, 1H), 7.26 - 7.25 (m, 1H), 7.09 - 7.08 (m, 1H), 6.90 - 6.87 (m, 1H), 5.10 - 5.06 (m, 1H), 3.56 - 3.52 (m, 1H), 2.95 - 2.85 (m, 1H), 2.58 - 2.52 (m, 2H), 2.33 (s, 3H), 2.04 - 2.02 (m, 1H), 1.11 - 1.06 (m, 4H); MS (ESI) m / z: 521.3 [M+1] +

[0328] Example 17: 2-(2,6-dioxo-3-piperidyl)-4-[[3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazol-5-yl]amino]isoindoline-1,3-dione [ka]

[0329] 6-Bromo-3-methyl-5-nitro-1,2-benzoxazole [ka] To a solution of 6-bromo-3-methyl-1,2-benzoxazole (2.00 g, 9.43 mmol) in concentrated sulfuric acid (30 mL, 9.43 mmol) was added concentrated nitric acid (1.26 mL, 28.30 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was slowly poured into ice water (100 mL). The aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-25% ethyl acetate in petroleum ether) to give 6-bromo-3-methyl-5-nitro-1,2-benzoxazole (0.40 g, 1.56 mmol, 16% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.43 (s, 1H), 2.60 (s, 3H)

[0330] 3-methyl-6-(2-methyl-4-pyridyl)-5-nitro-1,2-benzoxazole [ka] To a solution of 6-bromo-3-methyl-5-nitro-1,2-benzoxazole (0.360 g, 1.40 mmol) in 1,4-dioxane (5 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.368 g, 1.68 mmol), sodium carbonate (1.4 mL, 2 M, 2.80 mmol), and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct (0.098 g, 0.14 mmol). The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 80 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3-methyl-6-(2-methyl-4-pyridyl)-5-nitro-1,2-benzoxazole (0.260 g, 0.97 mmol, 68% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 5.2 Hz, 1H), 8.37 (s, 1H), 7.55 (s, 1H), 7.16 (s, 1H), 7.10 (dd, J = 1.2, 5.2 Hz, 1H), 2.70 (s, 3H), 2.65 (s, 3H); MS (ESI) m / z 270.1 [M+1] +

[0331] 3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazol-5-amine [ka] To a solution of 3-methyl-6-(2-methyl-4-pyridyl)-5-nitro-1,2-benzoxazole (0.180 g, 0.67 mmol) in acetic acid (5 mL) was added a solution of tin chloride (0.302 g, 1.34 mmol) in hydrogen chloride (0.67 mL, 1 M, 0.67 mmol). The mixture was stirred at 100 °C for 1 h. The mixture was concentrated under reduced pressure. The mixture was basified to pH 7-8 with ammonium hydroxide. The residue was purified by preparative TLC (ethyl acetate) to give 3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazol-5-amine (0.060 g, 0.25 mmol, 37% yield). MS (ESI) m / z 240.0 [M+1]+

[0332] 2-(2,6-Dioxo-3-piperidyl)-4-[[3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazol-5-yl]amino]isoindoline-1,3-dione [ka] To a solution of 3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazol-5-amine (0.060 g, 0.25 mmol) in 1,4-dioxane (5 mL) was added 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.101 g, 0.30 mmol), sodium carbonate (0.080 g, 0.75 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.020 g, 0.03 mmol). The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 80 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and preparative TLC (9% methanol in dichloromethane) to give 2-(2,6-dioxo-3-piperidyl)-4-[[3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazol-5-yl]amino]isoindoline-1,3-dione (4.01 mg, 0.007 mmol, 3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.47 - 7.40 (m, 2H), 7.30 (d, J = 5.6 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.07 (dd, J = 5.6, 12.8 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.62 - 2.60 (m, 1H), 2.59 (s, 3H), 2.58 - 2.56 (m, 1H), 2.41 (s, 3H), 2.06 - 2.01 (m, 1H); MS (ESI) m / z 496.1 [M+1] +

[0333] Example 18: 4-((1,2-dimethyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0334] 6-Bromo-2-methyl-5-nitro-1H-benzimidazole [ka] To a solution of 6-bromo-2-methyl-1H-benzimidazole (2.0 g, 9.48 mmol) in sulfuric acid (20 mL, 373.47 mmol) was added nitric acid (1.27 mL, 28.43 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 6-bromo-2-methyl-5-nitro-1H-benzimidazole and 6-bromo-2-methyl-7-nitro-1H-benzo[d]imidazole (1.40 g, 5.47 mmol, 58% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 2.49 (s, 3H); MS (ESI) m / z: 257.8 [M+1] +

[0335] 6-Bromo-1,2-dimethyl-5-nitrobenzimidazole [ka] To a solution of 6-bromo-2-methyl-5-nitro-1H-benzimidazole (0.500 g, 1.95 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (0.117 g, 2.93 mmol) at 0 °C. The mixture was stirred for 30 minutes. Iodomethane (0.25 mL, 3.91 mmol) was added, and the mixture was stirred at 20 °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 1:1) to give a mixture of 6-bromo-1,2-dimethyl-5-nitrobenzimidazole and 5-bromo-1,2-dimethyl-6-nitrobenzimidazole (0.45 g, 1.67 mmol, 85% yield). MS (ESI) m / z: 270.3 [M+1] +

[0336] 1,2-Dimethyl-5-(2-methyl-4-pyridyl)-6-nitrobenzimidazole [ka] To a solution of a mixture of 6-bromo-1,2-dimethyl-5-nitrobenzimidazole and 5-bromo-1,2-dimethyl-6-nitrobenzimidazole (0.40 g, 1.30 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.48 g, 2.22 mmol), cesium carbonate (0.96 g, 2.96 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.12 g, 0.15 mmol). The suspension was degassed and purged with nitrogen several times. The mixture was stirred at 110 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate 1:1) to give a mixture of 1,2-dimethyl-5-(2-methyl-4-pyridyl)-6-nitrobenzimidazole and 1,2-dimethyl-6-(2-methyl-4-pyridyl)-5-nitrobenzimidazole (0.40 g, 1.42 mmol, 96% yield). MS (ESI) m / z: 283.1 [M+1]+

[0337] 2,3-Dimethyl-6-(2-methyl-4-pyridyl)benzimidazol-5-amine [ka] To a solution of a mixture of 1,2-dimethyl-5-(2-methyl-4-pyridyl)-6-nitrobenzimidazole and 1,2-dimethyl-6-(2-methyl-4-pyridyl)-5-nitrobenzimidazole (0.40 g, 1.42 mmol) in water (2 mL) and ethanol (5 mL) was added iron powder (0.395 g, 7.08 mmol) and ammonium chloride (0.765 g, 14.17 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture of 2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazol-5-amine and 2,3-dimethyl-5-(2-methyl-4-pyridyl)benzimidazol-6-amine (0.20 g, 0.79 mmol, 56% yield). MS (ESI) m / z: 253.2 [M+1] +

[0338] Dimethyl 3-((1,2-dimethyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)phthalate [ka] To a solution of a mixture of 2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazol-5-amine and 2,3-dimethyl-5-(2-methyl-4-pyridyl)benzimidazol-6-amine (0.200 g, 0.79 mmol) in 1,4-dioxane (2 mL) was added potassium carbonate (0.328 g, 2.38 mmol), methanesulfonate (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.066 g, 0.08 mmol), and dimethyl 3-bromobenzene-1,2-dicarboxylate (0.303 g, 1.11 mmol). The mixture was stirred at 110 °C under nitrogen for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give dimethyl 3-[[2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazol-5-yl]amino]benzene-1,2-dicarboxylate (0.080 g, 0.18 mmol, 22% yield). 1 H NMR (400MHz, DMSO-d6) δ 8.66 (d, J = 6.0 Hz, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.73 (s, 1H), 7.28 - 7.24 (m, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H), 2.75 (s, 3H), 2.61 (s, 3H); MS (ESI) m / z: 445.3 [M+1] + Dimethyl 3-((1,2-dimethyl-6-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-5-yl)amino)phthalate (0.060 g, 0.13 mmol, 16.4% yield) 1H NMR (400MHz, DMSO-d6) δ 8.67 (d, J = 6.4 Hz, 1H), 8.07 (s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.57 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 3.71 (s, 3H), 2.78 (s, 3H), 2.61 (s, 3H)

[0339] 4-((1,2-dimethyl-5-(2-methylpyridin-4-yl)-1H-benzo[d]imidazol-6-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of dimethyl 3-[[2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazol-5-yl]amino]benzene-1,2-dicarboxylate (0.100 g, 0.220 mmol) in pyridine (2 mL) was added 3-aminopiperidine-2,6-dione (0.057 g, 0.450 mmol) and lithium iodide (50 mg). The suspension was stirred at 135 °C for 12 hours. The solution was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 4-[[2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazol-5-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (66 mg, 0.120 mmol, 53% yield). 1H NMR (400MHz, DMSO-d6) δ 11.12 (s, 1H), 8.59 (d, J = 6.4 Hz, 1H), 8.54 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.49 - 7.45 (m, 1H),7.15 (d, J = 6.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.12 - 5.07(m,1H), 3.93 (s, 3H), 2.90 - 2.89 (m, 1H), 2.58 (s, 3H), 2.54 - 2.53 (m, MS (ESI) m / z: 509.2 [M+1] +

[0340] Example 19: 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0341] 6-Cyclopropyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To a solution of 6-bromo-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.300 g, 0.92 mmol) in tert-amyl alcohol (4 mL) was added cyclopropylboronic acid (0.095 g, 1.11 mmol), cesium carbonate (0.900 g, 2.77 mmol), and methanesulfonato(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) dichloromethane adduct (0.034 g, 0.05 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 90 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 3:1) to give 6-cyclopropyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.070 g, 0.24 mmol, 26% yield). MS (ESI) m / z: 287.8 [M+1] +

[0342] 6-Cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine [ka] To a solution of 6-cyclopropyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.070 g, 0.24 mmol) in ethanol (3 mL) and water (1 mL) was added iron (II) powder (0.136 g, 2.44 mmol) and ammonium chloride (0.132 g, 2.44 mmol). The resulting mixture was stirred at 70 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:ethyl acetate 1:1) to give 6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine (0.060 g, 0.233 mmol, 95% yield). MS (ESI) m / z: 258.1 [M+1] +

[0343] 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of 6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine (0.060 g, 0.23 mmol) and 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.083 g, 0.24 mmol) in dioxane (2 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.018 g, 0.02 mmol) and potassium carbonate (0.097 mg, 0.70 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (26 mg, 0.051 mmol, 22% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.73 (s, 1H), 7.56 (dd, J = 7.2, 8.4 Hz, 1H), 7.51 (s, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 5.14 (dd, J = 5.6, 12.8 Hz, 1H), 4.98 - 4.91 (m, 1H), 4.01 (dd, J = 3.6, 11.2 Hz, 2H), 3.58 (t, J = 11.6 Hz, 2H), 2.96 - 2.86 (m, 1H), 2.64 - 2.55 (m, 2H), 2.13 - 2.06 (m, 3H), 2.01 - 1.96 (m, 1H), 1.87 (dd, J = 2.0, 12.8 Hz, 2H), 0.95 - 0.92 (m, 2H), 0.82 - 0.79 (m, 2H); MS (ESI) m / z: 514.3 [M+1] +

[0344] Example 20: 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

change

[0345] 6-ブロモ-1,3-ジメチル-5-ニトロ-1H-インダゾール

change

[0346] 1,3-Dimethyl-6-(2-methyl-4-pyridyl)-5-nitroindazole [ka] To a solution of 6-bromo-1,3-dimethyl-5-nitro-1H-indazole (0.190 g, 0.80 mmol) in dichloromethane (3 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.295 g, 1.10 mmol). The reaction was stirred at 110 °C for 12 hours. The reaction was filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5-15% ethyl acetate in petroleum ether) to give 1,3-dimethyl-6-(2-methyl-4-pyridyl)-5-nitroindazole (0.080 g, 0.28 mmol, 32% yield). MS (ESI) m / z: 283.1 [M+1] +

[0347] 1,3-Dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine [ka] To a solution of 1,3-dimethyl-6-(2-methyl-4-pyridyl)-5-nitroindazole (0.080 g, 0.28 mmol) in ethanol (0.6 mL) was added ammonium chloride (0.153 g, 2.83 mmol) and iron(II) powder (0.079 g, 1.42 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (0.050 g, 0.20 mmol, 69% yield). MS (ESI) m / z: 253.1 [M+1] +

[0348] Dimethyl 3-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalate [ka] To a solution of 1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (0.040 g, 0.16 mmol) in 1,4-dioxane (0.60 mL) was added dimethyl 3-bromophthalate (0.043 g, 0.16 mmol), potassium carbonate (0.061 g, 0.44 mmol), and methanesulfonate (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.013 g, 0.02 mmol). The reaction was stirred at 110 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give dimethyl 3-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalate (0.05 g, 0.11 mmol, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 6.0 Hz, 1H), 7.97 - 7.91 (m, 2H), 7.89 - 7.84 (m, 2H), 7.75 - 7.70 (m, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 4.03 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 2.61 (s, 3H), 2.52 - 2.51 (m, 3H); MS (ESI) m / z: 445.2[M+1] +

[0349] 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of dimethyl 3-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalate (0.05 g, 0.11 mmol) in pyridine (1 mL) was added 3-aminopiperidine-2,6-dione (0.021 g, 0.17 mmol) and lithium iodide (0.030 g, 0.22 mmol). The reaction was stirred at 130° C. for 12 hours. The reaction was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (21 mg, 0.04 mmol, 37% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.43 (s, 1H), 7.88 (d, J = 1.6 Hz, 3H), 7.76 (d, J = 3.6 Hz, 1H), 7.39 (dd, J = 7.2, 8.4 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.09 (dd, J = 5.6, 12.8 Hz, 1H), 4.05 (s, 3H), 2.96 - 2.84 (m, 1H), 2.63 (d, J = 2.4 MS (ESI) m / z: 509.2[M+1] +

[0350] Example 21: 4-((6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0351] 2-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] To a solution of 4-bromo-2-(difluoromethyl)pyridine (0.530 g, 2.55 mmol) in 1,4-dioxane (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.776 g, 3.06 mmol), potassium acetate (0.749 g, 7.64 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.208 g, 0.25 mmol). The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 100 °C for 12 h. The reaction was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (5-15% ethyl acetate in petroleum ether) to give 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.600 g, 2.3 mmol, 92% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.78 - 7.73 (m, 1H), 1.34 (s, 12H)

[0352] 6-(2-(difluoromethyl)pyridin-4-yl)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To a solution of 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.120 g, 0.47 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was added 6-bromo-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.122 g, 0.38 mmol), potassium carbonate (0.129 g, 0.94 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.038 g, 0.05 mmol). The suspension was degassed and purged with nitrogen several times. The mixture was stirred at 110 °C for 12 h. The reaction was filtered and the filtrate was concentrated and purified by preparative HPLC to give 6-(2-(difluoromethyl)pyridin-4-yl)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.140 g, 0.37 mmol, 79% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 4.4 Hz, 1H), MS (ESI) m / z: 375.1[M] +

[0353] 6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine [ka] To a solution of 6-(2-(difluoromethyl)pyridin-4-yl)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.140 g, 0.37 mmol) in ethanol (6 mL) was added ammonium chloride (0.202 g, 3.74 mmol) and iron(II) powder (0.104 g, 1.87 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine (0.110 g, 0.32 mmol, 85% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.84 (s, 1H), 7.76 (d, J = 5.2 Hz, 1H), 7.57 (s, 1H), 7.04 (s, 1H), 5.76 (s, 1H), 4.86 - 4.78 (m, 1H), 3.98 (dd, J = 3.6, 11.2 Hz, 2H), 3.57 - 3.48 (m, 2H), 2.12 -2.02 (m, 2H), 1.86 (dd, J = 2.4, 12.4 Hz, 2H); MS (ESI) m / z: 345.1[M+1] +

[0354] 4-((6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of 6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-amine (0.080 g, 0.23 mmol) and 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.082 g, 0.24 mmol) in 1,4-dioxane (3.5 mL) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.018 g, 0.02 mmol) and potassium carbonate (0.096 g, 0.70 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction was filtered, and the filtrate was concentrated and purified by preparative HPLC to give 4-((6-(2-(difluoromethyl)pyridin-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (46 mg, 0.07 mmol, 32% yield). 1 HNMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.63 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.73 (d, J = 5.2 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.07 - 6.75 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 5.12 - 5.01 (m, 2H), 4.07 - 4.00 (m, 2H), 3.60 - 3.54 (m, 2H), 2.96 - 2.84 (m, 1H), 2.65 - 2.55 (m, 2H), 2.20 - 2.12 (m, 2H), 2.06 - 1.99 (m, 1H), 2.02 - 1.95 (m, 2H); MS (ESI) m / z: 601.2[M+1] +

[0355] Example 22: 4-((3-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)-2-((S)-3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0356] (E)-6-Bromo-2,3-dihydro-1H-inden-1-one oxime [ka] To a solution of 6-bromoindan-1-one (5.0 g, 23.6 mmol) in ethyl alcohol (50 mL) was added hydroxylamine hydrochloride (3.2 g, 47.3 mmol) and pyridine (4.9 g, 61.9 mmol, 5 mL). The reaction was stirred at 80 °C for 12 hours. The reaction mixture was quenched with water (50 mL), and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were washed with saturated brine (50 mL), dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-bromoindan-1-one oxime (4.5 g, 19.9 mmol, 84% yield). 1 H NMR (400MHz DMSO-d6) δ 11.09 (s, 1H), 7.63 (brs, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 2.95 - 2.80 (m, 2H), 2.79 - 2.77 (m, 2H); MS (ESI) m / z 224.0 [M+1] +

[0357] 6-Bromo-2,3-dihydro-1H-inden-1-amine [ka] To a solution of 6-bromoindan-1-one oxime (4.6 g, 20.35 mmol) in methyl alcohol (100 mL) was added molybdenum trioxide (3.51 g, 24.42 mmol) and sodium borohydride (3.85 g, 101.74 mmol). The reaction was stirred at 25° C. for 12 hours. The reaction mixture was quenched with 1N aqueous hydrochloric acid (200 mL) and ethyl acetate (200 mL). The aqueous solution was made basic and then extracted with dichloromethane (3×200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6-bromoindan-1-amine (2.3 g, 10.8 mmol, 53%). MS (ESI) m / z 195.0 [M-16] +

[0358] 6-Bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine [ka] To a solution of 6-bromoindan-1-amine (2.3 g, 10.8 mmol) in formic acid (4 mL) in water was added formaldehyde (45.5 g, 500.9 mmol, 41.8 mL). The reaction was stirred at 100 °C for 12 h. The aqueous solution was made basic and then extracted with dichloromethane (3 × 100 mL) and dried over sodium sulfate. The extract was then filtered and concentrated under reduced pressure to give 6-bromo-N,N-dimethyl-indan-1-amine (1.1 g, 4.58 mmol, 42%). 1 H NMR (400MHz CDCl3) δ 7.49 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.30 (t, J = 6.8 Hz, 1H), 2.90 - 2.86 (m, 1H), 2.80 - 2.76 (m, 1H), 2.25 (s, 6H), 2.08 - 2.04 (m, 2H); MS (ESI) m / z 240.0, 242.0 [M+1] +

[0359] 4-((3-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)-2-((S)-3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of (S)-4-amino-2-(3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.100 g, 0.35 mmol) in 1,4-dioxane (3 mL) was added potassium carbonate (0.120 g, 0.87 mmol), [2-(2-aminophenyl)phenyl]chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.030 g, 0.04 mmol), and 6-bromo-N,N-dimethyl-2,3-dihydro-1H-inden-1-amine (0.100 g, 0.42 mmol). The resulting mixture was stirred at 100° C. under nitrogen for 12 hours. The mixture was diluted with dichloromethane (20 mL) and acetonitrile (20 mL) and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (4 mL) and filtered. The filtrate was purified by preparative HPLC to give 4-((3-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)-2-((S)-3-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (40 mg, 0.802 mmol, 23% yield). 1H NMR (400MHz DMSO-d6) δ 11.02 (s, 2H), 8.52 (s, 1H), 7.72 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.49 - 7.35 (m, 2H), 7.19 (d, J = 6.8 Hz, 1H), 4.95 - 4.94 (m, 1H), 3.11 - 3.02 (m, 1H), 2.92 - 2.85 (m, 1H), 2.73 (d, J = 4.8 Hz, 3H), 2.69 - 2.56 (m, 3H), 2.54 (d, J = 5.2 Hz, MS (ESI) m / z 447.1 [M+1] +

[0360] Example 23: (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione and (R)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0361] 6-Bromo-1-methyl-5-nitro-1H-indazole [ka] A 500 mL three-neck flask was charged with 4-bromo-2-fluoro-5-nitrobenzaldehyde (10.00 g, 40.32 mmol), potassium carbonate (8.400 g, 60.87 mmol), isopropanol (80 mL), and water (40 mL). The mixture was stirred at 41°C for 1 hour, and methylhydrazine (11.730 g, 101.85 mmol) was added dropwise. The resulting mixture was warmed to 77°C and stirred for 6 hours. The mixture was cooled to 20°C, and water (150 mL) was added. The mixture was stirred for 1 hour and filtered. The separated solid was rinsed with water (20 mL x 3) and dried under vacuum to give 6-bromo-1-methyl-5-nitro-1H-indazole (7.00 g, 27.34 mmol, 67.8% yield). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 4.12 (s, 3H)

[0362] 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole [ka] To a solution of 6-bromo-1-methyl-5-nitro-1H-indazole (2.0 g, 7.81 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.80 g, 8.22 mmol) in dioxane (30 mL) was added cesium carbonate (7.62 g, 23.43 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) (0.319 g, 0.39 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole (1.500 g, 5.59 mmol, 71.6% yield). 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 7.12 (d, J = 4.8 Hz, 1H), 4.15 (s, 3H), 2.64 (s, 3H); MS (ESI) m / z: 269.3[M+1] +

[0363] 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine [ka] To a solution of 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole (1.50 g, 5.59 mmol) in ethanol (15 mL) and water (5 mL) was added ammonium chloride (1.51 g, 27.96 mmol) and iron(II) powder (1.56 g, 27.96 mmol). The resulting mixture was stirred at 70 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was extracted with water (50 mL) and ethyl acetate (3 x 60 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (1.3 g, 5.46 mmol, 97.6% yield). MS (ESI) m / z: 239.1 [M+1]+ 1 H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 4.8 Hz, 1H), 7.81 (s, 1H), 7.35 (s, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.16 (s, 1H), 7.04 (s, 1H), 4.03 (s, 3H), 2.65 (s, 3H)

[0364] 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (1.300 g, 5.46 mmol) and 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.931 g, 5.73 mmol) in dioxane (30 mL) was added potassium carbonate (2.258 g, 16.36 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.215 g, 0.27 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC (5-35% acetonitrile in water, 0.1% 2,2,2-trifluoroacetic acid additive). The isolated material was lyophilized to give crude 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (1.80 g, 3.64 mmol, 66.7% yield). MS (ESI) m / z: 495.2 [M+1]+

[0365] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.600 g, 1.21 mmol) was purified by chiral preparative SFC (70% ethanol in acetonitrile). The isolated material was concentrated under reduced pressure to give (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (210 mg, 0.421 mmol, 34.7% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.13 (d, J = 0.8 Hz, 1H), 7.87 (s, 1H), 7.84 (s, 1H), 7.43 (s, 1H), 7.40 (dd, J = 7.2, 8.4 Hz, 1H), 7.33 (d, J = 4.4 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.08 (dd, J = 5.6, 12.8 Hz, 1H), 4.12 (s, MS (ESI) m / z: 495.3 [M+1]+

[0366] (R)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.600 g, 1.21 mmol) was purified by chiral preparative SFC (70% ethanol in acetonitrile). The isolated material was concentrated under reduced pressure to give (R)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (220 mg, 0.441 mmol, 36.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 8.13 (d, J = 0.8 Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.42 - 7.39 (m, 2H), 7.32 (dd, J = 1.6, 5.2 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 4.12 (s, 3H), 2.95 - 2.86 (m, 1H), 2.63 - 2.55 (m, 2H), 2.43 (s, 3H), 2.07 - 2.02 (m, 1H); MS (ESI) m / z: 495.1 [M+1]+

[0367] Example 24: (R)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and (S)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0368] 5-Bromo-1,3-dimethyl-benzimidazol-2-one [ka] To a solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5.00 g, 22.02 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (1.590 g, 66.06 mmol) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Iodomethane (15.63 g, 110.10 mmol) was added. The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with 60 mL of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-bromo-1,3-dimethylbenzimidazol-2-one (5.00 g, 20.74 mmol, 94.2% yield). MS (ESI) m / z: 241.1[M]

[0369] 5-Bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (5.00 g, 20.74 mmol) in acetic anhydride (83 mL) was added fuming nitric acid (1.85 mL, 41.48 mmol) slowly under nitrogen at -30 °C, taking care to maintain the temperature below -25 °C. The mixture was slowly warmed to 0 °C and stirred for 1 h. The reaction mixture was quenched with water (300 mL). The resulting solution was extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.50 g, 15.73 mmol, 75.8% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.70 (s, 1H), 3.37 (s, 6H); MS (ESI) m / z: 287.9[M+2]+

[0370] 1,3-Dimethyl-5-(2-methylpyridin-4-yl)-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 5-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.00 g, 13.98 mmol) in 1,4-dioxane (40 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.60 g, 20.97 mmol), cesium carbonate (13.63 g, 41.95 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.140 g, 1.39 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 110 °C for 12 h. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phase was washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (5-15% methanol in dichloromethane) to give 1,3-dimethyl-5-(2-methylpyridin-4-yl)-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.00 g, 13.41 mmol, 95.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 7.14 (dd, J = 1.2, 4.8 Hz, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 2.52 (s, 3H); MS (ESI) m / z: 299.1[M+1]+

[0371] 5-Amino-1,3-dimethyl-6-(2-methylpyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 1,3-dimethyl-5-(2-methylpyridin-4-yl)-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (4.00 g, 13 mmol) in ethanol (60 mL) and water (20 mL) was added ammonium chloride (7.24 g, 134 mmol) and iron powder (3.74 g, 67 mmol). The reaction was stirred at 80 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-amino-1,3-dimethyl-6-(2-methylpyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.600 g, 9.69 mmol, 72.3% yield). MS (ESI) m / z: 269.0 [M+1]+

[0372] 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of 5-amino-1,3-dimethyl-6-(2-methylpyridin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (2.60 g, 9.69 mmol) in 1,4-dioxane (50 mL) was added 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3.43 g, 10.17 mmol), potassium carbonate (4.01 g, 29.07 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.380 g, 0.48 mmol). The resulting suspension was degassed and purged with nitrogen. The mixture was stirred at 115 °C for 12 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure. The resulting material was purified by semi-preparative reverse-phase HPLC (15–45% acetonitrile in water, 0.1% trifluoroacetic acid additive). The relevant fractions were lyophilized to give 4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2.1 g, 3.82 mmol, 39% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.48 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.49 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.74 - 6.69 (m, 1H), 5.09 (dd, J = 5.4, 12.8 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 2.96 - 2.84 (m, 1H), 2.62 (s, 3H), 2.60 - 2.54 (m, 1H), 2.53 - 2.51 (m, 1H), 2.09 - 2.01 (m, 1H); MS (ESI) m / z: 525.2[M+1]+

[0373] (S)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 4-((1,3-Dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.00 g, 1.91 mmol) was separated by chiral preparative SFC (70-70% isopropyl alcohol in acetonitrile). Peak 1 was concentrated under reduced pressure and extracted with sodium bicarbonate (50 mL × 2) and dichloromethane (60 mL × 3). The combined organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was treated with acetonitrile (6 mL) and water (60 mL) and lyophilized to give (S)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (359 mg, 0.684 mmol, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.45 - 7.39 (m, 1H), 7.35 (s, 1H), 7.32 (d, J = 1.2 Hz, 2H), 7.25 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 2.95 - 2.83 (m, MS (ESI) m / z: 525.3[M+1]+

[0374] (R)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 4-((1,3-Dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.00 g, 1.91 mmol) was separated by chiral preparative SFC (70-70% isopropyl alcohol in acetonitrile). Peak 2 was concentrated under reduced pressure and extracted with sodium bicarbonate (50 mL × 2) and dichloromethane (60 mL × 3). The combined organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was treated with acetonitrile (6 mL) and water (60 mL) and lyophilized to give (R)-4-((1,3-dimethyl-6-(2-methylpyridin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (359 mg, 0.684 mmol, 35% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.42 (dd, J = 7.2, 8.4 Hz, 1H), 7.36 (s, 1H), 7.32 (s, 1H), 7.31 (s, 1H), 7.28 - 7.25 (m, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 3.39 (s, 3H), 3.36 (s, 3H), 2.95 - 2.83 (m, 1H), 2.64 - 2.56 (m, 1H), 2.56 - 2.52 (m, 1H), 2.41 (s, 3H), 2.08 - 2.01 (m, 1H); MS (ESI) m / z: 525.3[M+1]+

[0375] Example 25: (R)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and (S)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0376] 5-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 5-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.230 g, 0.80 mmol) in 1,4-dioxane (0.5 mL) was added 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.281 g, 1.21 mmol), cesium carbonate (0.784 g, 2.41 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.066 g, 0.08 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (5–15% methanol in dichloromethane) to give 5-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.180 g, 0.58 mmol, 71% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.30 (s, 1H), 7.02 (s, 2H), 3.43 (s, 3H), 3.39 (s, 3H), 2.46 (s, 6H); MS (ESI) m / z: 313.2 [M]

[0377] 5-Amino-6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 5-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.180 g, 0.58 mmol) in ethanol (3 mL) and water (1 mL) was added ammonium chloride (0.156 g, 2.88 mmol) and ferrous iron powder (0.322 g, 5.76 mmol). The reaction was stirred at 80 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 5-amino-6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.130 g, 0.46 mmol, 79% yield). MS (ESI) m / z: 283.1 [M+1] +

[0378] 4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of 5-amino-6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.130 g, 0.42 mmol) in 1,4-dioxane (3 mL) was added 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.168 g, 0.500 mmol), potassium carbonate (0.172 g, 1.25 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.033 g, 0.04 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 110 °C for 12 hours. The reaction was filtered, and the filtrate was concentrated. The resulting residue was purified by semi-preparative reverse-phase HPLC (13–43% acetonitrile in water, 0.1% trifluoroacetic acid additive). The collected fractions were lyophilized to give 4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (153 mg, 0.284 mmol, 68% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.53 (s, 1H), 7.82 (s, 2H), 7.48 (s, 1H), 7.45 - 7.40 (m, 1H), 7.39 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.71 - 6.67 (m, 1H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 3.42 (s, 3H), 3.38 (s, 3H), 2.96 - 2.85 (m, 1H), 2.65 - 2.62 (m, 1H), 2.60-2.57 (m, 1H), 2.57 (s, 6H), 2.09 - 2.02 (m, 1H); MS (ESI) m / z: 539.2[M+1] +

[0379] (R)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.120 g, 0.22 mmol) was separated by chiral preparative SFC (70-70% isopropyl alcohol in acetonitrile). After separation, one of the two separated peaks was concentrated under reduced pressure to give (R)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (42.74 mg, 0.079 mmol, 35.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.28 (s, 1H), 7.47 - 7.39 (m, 1H), 7.31 (d, J = 1.6 Hz, 2H), 7.14 (s, 2H), 7.08 (d, J = 7.2 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 5.4, 12.8 Hz, 1H), 3.39 (s, 3H), 3.37 (s, 3H), 2.96 - 2.84 (m, 1H), 2.65 - 2.60 (m, 1H), 2.58 - 2.53 (m, 1H), 2.35 (s, 6H), 2.07 - 1.99 (m, 1H); MS (ESI) m / z: 539.3[M+1] +

[0380] (S)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] 4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.120 g, 0.22 mmol) was separated by chiral preparative SFC (70-70% isopropyl alcohol in acetonitrile). After separation, one of the two separated peaks was concentrated under reduced pressure to give (S)-4-((6-(2,6-dimethylpyridin-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (58 mg, 0.108 mmol, 48% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.48 (s, 1H), 7.79 - 7.64 (m, 2H), 7.48 - 7.39 (m, 2H), 7.38 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 6.75 - 6.69 (m, 1H), 5.13 - 5.07 (m, 1H), 3.41 (s, 3H), 3.38 (s, 3H), 2.98 - 2.84 (m, 1H), 2.65 - 2.61 (m, 1H), 2.60-2.56 (m, 1H), 2.54 (s, 6H), 2.09 - 2.00 (m, 1H); MS (ESI) m / z: 539.3[M+1] +

[0381] Example 26: 2-((R)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione and 2-((S)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0382] (R)-6-Bromo-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole [ka] A mixture of 6-bromo-5-nitro-1H-indazole (5.00 g, 20.66 mmol), (S)-tetrahydrofuran-3-ol (2.18 g, 24.79 mmol), and triphenylphosphine (6.50 g, 24.78 mmol) was evaporated under reduced pressure for 30 minutes, followed by the addition of tetrahydrofuran (30 mL). A solution of di-tert-butyl (E)-diazene-1,2-dicarboxylate (5.70 g, 24.78 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC. The isolated target substance was freeze-dried to give (R)-6-bromo-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole (3.50 g, 11.21 mmol, 54% yield). 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 5.31 - 5.25 (m, 1H), 4.31 - 4.26 (m, 1H), 4.20 - 4.19 (m, 2H), 4.05 - 3.99 (m, 1H), 2.60 - 2.52 (m, 1H), 2.50 - 2.42 (m, 1H); MS (ESI) m / z: 313.9 [M+1] +

[0383] (R)-6-(2-methylpyridin-4-yl)-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole [ka] To a solution of (R)-6-bromo-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole (3.00 g, 9.61 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.53 g, 11.53 mmol) in dioxane (40 mL) was added potassium carbonate (3.90 g, 28.26 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct (0.393 g, 0.48 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (R)-6-(2-methylpyridin-4-yl)-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole (3.00 g, 9.25 mmol, 96% yield). 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.2 Hz, 1H), 8.52 (s, 1H), 8.25 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 7.10 (dd, J = 5.2, 1.2 Hz, 1H), 5.35 - 5.30 (m, 1H), 4.31 - 4.25 (m, 1H), 4.20 (d, J = 5.2 Hz, 2H), 4.05 - 3.99 (m, 1H), 2.63 (s, 3H), 2.59 - 2.49 (m, 2H); MS (ESI) m / z: 325.1 [M+1] +

[0384] (R)-6-(2-methylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-indazol-5-amine [ka] To a solution of (R)-6-(2-methylpyridin-4-yl)-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole (3.00 g, 9.25 mmol) in ethanol (30 mL) and water (10 mL) was added iron (II) powder (2.58 g, 46.25 mmol) and ammonium chloride (4.99 g, 92.5 mmol). The resulting mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude (R)-6-(2-methylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-indazol-5-amine (2.73 g, 9.27 mmol, 100% yield). 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 5.2 Hz, 1H), 7.85 (s, 1H), 7.34 (s, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.25 (s, 1H), 7.05 (s, 1H), 5.25 - 5.19 (m, 1H), 4.26 - 4.20 (m, 1H), 4.19 - 4.16 (m, 2H), 4.01 - 3.96 (m, 1H), 2.65 (s, 3H), 2.52 - 2.45 (m, 2H); MS (ESI) m / z: 295.1 [M+1] +

[0385] 2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of (R)-6-(2-methylpyridin-4-yl)-1-(tetrahydrofuran-3-yl)-1H-indazol-5-amine (2.730 g, 9.27 mmol) and 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (3.130 g, 9.27 mmol) in dioxane (40 mL) was added potassium carbonate (3.840 g, 27.81 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.365 g, 0.46 mmol). The mixture was degassed and purged with nitrogen. The resulting mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC. The isolated material was lyophilized to give 2-(2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione trifluoroacetate (1026 mg, 1.86 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.65 (d, J = 6.0 Hz, 1H), 8.46 (s, 1H), 8.23 ​​(s, 1H), 8.07 (s, 1H), 7.94 (s, 2H), 7.81 (d, J = 3.2 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.73 - 6.69 (m, 1H), 5.65 - 5.59 (m, 1H), 5.09 (dd, J = 5.2, 12.8 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.98 - 3.92 (m, 2H), 2.95 - 2.86 (m, 1H), 2.64 - 2.63 (m, 1H), 2.60 (s, 3H), 2.48 - 2.46 (m, 1H), 2.44 - 2.37 (m, 2H), 2.08 - 2.03 (m, 1H); MS (ESI) m / z: 551.2 [M+1]+

[0386] 2-((R)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.75 g, 1.36 mmol) was separated by chiral preparative SFC (70-70% isopropyl alcohol in acetonitrile). One of the two separated peaks was concentrated under reduced pressure to give 2-((R)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.33 g, 0.60 mmol, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.43 - 7.42 (m, 1H), 7.42 - 7.39 (m, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.64 - 5.58 (m, 1H), 5.08 (dd, J = 12.8, 5.2 Hz, 1H), 4.14 - 4.09 (m, 2H), 3.95 - 3.90 (m, 2H), 2.94 - 2.85 (m, 1H), 2.63 - 2.58 (m, 2H), 2.47 - 2.46 (m, 1H), 2.43 (s, 3H), 2.40 - 2.36 (m, 1H), 2.07 - 2.02 (m, 1H); MS (ESI) m / z: 551.3 [M+1] +

[0387] 2-((S)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.75 g, 1.36 mmol) was separated by chiral preparative SFC (70-70% isopropyl alcohol in acetonitrile). One of the two separated peaks was concentrated under reduced pressure to give 2-((S)-2,6-dioxopiperidin-3-yl)-4-((6-(2-methylpyridin-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (0.40 g, 0.73 mmol, 53% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.42 (s, 1H), 7.41 - 7.39 (m, 1H), 7.32 - 7.31 (m, 1H), 7.07 (d, J = 6.8 Hz, 1H), 6.82 - 6.78 (m, 1H), 5.64 - 5.58 (m, 1H), 5.08 (dd, J = 12.8, 5.6 Hz, 1H), 4.16 - 4.07 MS (ESI) m / z: 551.3 [M+1] +

[0388] Example 27: (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione [ka]

[0389] 7-Amino-6-bromo-3,4-dihydroquinolin-2(1H)-one [ka] To a mixture of 7-amino-3,4-dihydroquinolin-2(1H)-one (5.00 g, 30.83 mmol) suspended in dichloromethane (100 mL) and methanol (25 mL) was added tetra-n-butylammonium tribromide (6.00 g, 13.87 mmol). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was partitioned between dichloromethane and 10% aqueous sodium thiosulfate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give 7-amino-6-bromo-3,4-dihydroquinolin-2(1H)-one (1.00 g, 4.15 mmol, 13% yield). MS (ESI) m / z: 242.4 [M+1] +

[0390] 7-Amino-6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one [ka] 7-Amino-6-bromo-3,4-dihydroquinolin-2(1H)-one (1.00 g, 4.15 mmol) was dissolved in tetrahydrofuran (15 mL) and cooled to 0 °C. Potassium bis(trimethylsilyl)amide (1 M) (4.6 mL, 4.56 mmol) was then added dropwise, followed by iodomethane (0.65 g, 4.56 mmol). The mixture was stirred for 12 hours at 25 °C. The reaction was quenched with saturated ammonium chloride solution (10 mL) and then partitioned with ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 7-amino-6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.80 g, 3.14 mmol, 75% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 7.17 (s, 1H), 6.56 (s, 1H), 5.26 - 5.19 (m, 2H), 3.17 (s, 3H), 2.72 - 2.68 (m, 2H), 2.49 - 2.45 (m, 2H); (ESI) m / z: 255.1[M]

[0391] 7-Amino-1-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydroquinolin-2(1H)-one [ka] To a solution of a mixture of 7-amino-6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.80 g, 3.14 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.81 g, 3.70 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.25 g, 0.31 mmol), and potassium carbonate (1.29 g, 9.41 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give 7-amino-1-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.60 g, 2.24 mmol, 71% yield). MS (ESI) m / z: 268.0 [M+1] +

[0392] 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione [ka] To a solution of 7-amino-1-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.60 g, 2.24 mmol) in 1,4-dioxane (10 mL) was added 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.83 g, 2.47 mmol), potassium carbonate (0.92 g, 6.73 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.17 g, 0.22 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 115 °C for 12 h. The reaction was filtered, and the filtrate was concentrated and purified by semi-preparative reverse-phase HPLC. The collected fractions were lyophilized to give 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione (0.60 g, 1.15 mmol, 51% yield). MS (ESI) m / z: 524.2 [M+1] +

[0393] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-Dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione (0.60 g, 1.15 mmol) was separated by chiral preparative SFC (40-40% isopropyl alcohol in acetonitrile). After separation, peak (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione (261 mg, 0.49 mmol, 43% yield) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 7.49 - 7.43 (m, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H), 7.20 (s, 1H), 7.15 - 7.11 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 3.27 (s, 3H), 2.99 - 2.93 (m, 2H), 2.92 - 2.83 (m, 1H), 2.64(t, J = 7.2Hz, 2H), 2.60 - 2.55 (m, 1H), 2.54 (s, 1H), 2.41 (s, 3H), 2.07 - 1.99 (m, 1H); MS (ESI) m / z: 524.3[M+1] +

[0394] Example 28: 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(4-methylthiazol-2-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione [ka]

[0395] 7-Amino-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one [ka] To a solution of 7-amino-6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.50 g, 1.96 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.59 g, 2.35 mmol) in 1,4-dioxane (8 mL) was added potassium acetate (0.57 g, 5.88 mmol). The mixture was degassed and purged with nitrogen. To the mixture was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.16 g, 0.20 mmol), and the mixture was stirred at 110 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography to give 7-amino-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.28 g, 0.93 mmol, 47% yield). MS (ESI) m / z: 303.4 [M+1] +

[0396] 7-Amino-1-methyl-6-(4-methylthiazol-2-yl)-3,4-dihydroquinolin-2(1H)-one [ka] To a solution of 7-amino-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.20 g, 0.66 mmol) and 2-bromo-4-methylthiazole (0.14 g, 0.79 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was added sodium carbonate (0.21 mg, 1.99 mmol). The mixture was degassed and purged with nitrogen. To the mixture was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.06 mg, 0.07 mmol), and the reaction was stirred at 110 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude residue was purified by preparative TLC to give 7-amino-1-methyl-6-(4-methylthiazol-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.06 g, 0.22 mmol, 33% yield). 1 H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 6.73 (s, 1H), 6.35 (s, 1H), 3.34 (s, 3H), 2.88 - 2.82 (m, 2H), 2.69 - 2.63 (m, 2H), 2.47 (s, 3H)

[0397] 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(4-methylthiazol-2-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione [ka] To a solution of 7-amino-1-methyl-6-(4-methylthiazol-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.05 g, 0.18 mmol) in 1,4-dioxane (2 mL) was added 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.068 g, 0.20 mmol), potassium carbonate (0.076 g, 0.55 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.014 g, 0.02 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 115 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude residue was purified by semi-preparative reverse-phase HPLC, and the collected fractions were lyophilized to give 2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(4-methylthiazol-2-yl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)isoindoline-1,3-dione (12 mg, 0.023 mmol, 12% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 11.11 - 11.06 (m, 1H), 7.75 - 7.70 (m, 2H), 7.67 - 7.62 (m, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 0.8 Hz, 1H), 7.28 (s, 1H), 5.14 (dd, J = 5.4, 12.4 Hz, 1H), 3.27 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 2.93 - 2.87 (m, 1H), 2.65 - 2.60 (m, 2H), 2.58 - 2.56 (m, 1H), 2.55 - 2.54 (m, 1H), 2.42 (s, 3H), 2.13 - 2.06 (m, 1H); MS (ESI) m / z: 530.0[M+1] +

[0398] Example 29: (S)-4-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0399] 7-Amino-6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one [ka] To a solution of 7-amino-6-bromo-1-methyl-3,4-dihydroquinolin-2-one (0.20 g, 0.78 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.20 g, 0.86 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.10 g, 0.12 mmol), and potassium carbonate (0.76 g, 2.35 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5-15% methanol in dichloromethane) to give 7-amino-6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.25 g, 0.91 mmol, 100% yield). MS (ESI) m / z: 283.0 [M+1] +

[0400] Dimethyl 3-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate [ka] To a solution of 7-amino-6-(1-cyclopropylpyrazol-4-yl)-1-methyl-3,4-dihydroquinolin-2-one (0.197 g, 0.70 mmol) and dimethyl 3-bromobenzene-1,2-dicarboxylate (0.226 g, 0.83 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (0.680 g, 2.09 mmol) and methanesulfonate (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.029 g, 0.04 mmol). The mixture was degassed and purged with nitrogen. The reaction mixture was stirred at 110 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC to give dimethyl 3-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate (0.127 g, 0.25 mmol, 38.4% yield). 1 H NMR (400 MHz, CDCl3) δ 7.26 (s, 2H), 7.24 (s, 1H), 7.07 (s, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 7.01 (s, 1H), 6.93 (s, 1H), 3.90 (s, 3H); MS (ESI) m / z: 475.2 [M+1] +

[0401] 3-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid [ka] To a solution of dimethyl 3-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate (0.170 g, 0.36 mmol) in water (1 mL) and methanol (3 mL) was added sodium hydroxide (0.043 g, 1.07 mmol). The mixture was stirred at 80° C. for 12 hours. The mixture was adjusted to pH 3 with dilute hydrochloric acid and filtered. The filtrate was concentrated under reduced pressure to give crude 3-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid (0.088 g, 0.20 mmol, 55.0% yield). MS (ESI) m / z: 447.2 [M+1] +

[0402] tert-Butyl rac-(4S)-5-amino-4-[4-[[6-(1-cyclopropylpyrazol-4-yl)-1-methyl-2-oxo-3,4-dihydroquinolin-7-yl]amino]-1,3-dioxoisoindolin-2-yl]-5-oxopentanoate [ka] To a solution of 3-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid (0.088 g, 0.20 mmol) in toluene (1.5 mL) and triethylamine (0.34 mL, 1.97 mmol) was added tert-butyl rac-(4S)-4,5-diamino-5-oxopentanoate (0.040 g, 0.20 mmol). The mixture was stirred at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give tert-butyl rac-(4S)-5-amino-4-[4-[[6-(1-cyclopropylpyrazol-4-yl)-1-methyl-2-oxo-3,4-dihydroquinolin-7-yl]amino]-1,3-dioxoisoindolin-2-yl]-5-oxopentanoate (0.069 g, 0.11 mmol, 57.1% yield).

[0403] (S)-4-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of tert-butyl rac-(4S)-5-amino-4-[4-[[6-(1-cyclopropylpyrazol-4-yl)-1-methyl-2-oxo-3,4-dihydroquinolin-7-yl]amino]-1,3-dioxoisoindolin-2-yl]-5-oxopentanoate (0.069 g, 0.11 mmol) in acetonitrile (1 mL) was added benzenesulfonic acid (0.018 g, 0.11 mmol). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was extracted with dichloromethane (30 mL × 3) and saturated sodium bicarbonate solution (30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to give (S)-4-((6-(1-cyclopropyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12 mg, 0.023 mmol, 20% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.29 (s, 1H), 7.65 (s, 1H), 7.53-7.49 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12(s, 1H ), 7.0 (m, J = 8.0 Hz, 1H), 5.16 (dd, J = 4.0 ,12.0 Hz 12, 1H), 3.71-3.62 (m, 2H), 3.24 (s, 1H), 2.95-2.88 (m, 3H), 2.65 (s, 1H), 2.62-2.60 (m, 2H), 2.10-2.08 (m, 1H), 1.24 (s, 3H); MS (ESI) m / z: 539.2 [M+1] +

[0404] Example 30: (S)-4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0405] 7-Amino-6-(1,3-dimethylpyrazol-4-yl)-1-methyl-3,4-dihydroquinolin-2-one [ka] To a solution of 7-amino-6-bromo-1-methyl-3,4-dihydroquinolin-2-one (0.17 g, 0.67 mmol) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.16 g, 0.73 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was added potassium carbonate (0.27 g, 2.00 mmol). The mixture was degassed and purged with nitrogen. (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.05 g, 0.07 mmol) was added, and the mixture was stirred at 110 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC to give 7-amino-6-(1,3-dimethylpyrazol-4-yl)-1-methyl-3,4-dihydroquinolin-2-one (0.12 g, 0.44 mmol, 66% yield). MS (ESI) m / z: 271.2 [M+1]

[0406] Dimethyl 3-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate [ka] To a solution of 7-amino-6-(1,3-dimethylpyrazol-4-yl)-1-methyl-3,4-dihydroquinolin-2-one (0.12 g, 0.44 mmol) and dimethyl 3-bromobenzene-1,2-dicarboxylate (0.13 g, 0.49 mmol) in 1,4-dioxane (3 mL), potassium carbonate (0.18 g, 1.33 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.03 g, 0.04 mmol) were added. The mixture was stirred at 110 °C for 12 h. The suspension was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC to give dimethyl 3-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate (0.15 g, 0.32 mmol, 73% yield). MS (ESI) m / z: 463.1 [M+1]

[0407] 3-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid [ka] To a solution of dimethyl 3-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate (0.15 g, 0.32 mmol) in methanol (3 mL) was added sodium hydroxide (0.06 g, 1.63 mmol) in water (1.5 mL). The mixture was stirred at 80° C. for 12 hours. The pH of the mixture was adjusted to 6 by adding 1 M HCl. The resulting precipitated solid was collected by filtration, washed with water (20 ml), and dried under reduced pressure to give 3-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid (0.11 g, 0.25 mmol, 78% yield).1 H NMR (400 MHz, DMSO-d6) δ 13.60 - 12.78 (m, 2H), 7.93 - 7.83 (m, 1H), 7.60 (s, 1H), 7.36 - 7.31 (m, 2H), 7.10 - 7.07 (m, 1H), 7.05 - 6.99 (m, 2H), 3.78 - 3.74 (m, 3H), 3.22 - 3.20 (m, 3H), 2.87 - 2.82 (m, 2H), 2.59 - 2.55 (m, 2H), 2.04 - 2.00 (m, 3H)

[0408] tert-Butyl (S)-5-amino-4-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate [ka] To a solution of tert-butyl rac-(4S)-4,5-diamino-5-oxopentanoate (0.052 g, 0.26 mmol) and 3-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid (0.110 g, 0.25 mmol) in toluene (2.5 mL) was added triethylamine (0.44 mL, 2.53 mmol). The resulting mixture was stirred at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give tert-butyl (S)-5-amino-4-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (0.090 g, 0.15 mmol, 59.2% yield). MS(ESI) m / z: 601.3[M+1]

[0409] (S)-4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of tert-butyl (S)-5-amino-4-(4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (0.09 g, 0.15 mmol) in acetonitrile (1.5 mL) was added benzenesulfonic acid (0.047 g, 0.30 mmol). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was quenched with dichloromethane (20 ml) and sodium bicarbonate (saturated aqueous solution, 10 mL), followed by extraction with dichloromethane (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The isolated product was lyophilized to give (S)-4-((6-(1,3-dimethyl-1H-pyrazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.07 g, 0.13 mmol, 88% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.13 - 11.10 (m, 1H), 8.06 - 8.00 (m, 1H), 7.65 - 7.61 (m, 1H), 7.58 - 7.52 (m, 1H), 7.30 - 7.27 (m, 1H), 7.20 - 7.16 (m, 3H), 5.12 - 5.06 (m, 1H), 3.74 - 3.70 (m, 3H), 3.27 (s, 3H), 2.93 - 2.86 (m, 3H), 2.60 (br s, 4H), 2.09 - 2.05 (m, 1H), 2.04 (s, 3H). MS (ESI) m / z: 527.2[M+1]

[0410] Example 31: (S)-4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0411] 7-Amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one [ka] To a solution of potassium carbonate (0.48 g, 3.5 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.048 g, 0.06 mmol), 7-amino-6-bromo-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.300 g, 1.18 mmol), and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.293 g, 1.18 mmol). The suspension was degassed and purged with nitrogen. The mixture was stirred at 110 °C for 12 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (5-15% methanol in dichloromethane) to give 7-amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.15 g, 0.50 mmol, 42% yield). MS (ESI) m / z: 298.1 [M+1] +

[0412] Dimethyl 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate [ka] To a solution of 7-amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (0.150 g, 0.50 mmol) and dimethyl 3-bromophthalate (0.165 g, 0.61 mmol) in 1,4-dioxane (1 mL) was added cesium carbonate (0.492 g, 1.51 mmol) and methanesulfonate (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.042 g, 0.05 mmol). The mixture was degassed and purged with nitrogen. The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction was filtered, and the filtrate was concentrated and purified by semi-preparative reverse-phase HPLC (45-65% acetonitrile in water, 0.1% trifluoroacetic acid additive). The isolated fractions were lyophilized to give dimethyl 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate (0.05 g, 0.10 mmol, 20% yield). MS (ESI) m / z: 490.2 [M+1] +

[0413] 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid [ka] To a solution of dimethyl 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalate (0.050 g, 0.10 mmol) in methanol (1 mL) was added a solution of sodium hydroxide (0.041 g, 1.02 mmol) in water (1 mL). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was added to water (10 mL) and the pH was adjusted to 6. The resulting suspension was filtered and the solid thus obtained was dried under reduced pressure. The filtrate was extracted with dichloromethane (20 mL X 3) and water (20 mL), and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid (0.04 g, 0.087 mmol, 85% yield). MS (ESI) m / z: 462.1 [M+1] +

[0414] tert-Butyl (S)-5-amino-4-(4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate [ka] To a solution of 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)phthalic acid (0.040 g, 0.09 mmol) and tert-butyl (S)-4,5-diamino-5-oxopentanoate (0.018 g, 0.09 mmol) in toluene (0.5 mL) was added triethylamine (0.15 mL, 0.87 mmol). The resulting mixture was stirred at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (S)-5-amino-4-(4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (0.040 g, 0.06 mmol, 73.5% yield). MS (ESI) m / z: 628.3 [M+1] +

[0415] (S)-4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] To a solution of tert-butyl (S)-5-amino-4-(4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (0.040 g, 0.06 mmol) in acetonitrile (2 mL) was added benzenesulfonic acid (0.023 g, 0.14 mmol). The resulting mixture was stirred at 60° C. for 12 hours under nitrogen. The reaction mixture was quenched with dichloromethane (20 ml) and sodium bicarbonate (saturated aqueous solution, 10 mL), followed by extraction with dichloromethane (30 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, followed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was repurified by chiral preparative SFC (40-40% isopropyl alcohol in acetonitrile). After separation, the main peak was lyophilized to give (S)-4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (28.59 mg, 0.0516 mmol, 72.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.30 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.37 (d, J = 1.2 Hz, 1H), 7.29 (s, 1H), 7.18 - 7.13 (m, 2H), 7.02 (t, J = 8.4 Hz, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 3.39 (s, 3H), 3.26 (s, 3H), 2.95 - 2.90 (m, 2H), 2.90 - 2.83 (m, 1H), 2.64 - 2.56 (m, 4H), 2.07 - 2.00 (m, 1H), 1.90 (s, 3H); MS (ESI) m / z: 554.2[M+1] +

[0416] Example 32: (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka]

[0417] 6-Bromo-1-methyl-5-nitro-1H-indazole [ka] A 500 mL three-neck flask was charged with 4-bromo-2-fluoro-5-nitrobenzaldehyde (10.0 g, 40.3 mmol), potassium carbonate (8.4 g, 60.8 mmol), isopropanol (80 mL), and water (40 mL). The mixture was stirred at 41°C for 1 hour, and methylhydrazine (11.7 g, 101.8 mmol) was added dropwise. The resulting mixture was warmed to 77°C and stirred for 6 hours. The mixture was cooled to 20°C, and water (150 mL) was added. The mixture was stirred for 1 hour and filtered. The separated solid was rinsed with water (20 mL x 3) and dried under vacuum to give 6-bromo-1-methyl-5-nitro-1H-indazole (6.7 g, 26.2 mmol, 64% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.33 (d, J = 2.4 Hz, 2H), 4.11 (s, 3H)

[0418] 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole [ka] To a solution of 6-bromo-1-methyl-5-nitro-1H-indazole (10.0 g, 39.0 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (8.7 g, 39.8 mmol) in dioxane (100 mL) and water (10 mL) was added potassium carbonate (16.0 g, 115.9 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct (0.16 g, 0.20 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole (9 g, 33.5 mmol, 85% yield). 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.2 Hz, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 7.12 (d, J = 4.8 Hz, 1H), 4.15 (s, 3H), 2.64 (s, 3H); MS (ESI) m / z: 269.3[M+1] +

[0419] 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine [ka] To a solution of 1-methyl-6-(2-methylpyridin-4-yl)-5-nitro-1H-indazole (9.0 g, 33.5 mmol) in ethanol (90 mL) and water (30 mL) was added ammonium chloride (9.0 g, 168.2 mmol) and iron(II) powder (6.0 g, 107.1 mmol). The resulting mixture was stirred at 70 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was extracted with water (200 mL) and ethyl acetate (3 x 200 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (6.3 g, 26.4 mmol, 78% yield). 1 H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 4.8 Hz, 1H), 7.81 (s, 1H), 7.35 (s, 1H), 7.30 (d, J = 5.2 Hz, 1H), 7.16 (s, 1H), 7.04 (s, 1H), 4.03 (s, 3H), 2.65 (s, 3H); MS (ESI) m / z: 239.1[M+1]+

[0420] Dimethyl 3-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalate [ka] To a solution of 1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-amine (5.3 g, 22.2 mmol) and dimethyl 3-bromophthalate (6.2 g, 22.7 mmol) in dioxane (60 mL) was added cesium carbonate (21.6 g, 66.7 mmol) and methanesulfonate (2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (0.93 g, 1.11 mmol). The resulting mixture was stirred at 110 °C for 12 hours under nitrogen. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain dimethyl 3-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalate (8.0 g, 18.5 mmol, 83% yield). 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.23 - 7.18 (m, 2H), 7.13 (d, J = 5.2 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.12 (s, 3H), 3.86 (s, 3H), 3.78 (s, 3H), 2.56 (s, 3H); MS (ESI) m / z: 431.2 [M+1] +

[0421] 3-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalic acid [ka] To a solution of dimethyl 3-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalate (8.0 g, 18.58 mmol) in methanol (90 mL) was added a solution of sodium hydroxide (7.43 g, 185.85 mmol) in water (30 mL). The resulting mixture was stirred at 80° C. for 12 hours. The reaction mixture was added to water (300 mL) and the resulting suspension was filtered. The solid thus obtained was dissolved in methanol (800 mL), which was then adjusted to pH 4 with aqueous HCl (6 M). The solution was concentrated under reduced pressure. The filtrate was adjusted to pH 4 with aqueous HCl (6 M). The resulting precipitate was isolated by suction filtration and dried under reduced pressure. The isolated materials were combined to give 3-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalic acid (4.0 g, 9.94 mmol, 53% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.51 - 12.72 (m, 2H), 8.41 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 5.2 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.09 (s, 3H), 2.47 (s, 3H); MS (ESI) m / z: 403.2 [M+1] +

[0422] tert-Butyl (S)-5-amino-4-(4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate [ka] To a solution of 3-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)phthalic acid (4.0 g, 9.94 mmol) in toluene (60 mL) was added tert-butyl (S)-4,5-diamino-5-oxopentanoate (2.01 g, 9.94 mmol) and triethylamine (17 mL, 99.4 mmol). The resulting mixture was stirred at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (S)-5-amino-4-(4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (2.83 g, 4.97 mmol, 50% yield). 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 4.8 Hz, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.44 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.37 - 6.12 (m, 1H), 5.54 - 5.33 (m, 1H), 4.78 (t, J = 7.2 Hz, 1H), 4.14 (s, 3H), 2.57 (s, 3H), 2.52 - 2.44 (m, 2H), 2.36 - 2.26 (m, 2H), 1.43 (s, 9H); MS (ESI) m / z: 569.3 [M+1] +

[0423] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione [ka] To a solution of tert-butyl (S)-5-amino-4-(4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)-1,3-dioxoisoindolin-2-yl)-5-oxopentanoate (2.83 g, 4.98 mmol) in acetonitrile (30 mL) was added benzenesulfonic acid (2.36 g, 14.93 mmol). The resulting mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane (200 mL × 3) and sodium bicarbonate (200 mL). The combined organic layer was dried over anhydrous sodium sulfate, followed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC and lyophilized to give (S)-2-(2,6-dioxopiperidin-3-yl)-4-((1-methyl-6-(2-methylpyridin-4-yl)-1H-indazol-5-yl)amino)isoindoline-1,3-dione (1.80 g, 3.64 mmol, 73% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.68 - 8.64 (m, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 8.00 - 7.94 (m, 2H), 7.93 (s, 1H), 7.84 (s, 1H), 7.42 - 7.38 (m, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.70 - 6.66 (m, 1H), 5.09 (dd, J = 5.2, 12.8 Hz, 1H), 4.15 (s, 3H), 2.94 - 2.87 (m, 1H), 2.64 (s, 1H), 2.60 (d, J = 2.0 Hz, 3H), 2.60 - 2.58 (m, 1H), 2.08 - 2.01 (m, 1H); MS (ESI) m / z: 495.2 [M+1] +

[0424] In vitro assays HbF induction assay Using a two-stage liquid culture model (Moutouh-de Parseval LA, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest. 2008 Jan;118(1):248-58), we investigated the effects of GCSF-mobilized human CD34 + (STEMCELL Technologies Inc.) cells were expanded, differentiated, and matured into erythroid cells. In the first step, cells were cultured in StemSpan erythroid cells supplemented with 1X BIT 9500, penicillin-streptomycin (50 U / mL), 100 ng / mL recombinant human (rh) SCF, 100 ng / mL rh Flt3-L, 20 ng / mL rh IL-3, and 10 ng / mL rh EPO. TM GCSF-mobilized human CD34 cells were cultured in -XF (STEMCELL Technologies Inc.) medium. + Cells were cultured and maintained in logarithmic growth phase at 37°C, 5% CO2 for 7 days to support proliferation and progenitor differentiation before the second stage and compound treatment. In the second stage, the medium was changed to StemSpan 1000 supplemented with 1X BIT 9500, penicillin-streptomycin (50 U / mL), 50 ng / mL rh SCF, and 40 ng / mL rh EPO. TM The medium was changed to -XF medium to promote further differentiation and maturation of erythrocytes, and compound treatment was initiated. Compounds were dispensed in duplicate at a final concentration of 1 μM with a final DMSO volume of 0.1%. Fresh compound was applied again, and cell density was kept constant every two days. After 7 days, cells were assessed for viability and fetal hemoglobin expression using flow cytometry. Viability analysis was performed using eBioscience TM Fixable Viability Dye eFluor TM780 (1:1000, eBioscience; Cat# 65-0865-14) was added to the cells and incubated in the dark for 10 minutes. For fetal hemoglobin (HbF) analysis, cells were fixed and permeabilized using Fixation Buffer (BioLegend; Cat# 420801) and Intracellular staining permeabilization buffer (BioLegend, Cat# 420201) according to the manufacturer's instructions. During the permeabilization step, cells were stained with PE-labeled Mouse Anti-Human Fetal Hemoglobin (1:10, clone 2D12; BD Biosciences, Cat# BDB560041) and incubated for 20 minutes at room temperature, protected from light. PE-labeled Mouse anti-IgG kappa (1:10, clone MOPC-21; BD Biosciences, Cat# BDB551436) was used as an isotype control.

[0425] Viability, cell count, and fetal hemoglobin (HbF) levels were measured using an Attune NXT flow cytometer (Thermofisher), and data were analyzed using FCS express software (De Novo Software). Table 1 below shows the effects of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) compounds on % live cells, viable cell count, % HbF-positive cells, and the median fluorescence intensity (MFI) of the HbF-positive cell population compared to the DMSO control. All gates were set using an isotype negative control. The baseline % HbF-positive cells in DMSO-treated control cells was 15%. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) with HbF induction of 66% to 100% were classified as Level A. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having an HbF induction of 33% to 66% are Level B. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a % HbF induction of less than 33% are Level C. For certain compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III), % HbF induction values ​​of 0 to 33% (activity level C), 33% to 66% (activity level B), and 67% to 100% (activity level A) are shown in Table 2 below.

[0426] WIZ assay and ZBTB7A EC50 assay HiBiT degradation assays for WIZ and ZBTB7A in HUDEP-2 cells were performed as follows. HUDEP-2 cells engineered to express a HiBiT tag in either WIZ (widely interspaced zinc finger) or ZBTB7A (zinc finger and BTB domain containing 7A) proteins were maintained in low-adhesion flasks in StemSpan SFEM II medium supplemented with penicillin-streptomycin (50 U / mL), rhSCF (50 ng / mL), rhEPO (3 IU / mL), dexamethasone (0.4 μg / mL), and doxycycline (1 μg / mL). Prior to the assay, cell number and cell viability were measured by trypan blue exclusion using a Vi-cell XR cell viability analyzer. For the HUDEP-2 WIZ HiBiT assay, cells were transferred to a 50 mL conical beaker and centrifuged at 500 g for 5 minutes. Cells were cultured at 1.0x10 cells / well in fresh StemSpan SFEM II medium supplemented with penicillin-streptomycin (50 U / mL), rhSCF (50 ng / mL), rhEPO (3 IU / mL), dexamethasone (0.4 μg / mL), and doxycycline (1 μg / mL). 6Cells were resuspended at a density of 1000 cells / ml. Forty microliters of the cell suspension was dispensed into a 384-well Low Flange White Flat Bottom Polystyrene TC-treated Microplate containing pre-dispensed compounds using a VIAFLO 384 liquid hander and placed in a 37°C, 5% CO2 incubator. Each compound was dispensed in duplicate, with a final DMSO concentration of 0.1%. Twenty-four hours after treatment, 40 μL Nano-Glo HiBiT Lytic Detection System reagent was dispensed into each well using a VIAFLO 384 liquid hander. Plates were incubated for 25 minutes at room temperature, and luminescence was read as relative light units using an EnVision plate reader. EC50 and Y-min values ​​were calculated using curves calculated with dotmatics software after normalization to DMSO control at 10 concentrations (10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.0137, 0.0046, 0.0015, and 0.0005 μM, respectively).

[0427] For the HUDEP-2 ZBTB7A HiBiT assay, cell number and viability were determined by trypan blue exclusion using a Vi-cell XR cell viability analyzer. Cells were transferred to a 50-mL conical beaker and centrifuged at 500 x g for 5 minutes. Cells were resuspended in fresh IMDM medium supplemented with L-glutamine (1X), penicillin-streptomycin (50 U / mL), holotransferrin (330 μg / mL), heparin (2 IU / mL), r-human insulin (10 μg / mL), rhEPO (3 IU / mL), rhSCF (100 ng / mL) + Dox (1 μg / mL), and 5% human plasma in a low-attachment flask and placed in a 37°C, 5% CO2 incubator. After 48 hours, cell number and viability were measured by trypan blue exclusion using a Vi-cell XR cell viability analyzer. HUDEP-2 ZBTB7A cells were transferred to a 50-mL conical beaker, centrifuged at 500 g for 5 minutes, and then cultured at 1.0x10 cells / mL in IMDM medium supplemented with L-glutamine (1X), penicillin-streptomycin (50 U / mL), holotransferrin (330 μg / mL), heparin (2 IU / mL), r-human insulin (10 μg / mL), rhEPO (3 IU / mL), rhSCF (100 ng / mL) + Dox (1 μg / mL), and 5% human plasma. 6Cells were resuspended at a density of 1000 cells / ml. Forty microliters of the cell suspension was dispensed into a 384-well Low Flange White Flat Bottom Polystyrene TC-treated Microplate containing pre-dispensed compounds using a VIAFLO 384 liquid hander and placed in a 37°C, 5% CO2 incubator. Each compound was dispensed in duplicate, with a final DMSO concentration of 0.1%. Twenty-four hours after treatment, 40 μL Nano-Glo HiBiT Lytic Detection System reagent was dispensed into each well using a VIAFLO 384 liquid hander. Plates were incubated for 25 minutes at room temperature, and luminescence was read as relative light units using an EnVision plate reader. EC50 and Y-min values ​​were calculated using curves calculated with dotmatics software after normalization to DMSO control at 10 concentrations (10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.0137, 0.0046, 0.0015, and 0.0005 μM, respectively).

[0428] Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a WIZ EC50<0.01 μM are Level D. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a WIZ EC50>0.01 μM-0.1 μM are Level E. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a WIZ EC50>0.1 μM are Level F. Specific compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having WIZ EC50 values ​​<0.01 μM (activity level D), WIZ EC50 >0.01 μM-0.1 (activity level E), and <0.01 μM (activity level F) are shown in Table 2 below.

[0429] Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a ZBTB7A EC50<0.03 μM are Level G. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a ZBTB7A EC50>0.03 μM-0.1 μM are Level H. Compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having a ZBTB7A EC50>0.1 μM are Level I. Specific compounds of Formula (I), Formula (I'), Formula (II), Formula (II'), and Formula (III) having ZBTB7A EC50 values ​​<0.01 μM (activity level G), ZBTB7A EC50 >0.01 μM-0.1 (activity level H), and <0.01 μM (activity level I) are shown in Table 2 below. [Table 29] [Table 30]

[0430] Several references are cited, the disclosures of which are incorporated herein by reference in their entireties.

Claims

1. The following formula (III): 【Chemistry 1】 [In the formula, Q" is H or CH ３ and R １２ is a substituted or unsubstituted pyridyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted C ３ -C ６ is cycloalkyl] or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein Q" is H.

3. Q" is CH ３ 2. The compound of claim 1, wherein:

4. R １２ But CH ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, wherein the compound is selected from: cyclopropyl, substituted or unsubstituted thiazole, or substituted or unsubstituted pyrazole.

5. R １２ but, 【Chemistry 2】 where: Q ３ is selected from H, Cl, or F; Q ４ is H, CH ３ , or CH(F) ２ Selected from: Q ５ is H, CH ３ , or OCH ３ Selected from: Q ６ is selected from H or F; 10. The compound of claim 1 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

6. Q ３ is F, and / or Q ５ But OCH ３ Or CH ３ 6. The compound of claim 5, wherein:

7. Q ３ is H and Q ４ is H and Q ５ But CH ３ and Q ６ is H; Q ３ is H and Q ４ But CH(F) ２ and Q ５ is H and Q ６ is H; Q ３ is F and Q ４ But CH ３ and Q ５ is H and Q ６ is H; Q ３ is F and Q ４ is H and Q ５ But CH ３ and Q ６ is H; Q ３ is Cl and Q ４ But CH ３ and Q ５ is H and Q ６ is H; Q ３ is H and Q ４ But CH ３ and Q ５ But CH ３ and Q ６ is H; Q ３ is H and Q ４ But CH ３ and Q ５ But OCH ３ and Q ６ is H; Q ３ is F and Q ４ is H and Q ５ But OCH ３ and Q ６ is H; or Q ３ is H and Q ４ is H and Q ５ But OCH ３ and Q ６ But F, 6. The compound of claim 5 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof.

8. A compound of formula (III) selected from: or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof. 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Request Item 9】 【Chemistry 9】 9. The compound of claim 8, wherein: 【Request Item 10】 【Chemistry 10】 9. The compound of claim 8, wherein:

11. A compound of the following structure: 【Chemistry 11】

12. A compound of the following structure: 【Chemistry 12】

13. A pharmaceutically acceptable salt of the following compound: 【Chemistry 13】

14. A pharmaceutically acceptable salt of the following compound: 【Chemistry 14】

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, a compound according to claim 11 or 12, or a pharmaceutically acceptable salt according to claim 13 or 14, and a pharmaceutically acceptable carrier, excipient, or vehicle.

16. A method for inducing HbF expression in a cell and / or decreasing ZBTB7A expression in a cell and / or decreasing WIZ expression in a cell, comprising contacting the cell with a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, a compound of claim 11 or 12, or a pharmaceutically acceptable salt of claim 13 or 14.

17. A composition for treating hemoglobinopathy, comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, isotope, or stereoisomer thereof, a compound according to claim 11 or 12, or a pharmaceutically acceptable salt according to claim 13 or 14.

18. 18. The composition of claim 17, wherein the hemoglobinopathy is anemia, sickle cell disease, thalassemia, alpha thalassemia, or beta thalassemia.

19. 15. A composition for treating a hemoglobinopathy comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, isotopologue, or stereoisomer thereof, a compound according to claim 11 or 12, or a pharmaceutically acceptable salt according to claim 13 or 14, wherein the composition is used to be administered in combination with a second active agent and / or therapy.

20. 20. The composition of claim 19, wherein the second active agent and / or therapy is luspatercept, voxerotol, crizanlizumab-tmca, hydroxyurea, L-glutamine, etabopivat, mitapivat, ocybelotol, inlacumab, blood transfusion, stem cell transplant, bone marrow transplant, or gene therapy.

21. 21. The composition of claim 20, wherein the second active agent and / or therapy is a gene therapy, and the gene therapy is a CRISPR therapy.

22. 20. The composition of claim 19, wherein the hemoglobinopathy is anemia, sickle cell disease, thalassemia, alpha thalassemia, or beta thalassemia.

Images