Compounds and their use for the treatment of abnormal hemoglobin disorders

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 with related applications This application claims priority to U.S. Provisional Application No. 63 / 422,847, filed on 4 November 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] field Compounds and methods for preventing and / or treating abnormal hemoglobin disorders are disclosed herein. Such compounds for use in such methods are also provided herein. Pharmaceutical compositions comprising such compounds for use in such methods for preventing or treating abnormal hemoglobin disorders are also disclosed herein. [Background technology]

[0003] Hemoglobin is an iron-containing metalloprotein found in red blood cells. Hemoglobin transports oxygen to various tissues throughout the body. Fetal hemoglobin (HbF) is present in fetal red blood cells and is involved in the transport of oxygen from the mother to the fetus. After birth, "fetal switching" occurs, during which red blood cell progenitor cells switch from predominantly producing fetal hemoglobin to predominantly producing adult hemoglobin. Adult hemoglobin 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 to oxygen more strongly than adult hemoglobin.

[0004] Abnormal hemoglobin disorders can occur, for example, when there is an abnormal expression of adult-type hemoglobin or a structural abnormality in the adult-type hemoglobin protein. For example, sickle cell anemia occurs when a point mutation in the betaglobin gene results in the formation of hemoglobin S (HbS) composed of two normal alphaglobin chains and two betaglobin 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, obstructing blood flow and potentially leading to hemolysis. Patients with sickle cell anemia suffer from a variety of symptoms, including pain, anemia, bacterial infections, an increased risk of stroke, and a reduced life expectancy.

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

[0006] Reactivation of HbF function expression in adult hematopoietic cells may be clinically very useful for patients with hemoglobin abnormalities such as sickle cell disease and beta-thalassemia. Hydroxyurea is the current standard treatment for sickle cell disease, functioning by inducing fetal hemoglobin, but it is limited by variable clinical responses, myelotoxicity, and carcinogenic risk. Therefore, alternative, more effective treatments for hemoglobin abnormalities are needed. [Overview of the Initiative]

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

[0008] Compound of formula (II): [ka] [In the formula, Y, Q', R 7 , and R 8 [This is defined herein] Also provided herein are pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers thereof.

[0009] Compound of formula (III): [ka] [In the formula, Q'' and R 12 [This is defined herein] Also provided herein are pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers thereof.

[0010] In one embodiment, compounds such as those described herein, for example, compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or the compounds listed in Table 1, are provided herein.

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

[0012] In one embodiment, a method for treating a subject having an abnormal hemoglobinopathy is provided herein. In another embodiment, the 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 an abnormal hemoglobinopathy is provided herein, characterized by administering 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, to a subject suffering from an abnormal hemoglobinopathy.

[0013] In one embodiment, the method described herein is characterized by administering 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, isotopolog, or stereoisomer thereof to the target.

[0014] In one embodiment, the use of compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or the compounds of Table 1 for the treatment or prevention of abnormal hemoglobinopathy is provided herein, characterized by administering an effective amount of a compound of formula (I), formula (I'), formula (II), formula (II'), formula (III), or the compounds of Table 1, as described herein, to a subject suffering from abnormal hemoglobinopathy.

[0015] In one embodiment, compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or compounds of Table 1 are provided herein for use as pharmaceuticals. In certain embodiments, compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or compounds of Table 1 are provided herein for use in a method of treating or preventing abnormal hemoglobin disorders, characterized by administering an effective amount of a compound of formula (I), formula (I'), formula (II), formula (II'), formula (III), or compounds of Table 1 to a subject.

[0016] In another embodiment, methods for preparing compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III) as described herein, or compounds of Table 1 are provided herein.

[0017] The embodiments of this application can be understood in more detail by referring to the embodiments and examples for carrying out the invention, which are intended to illustrate non-limiting embodiments. [Modes for carrying out 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 exist as mentioned, but not as excluding the presence or addition of one or more features or components, or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of.” Accordingly, the term “consisting of” may be used instead 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 described features or components that constitute it. In another embodiment, the term "consisting of" excludes from any subsequent description any other features or components that are not essential to the technical effect to be achieved.

[0020] As used herein, the term “or” should be interpreted as an inclusive “or” meaning any one of the following or any combination thereof. 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 arise only if the combination of elements, functions, processes, or actions is in any way inherently mutually exclusive.

[0021] Unless otherwise specified, the “alkyl” group as used herein is a saturated, partially saturated, or unsaturated linear or branched acyclic hydrocarbon having 1 to 10 carbon atoms, typically 1 to 8 carbon atoms, 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. The “alkenyl” group is an alkyl group containing one or more carbon-carbon double bonds. The “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(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3). Alkyl groups may be substituted or unsubstituted.Where an alkyl group described herein is referred to as “substituted,” it means any substituent as found in the representative compounds and embodiments disclosed herein, as well as halogens; hydroxyl; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo(=O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino These may be substituted with heteroarylaminos, heterocycloalkylaminos; iminos; imides; amidinos; guanidinos; enaminos; acylaminos; sulfonylaminos; ureas, nitroureas; oximes; hydroxylaminos; alkoxyaminos; aralkoxyaminos; hydrazinos; hydrazides; hydrazinos; azides; nitros; thio(-SH), alkylthios; =S; sulfinyls; sulfonyls; aminosulfonyls; phosphonates; phosphinyls; acyls; formyls; carboxylates; carbamates; amides; cyanos; isocyanates; isothiocyanates; cyanates; thiocyanates; or -B(OH)2. In some embodiments, one or more hydrogens in the alkyl group, for example, one, two, three, four, or five hydrogens, may be substituted with halogens.

[0022] Unless otherwise specified, the “cycloalkyl” group as used herein is a saturated or partially saturated cyclic alkyl group having 3 to 10 carbon atoms, having a monocyclic ring or a plurality of fused or crosslinked rings, which may be optionally substituted. In some embodiments, the 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. Examples of such cycloalkyl groups include monocyclic structures (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like) or bicyclic or crosslinked 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, in particular, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. Cycloalkyl groups can be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and its derivatives.

[0023] Unless otherwise specified, the “aryl” group as used herein is an aromatic carbocyclic group of 6 to 14 carbon atoms having a monocyclic ring (e.g., phenyl) or a fused group of multiple rings (e.g., naphthyl or anthryl). In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, and in other embodiments, 6 to 12 or 6 to 10 carbon atoms. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. The aryl group may be substituted or unsubstituted. The term “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, the “heteroaryl” group as used herein is an aromatic ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, where the remaining atoms are carbon atoms. In some embodiments, the heteroaryl group contains 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 some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-restrictive examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridadinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl (e.g., indole-2-onyl), isoindoline-1-onyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), azabenzimidazolyl Examples of heteroaryl groups include, but are not limited to, 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]xazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinoline-1(2H)-onyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups may be substituted or unsubstituted.

[0025] Unless otherwise specified, the term "heterocyclyl" as used herein refers to an aromatic ring system (also called heteroaryl) or a non-aromatic cycloalkyl (also called heterocycloalkyl) in which 1 to 4 of the ring carbon atoms are independently substituted with heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, the 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. The heterocyclyl may also be bonded to other groups at any ring atom (i.e., at any carbon or heteroatom of the heterocyclic ring). The heterocyclyl group may be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl) groups. The term heterocyclyl includes fused ring species, such as 1- and 2-aminotetraline, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl, which contain fused aromatic and non-aromatic groups. This term also includes, but is not limited to, bridging polycyclic ring systems containing heteroatoms, such as quinuclidyl. Representative examples of heterocyclyl groups include azilidinyl, azetidinyl, azepanil, oxetanyl, pyrrolidyl, and imidazolidinyl (e.g., imidazolidinyl-4-onyl or imidazolidinyl-2).4-Dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolinil, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzoisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinil, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-o Nyl), Morpholinyl, Thiomorpholinyl, Tetrahydropyranyl (e.g., Tetrahydro-2H-pyranyl), Tetrahydrothiopyranyl, Oxathianyl, Dioxyl, Dithianyl, Pyranyl, Pyridyl, Pyrimidyl, Pyridazinyl, Pyrazinyl, Triazinyl, Dihydropyridyl, Dihydrodithinyl, Dihydrodithionyl, 1,4-Dioxaspiro[4.5]decanyl, Homopiperazinyl, Quinuclidyl, Indolyl (e.g., Indole-2-onyl), Isoindolin-1-onyl, Indolinyl, Iso Indolyl, isoindlinyl, azaindolyl, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolidinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazole-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithinyl, benzoxathi Nyl, benzothiadinyl, 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,Examples include, but are not limited to, 4-dihydroisoquinoline-1(2H)-onyl, quinolidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, phthalazinyl, naphthylidinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidine-2(1H)-one, and tetrahydroquinolinyl groups. Typical non-aromatic heterocyclyl groups do not include condensed ring species containing condensed aromatic groups. Examples of non-aromatic heterocyclyl groups include azilidinyl, azetidinyl, azepanil, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4-onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranil (e.g., tetrahydro-2H-pyranil), tetrahydrothiopyranil, oxathianil, dithianil, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidine-2(1H)-one. Typical substituted heterocyclyl groups may be monosubstituted or multiple substituted (for example, pyridyl or morpholinyl groups that are two, three, four, five, or six-substituted, or two-substituted, by various substituents such as those described below, but are not limited to these).

[0026] Unless otherwise specified, the “cycloalkylalkyl” group as used herein is a radical of the formula :-alkyl-cycloalkyl, where alkyl and cycloalkyl are defined above. Substituted cycloalkylalkyl groups may be substituted with the alkyl moiety, the cycloalkyl moiety, or both the alkyl and cycloalkyl moieties 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, the “aralkyl” group as used herein is a radical of the formula :-alkyl-aryl, where alkyl and aryl are defined above. Substituted aralkyl groups may be substituted with the alkyl moiety, the aryl moiety, or both the alkyl and aryl moieties. Typical aralkyl groups include, but are not limited to, the benzyl and phenethyl groups, as well as aralkyl groups formed by the condensation of an aryl group, such as indan-4-ylethyl, with a cycloalkyl group.

[0028] Unless otherwise specified, the “heterocyclylalkyl” group as used herein is the radical of the formula:-alkyl-heterocyclyl, where alkyl and heterocyclyl are defined above. The “heteroarylalkyl” group is the radical of the formula:-alkyl-heteroaryl, where alkyl and heteroaryl are defined above. The “heterocycloalkylalkyl” group is the radical of the formula:-alkyl-heterocycloalkyl, where alkyl and heterocycloalkyl are defined above. A substituted heterocyclylalkyl group may be substituted with the alkyl moiety, the heterocyclyl moiety, or both the alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholine-4-ylethyl, morpholine-4-ylpropyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0029] Unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine.

[0030] Unless otherwise specified, the “hydroxyalkyl” group as used herein refers to an alkyl group as described above, substituted with one or more hydroxyl groups.

[0031] Unless otherwise specified, the “alkoxy” group used herein is -O-(alkyl), where alkyl is defined above. The “alkylthio” group is -S-(alkyl), where alkyl is defined above.

[0032] Unless otherwise specified, the “alkoxyalkyl” group used herein is -(alkyl)-O-(alkyl), where alkyl is defined above.

[0033] Unless otherwise specified, the “cycloalkyloxy” group used herein is -O-(cycloalkyl), where cycloalkyl is defined above.

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

[0035] Unless otherwise indicated, the term "heterocyclyloxy" as used herein is -O-(heterocyclyl), where heterocyclyl is as defined above. The term "heteroaryloxy" is -O-(heteroaryl), where heteroaryl is as defined above. The term "heterocycloalkyloxy" is -O-(heterocycloalkyl), where heterocycloalkyl is as defined above.

[0036] Unless otherwise indicated, the term "amino" as used herein is a radical of the formula: -NH2, -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, and these groups are each independently substituted or unsubstituted.

[0037] In one embodiment, the "amino" group is an "alkylamino" group which is a radical of the formula: -NH-alkyl or -N(alkyl)2, where alkyl is each independently as defined above. The terms "cycloalkylamino", "arylamino", "heterocyclylamino", "heteroarylamino", "heterocycloalkylamino" or the like are defined in the same manner as the above description for "alkylamino", where the term "alkyl" is replaced by "cycloalkyl", "aryl", "heterocyclyl", "heteroaryl", "heterocycloalkyl", or the like, respectively.

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

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

[0040] Unless otherwise specified, the “amide” group used herein refers to the formulas: -C(O)-NH2, -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 # ) is a radical, in the formula R # Each of these is defined independently above.

[0041] In one embodiment, the "amide" group is of the formula: -C(O)-NH2, -C(O)-NH(R # ), -C(O)-N(R # )2 is an aminocarbonyl group, and in the formula, R # Each of these is defined independently above.

[0042] In one embodiment, the "amide" group is of the formula: -NH-C(O)H, -NH-C(O)-(R # ), -N(R # )-C(O)H, or -N(R # )-C(O)-(R # The radical of ) is the "acylamino" group, in the formula R # Each of these is defined independently above.

[0043] Unless otherwise specified, the "sulfonylamino" group used herein is of the formula: -NHSO2(R # ) or -N(R # )SO2(R # ) is a radical, in the formula, each R # It is defined above.

[0044] Unless otherwise specified, the “ester” group used herein is of the formula: -C(O)-O-(R # ) or -OC(O)-(R # ) is a radical, in the formula R # It is defined above.

[0045] In one embodiment, the “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,” and “heterocycloalkyloxycarbonyl,” or similar terms, are described in the same way as the above description of “alkoxycarbonyl,” where the term “alkoxy” is replaced by “cycloalkyloxy,” “aryloxy,” “heterocyclyloxy,” “heteroaryloxy,” “heterocycloalkyloxy,” or similar terms, respectively.

[0046] Unless otherwise specified, the "carbamate" group used herein refers to the formulas: -OC(O)-NH2, -OC(O)-NH(R # ), -OC(O)-N(R # )2,-NH-C(O)-O-(R # ), or -N(R # )-C(O)-O-(R # ) is a radical, in the formula R # Each of these is defined independently above.

[0047] Unless otherwise specified, the “urea” group used herein refers to the formula: -NH(CO)NH2, -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 #) is a radical of 2, in the formula R # Each of these is defined independently above.

[0048] Unless otherwise specified, the "sulfinyl" group used herein is of the formula: -S(O)R # It is a radical of, and in the formula, R # It is defined above.

[0049] Unless otherwise specified, the "sulfonyl" group used herein has the formula: -S(O)2R # It is a radical of, and in the formula, R # It is defined above.

[0050] Unless otherwise specified, the "aminosulfonyl" group used herein is of the formula: -SO2NH2, -SO2NH(R # ), or -SO2N(R # ) is a radical of 2, in the formula R # Each of these is defined independently above.

[0051] Except for alkyl groups, when a group described herein is said to be “substituted,” it may be substituted with any suitable substituent. Examples of substituents are those found in the representative compounds and embodiments disclosed herein, as well as halogens; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, heterocycloalkylalkyl (these may be further substituted at will); hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkylalkyloxy; oxo (=O); oxide ( For example, a nitrogen atom substituted with an oxide is called an N-oxide; amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imide; 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; amide; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(OH)2. In some embodiments, one or more hydrogens in a substituent, for example, one, two, three, four, or five hydrogens, may be substituted with halogens. In some embodiments, the hydrogen atom is replaced by an alkyl, alkoxy, aryloxy, halogen, or haloalkyl group by substitution.

[0052] As used herein, the term “hemoglobin disorders” refers to any disease or disorder that affects red blood cells. Hemoglobin disorders include, but are not limited to, sickle cell anemia and anemia.

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

[0054] As used herein, the term “gene therapy” means the treatment of a disease or condition by introducing or contacting genetic material into cells.

[0055] As used herein, the term "CRISPR" refers to a clustered, regularly arranged sequence of short palindromic repeats.

[0056] As used herein, the term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and inorganic bases, as well as organic acids and organic bases. Suitable pharmaceutically acceptable base addition salts of formulas (I), (I'), (II), (II'), (III), and the compounds in Table 1 include, but are not limited to, metal 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, ethensulfonic acid, formic acid, fumaric acid, furic 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, mucinic 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 salts and mesylate salts. Other details are well known in this technical field, for example, Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th See eds., Mack Publishing, Easton PA (1995).

[0057] Unless otherwise specified, the terms “stereoisomer” or “stereoisomerically pure” as used herein mean one stereoisomer of formula (I), formula (I'), formula (II), formula (II'), formula (III), or one of the compounds in Table 1 that substantially does not contain any other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center substantially does not contain the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers substantially does not contain any other diastereomers of the compound. A typical stereoisomerically pure compound contains about 80% by weight of one stereoisomer of the compound and less than 20% by weight of the other stereoisomers of the compound, or about 90% by weight of one stereoisomer of the compound and less than 10% by weight of the other stereoisomers of the compound, or about 95% by weight of one stereoisomer of the compound and less than 5% by weight of the other stereoisomers of the compound, or about 97% by weight of one stereoisomer of the compound and less than 3% by weight of the other stereoisomers of the compound. Formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 may have a chiral center 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 stereoisomerically pure forms of formulas (I), (I'), (II), (II'), (III), and the compounds listed in Table 1, as well as the use of mixtures of such forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equimolar or unequal amounts of enantiomers of formulas (I), (I'), (II), (II'), (III), or certain compounds in Table 1 may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques (e.g., chiral columns or chiral resolving agents). For example, see Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0059] It should also be noted that compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or those in Table 1 may include E isomers and Z isomers, or mixtures thereof, as well as cis isomers and trans isomers, or mixtures thereof. In certain embodiments, the compound is isolated as either the E or Z isomer. In other embodiments, the compound is a mixture of E and Z isomers. In some embodiments, compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or those in Table 1 are isolated as either the E isomer or the Z isomer. In other embodiments, compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or those in Table 1 are a mixture of E and Z isomers.

[0060] "Tautomers" refer to isomers of a compound that are in equilibrium with each other through proton rearrangement. The concentration of isomers depends on the environment in which the compound is found; for example, it may differ depending on whether the compound is a solid or in an organic solution or aqueous solution. For example, pyrazole may exhibit the following isomers in aqueous solution, and these are called tautomers of each other. [ka]

[0061] As will be readily apparent to those skilled in the art, various functional groups and other structures may exhibit tautomerism, and all tautomers of formula (I), formula (I'), formula (II), formula (II'), formula (III), or the compounds in Table 1 are within the scope of this disclosure.

[0062] It should also be noted that compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or those in Table 1 may contain atomic isotopes in unnatural proportions, at least one of the atoms. For example, a compound may contain radioactive isotopes (e.g., tritium). 3 H), Iodine-125 ( 125 I), Sulfur 35 ( 35 S), or carbon-14 ( 14It may be radioactively labeled with C, etc., or carbon-13 ( 13 C) or nitrogen 15 ( 15 Isotope enrichment may occur in N), etc. As used herein, “isotopologs” are isotope-enriched compounds. The term “isotopically enriched” refers to an atom that has an isotope composition other than the natural isotope composition of that atom. “Isotope enriched” may also refer to a compound that contains at least one atom that has an isotope composition other than the natural isotope composition of that atom. The term “isotopically enriched” refers to the amount of each isotope present for a given atom. Radiolabeled compounds and isotope-enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation treatments, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo contrast agents. All isotope variations of formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 described herein, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopologs of formulas (I), (I'), (II), (II'), (III), or compounds of Table 1 are provided, for example, the isotopolog being a compound of formula (I), (I'), (II), (II'), (III), or a compound of Table 1 enriched with carbon 13 or nitrogen 15. As used herein, “deuterated” means that at least one hydrogen (H) is deuterated (D or 2 A compound substituted with (indicated by H) means that the compound is concentrated with deuterium at at least one position. Note that if there is a discrepancy between the depicted structure and the name of that structure, the depicted structure should take precedence.

[0063] As used herein, “to treat” means the overall or partial relief of one or more symptoms of a disorder, disease, or condition, or symptoms associated with such a disorder, disease, or condition, or the slowing or cessation of further progression or worsening of those symptoms, or the reduction or eradication of the cause of the disorder, disease, or condition itself. In one embodiment, the disorder, disorder, or condition is an abnormal hemoglobin disorder.

[0064] As used herein, “prevent” means a method of delaying, and / or preventing, in whole or in part, the onset, recurrence, or progression of a disorder, disease, or condition; a method of preventing a subject from contracting a disorder, disease, or condition; or a method of reducing the risk to a subject from contracting a disorder, disease, or condition. In one embodiment, the disorder, disorder, or condition is an abnormal hemoglobin disorder.

[0065] The term “effective amount” in relation to formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 means an amount that can treat or prevent the disorder, disease, or condition, or symptoms thereof, disclosed herein. In one embodiment, the disorder, disorder, or condition is an abnormal hemoglobin disorder.

[0066] The terms "subject" or "patient" include human beings.

[0067] The terms “combined” or “combined” administration include administering as a mixture, administering simultaneously using separate formulations, and administering sequentially in any order.

[0068] Unless otherwise defined, technical and scientific terms used herein have the same meanings as those generally understood by a person of the ordinary art in the field to which this application pertains.

[0069] compound The following equation (I): [ka] [In the formula, [ka] It is either a single bond or a double bond; A 1 , NR 1 , O, CH(R 2 ), or C(R 2 )2; A 2 , NR 1 , C=O, CH(R 2 ), or C(R 2 )2; A 3 , NR 1 , O, CH(R 2 ), or C(R 2 )2; R 1 Each of these is independently either absent, H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cyclylalkyl group, a substituted or unsubstituted heterocyclyl group, or a substituted or unsubstituted heterocyclylalkyl group; R 2 Each of these is independently either absent, H, an amine, or a substituted or unsubstituted alkyl group; R 3 These are, independently, H, substituted or unsubstituted cycloalkyl, and -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 a cycloalkyl; Q is either H or CH3. Compounds of the above are provided herein.

[0070] The following equation (I'): [ka] [Wherein, [Chem.] is a single bond or a double bond; A 1’ is NR 1’ , O, or CH(R 2’ ); A 2’ is NR 1’ , C=O, CR 2’ , or CH(R 2’ );[[ID=H27]] A 3’ is NR 1’ , O, CR 2’ , or CH(R 2’ ); R 1’ are each independently absent, H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heteroalkylalkyl; R 2’ are each independently H, an amine, or substituted or unsubstituted alkyl;.5 R 3’ are each independently H, substituted or unsubstituted cycloalkyl, -O-R 4’ , CH2-R*, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted 3,4-dihydro-2(1H)-quinolinone; R 4’ are substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R* is cycloalkyl; Q* is H or CH3] Compounds of formula (I) as represented herein and their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers are provided herein.

[0071] In certain embodiments, [Chem.] is a single bond.

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

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

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

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

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

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

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

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

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

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

[0082] In one embodiment, R* is cyclopropyl. In another embodiment, R' is cyclopropyl.

[0083] In one embodiment, R 3’ teeth [ka] And in the formula, R 5’ is H, a substituted or unsubstituted alkyl group, or an alkoxy group; R 6’ is H, a halogen, or a substituted or unsubstituted alkyl group.

[0084] In one embodiment, R 3 teeth, [ka] And in the formula, R 5 is H, a substituted or unsubstituted alkyl group, or an alkoxy group; R 6 is H, a halogen, or a substituted or unsubstituted alkyl group.

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

[0086] In one embodiment, R 6’ is a haloalkyl. In one embodiment, R 6 It is a haloalkyl.

[0087] In one embodiment, [ka]

[0088] Compounds of formula (I) selected from the following are provided herein, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0089] The following equation (II): [ka] [In the formula, Q' is either H or CH3; Y is CR 13 It is CH or N; R 7 H, OR 9 , substituted or unsubstituted aryl, or substituted or unsubstituted alkyl; R 8 H, OR 10 , or a substituted or unsubstituted aryl; R 9 These are substituted or unsubstituted alkyl, aryl, CH2CH2N(CH3)2, or CH2CH2-R 11 and; R 10 is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aryl; R 11 It is piperidinyl; R 13 [It is a substituted or unsubstituted alkyl group.] Compounds thereof, as well as pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers thereof, are provided herein.

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

[0091] In certain embodiments, Y is CH. In certain embodiments, Y’ is CH.

[0092] In certain embodiments, Y is N. In certain embodiments, Y’ is N.

[0093] In certain embodiments, R 7 is CH3. In certain embodiments, R 7’ is CH3.

[0094] In certain embodiments, R 10 is CH3. In certain embodiments, R 10’ is CH3.

[0095] In certain embodiments, R 10 is aryl. In certain embodiments, R 10’ is aryl.

[0096] In certain embodiments, R 10 is phenyl. In certain embodiments, R 10’ is phenyl.

[0097] In certain embodiments, R 10 is substituted phenyl. In certain embodiments, R 10’ is substituted phenyl.

[0098] In certain embodiments, R13 It is a C1-C6 alkyl group substituted with an aryloxy.

[0099] Compounds of formula (II) selected from the following are provided herein, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof. [ka] [ka]

[0100] The following equation (III): [ka] [In the formula, Q is either H or CH3; R 12 [These are substituted or unsubstituted pyridyls, substituted or unsubstituted alkyls, substituted or unsubstituted heterocyclyls, or substituted or unsubstituted C3-C6 cycloalkyls.] Compounds thereof, as well as pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers thereof, are provided herein.

[0101] In one embodiment, Q'' is H.

[0102] In one embodiment, Q'' is CH3.

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

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

[0105] In one embodiment, R 12 This is selected from substituted or unsubstituted thiazoles or substituted or unsubstituted pyrazoles.

[0106] In one embodiment, R 12 is [Chemical formula] wherein 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, Q 4 is H, Q<C 5 is CH3, Q 6 is H.

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

[0112] In one embodiment, Q​​​​​​​​​​​​​​​​5 CH3 is Q 6 H is H.

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

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

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

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

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

[0119] Compounds of formula (III) selected from the following are provided herein, or pharmaceutically acceptable salts, tautomers, isotopologs, 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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 4-((1-cyclopropyl-5-(2-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-6-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazole-4-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-5-(2-methylpyridine-4-yl)-1H-indazole-6-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((3-methyl-6-(2-methylpyridine-4-yl)benzo[d]isoxazole-5-yl)amino)isoindoline-1,3-dione; 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridine-3-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione; 4-((6-(2-(difluoromethyl)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((2-methoxy-4-(2-(piperidine-1-yl)ethoxy)phenyl)amino)isoindoline-1,3-dione; 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-4-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-phenoxy-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-methyl-4-phenoxypyridine-3-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 4-((1,2-dimethyl-6-(2-methylpyridine-4-yl)-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(6-methylpyridazine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 4-((6-(3-chlorophenoxy)-1-methyl-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-5-((4-methylpyrimidine-5-yl)oxy)-1H-indazole-4-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-5-phenoxy-1H-indazole-6-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(3-(trifluoromethyl)phenyl)-1H-indazole-5-yl)amino)isoindorine-1,3-dione; 4-((6-(2,3-dimethylpyridine-4-yl)-1-methyl-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorine-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-methoxy-4-phenylpyridine-3-yl)amino)isoindoline-1,3-dione; 4-((3-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)-2-((S)-3-methyl-2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione; (S)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 4-((1,6-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; 4-((6-cyclopropyl-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; (S)-4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(1-methyl-1H-pyrazole-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; (S)-4-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; (S)-4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(4-methylthiazole-2-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; (S)-4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione; (S)-4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione; (S)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 2-((S)-2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluoro-2-methylpyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(5-fluoro-2-methylpyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 4-((6-(3-chloro-2-methylpyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; 4-((6-(2,6-dimethylpyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione; (S)-2-(2,6-dioxopiperidine-3-yl)-4-((6-(2-methoxy-6-methylpyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluoro-2-methoxypyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 2-(2,6-dioxopiperidine-3-yl)-4-((6-(5-fluoro-2-methoxypyridine-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 2-((R)-2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione; (R)-2-(3-methyl-2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione; 2-(3-methyl-2,6-dioxopiperidine-3-yl)-4-((3-(phenoxymethyl)phenyl)amino)isoindoline-1,3-dione, or pharmaceutically acceptable salts, tautomers, isotopologs, and / or stereoisomers thereof.

[0121] In one embodiment, the compound is 4-((1,2-dimethyl-5-(2-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0122] In one embodiment, the compound is 4-((1-cyclopropyl-5-(2-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0123] In one embodiment, the compound is 4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0124] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0125] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-6-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0126] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazole-4-yl)amino)isoindoline-1,3-dione.

[0127] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-5-(2-methylpyridine-4-yl)-1H-indazole-6-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0128] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((3-methyl-6-(2-methylpyridine-4-yl)benzo[d]isoxazole-5-yl)amino)isoindoline-1,3-dione.

[0129] In one embodiment, the compound is 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridine-3-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0130] In one embodiment, the compound is 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0131] In one embodiment, the compound is 4-((6-(2-(difluoromethyl)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0132] In one embodiment, the compound is 2,6-dioxopiperidine-3-yl)-4-((2-methoxy-4-(2-(piperidine-1-yl)ethoxy)phenyl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0133] In one embodiment, the compound is 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-4-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0134] In one embodiment, the compound is 4-((5-(2-chlorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-4-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0135] In one embodiment, the compound is (S)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione.

[0136] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-5-yl)amino)isoindoline-1,3-dione, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, and / or stereoisomer.

[0137] In one embodiment, the compound is 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione.

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

[0139] Representative compounds of formulas (I), (I'), (II), (II'), and (III) are listed in Table 1.

[0140] How to use In some embodiments, the present disclosure provides a method for inducing HbF expression in cells, comprising contacting cells with formula (I), formula (I'), formula (II), formula (II'), formula (III), the compounds of Table 1, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof.

[0141] In some embodiments, the present disclosure provides a method for reducing WIZ expression in cells, comprising contacting cells with formula (I), formula (I'), formula (II), formula (II'), formula (III), the compounds of Table 1, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof.

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

[0143] In some embodiments, the present disclosure provides a method for inducing HbF expression in cells and / or decreasing ZBTB7A expression in cells and / or decreasing WIZ expression in cells, the method comprising contacting cells with formula (I), formula (I'), formula (II), formula (II'), formula (III), the compounds of Table 1, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof.

[0144] In some embodiments, the present disclosure provides a method for treating an abnormal hemoglobin disorder, characterized by administering formula (I), formula (I'), formula (II), formula (II'), formula (III), the compounds of Table 1, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof to a subject in need of treatment.

[0145] In some embodiments, the present disclosure provides the use of compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), Table 1, or pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers thereof for the treatment of abnormal hemoglobin disorders.

[0146] In one embodiment, the abnormal hemoglobinosis is anemia. In one embodiment, the abnormal hemoglobinosis is sickle cell disease. In one embodiment, the abnormal hemoglobinosis is thalassemia. In one embodiment, the abnormal hemoglobinosis is alpha-thalassemia. In one embodiment, the abnormal hemoglobinosis is beta-thalassemia.

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

[0148] In one embodiment, a method for inducing HbF expression in cells is provided herein, comprising contacting the cells with formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1.

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

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

[0151] In one embodiment, a method for treating an abnormal hemoglobin disorder is provided herein, characterized by administering to a subject in need of treatment a pharmaceutical composition of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1, or a compound from formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1.

[0152] In one embodiment, abnormal hemoglobinopathy is anemia.

[0153] In one embodiment, the abnormal hemoglobin disorder is sickle cell anemia.

[0154] In one embodiment, the abnormal hemoglobin disorder is sickle cell anemia.

[0155] In one embodiment, the abnormal hemoglobin disorder is thalassemia.

[0156] In one embodiment, the abnormal hemoglobin disorder is alpha-thalassemia.

[0157] In one embodiment, the abnormal hemoglobin disorder is beta-thalassemia.

[0158] In one embodiment, a method for treating an abnormal hemoglobin disorder is provided herein, characterized by administering to a subject in need of treatment a pharmaceutical composition of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1, or formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1, in combination with a second active agent and / or a second therapy. In one embodiment, the second active agent is ruspatercept. In one embodiment, the second active agent is voxerotol. In one embodiment, the second active agent is chryzanlizumab-tmca. In one embodiment, the second active agent is hydroxyurea. In one embodiment, the second active agent is L-glutamine. In one embodiment, the second active agent is etavopibat. In one embodiment, the second active agent is mitapibat. In one embodiment, the second active agent is osivelotol. In one embodiment, the second active agent is incrumab. In one embodiment, the second therapy is blood transfusion. In one embodiment, the second therapy is stem cell transplantation. In one embodiment, the second therapy is bone marrow transplantation. In one embodiment, the second therapy is gene therapy. In one embodiment, the gene therapy is CRISPR therapy. In one embodiment, the abnormal hemoglobinopathy is anemia. In one embodiment, the abnormal hemoglobinopathy is sickle cell disease. In one embodiment, the abnormal hemoglobinopathy is thalassemia. In one embodiment, the abnormal hemoglobinopathy is alpha-thalassemia. In one embodiment, the abnormal hemoglobinopathy is beta-thalassemia.

[0159] Formulas (I), (I'), (II), (II'), (III), or those listed in Table 1 have medicinal properties for treating, preventing, or improving hemoglobin disorders. The compounds provided herein are useful for treating or preventing all diseases, disorders, or conditions disclosed herein.

[0160] In one embodiment, a method for treating a disease caused by abnormal hemoglobinosis is provided herein. In one embodiment, the compounds described herein are used in medical therapy for humans, in particular for the treatment of abnormal hemoglobinosis.

[0161] In one embodiment, a method for treating a disease caused by abnormal hemoglobinosis is provided herein. In one embodiment, the compounds described herein are used in medical therapy for humans, in particular for the treatment of abnormal hemoglobinosis. In one embodiment, the method is characterized by administering a therapeutically effective amount of the compounds described herein to a subject having a disease caused by abnormal hemoglobinosis.

[0162] In one embodiment, a method for treating or preventing an abnormal hemoglobin disorder is provided herein, characterized by administering to a subject an effective amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer thereof. In one embodiment, the abnormal hemoglobin disorder is anemia. In one embodiment, the abnormal hemoglobin disorder is sickle cell disease. In one embodiment, the abnormal hemoglobin disorder is sickle cell anemia.

[0163] In another embodiment, a method for preventing diseases caused by abnormal hemoglobinosis is also provided herein. In one embodiment, formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer is used in medical therapy for humans, in particular for the prevention of abnormal hemoglobinosis. In one embodiment, the method is characterized by administering to a subject a therapeutically effective amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer, in order to prevent diseases caused by abnormal hemoglobinosis.

[0164] Second active agent and second therapy In one embodiment, the second active agent used in the method provided herein is selected from the group consisting of ruspatercept, voxerotol, chryzanlizumab-tmca, hydroxyurea, L-glutamine, etavo pivat, mita pivat, osivelotol, and incrumab.

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

[0166] Treatment methods and / or preventive methods In one embodiment, a method for treating an abnormal hemoglobin disorder is provided herein, characterized by administering to a patient a therapeutically effective amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in combination with a second active agent, wherein the second active agent is selected from the group consisting of ruspatercept, voxerotol, chryzanlizumab-tmca, hydroxyurea, L-glutamine, etavopivat, mitapivat, osivelotol, and incrumab.

[0167] In one embodiment, a method for treating an abnormal hemoglobin disorder is provided, characterized by administering to a patient a therapeutically effective amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, 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 transplantation and / or bone marrow transplantation, and / or gene therapy. In one embodiment, the gene therapy is CRISPR therapy.

[0168] Pharmaceutical composition and route of administration Pharmaceutical compositions 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 are provided herein. Compounds of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1 may be administered enterally (e.g., orally, rectally), topically, or parenterally (e.g., intravenously, intramuscularly, subcutaneously) to a target in conventional formulations (e.g., capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions).Suitable formulations include conventional organic or inorganic additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, acacia gum, polyethylene glycol, sucrose, or starch), and disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or citrate). It can be prepared by commonly used methods using calcium benzoate, lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavorings (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersants (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), cosolvents (e.g., propylene glocyl / glycofurol), buffers, copolymers (e.g., polylactic acid-glycolic acid, i.e., PLGA), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol), etc. The effective amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or the compounds in Table 1 in the pharmaceutical composition may be at a level that produces the desired effect, for example, the unit dose for both oral and parenteral administration is approximately 0.005 mg / kg (body weight of the subject) to approximately 20 mg / kg (body weight of the subject).

[0169] The dosage of formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 to be administered to a subject may vary considerably and be subject to the judgment of the healthcare provider. Generally, formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 may be administered once to four times daily at doses ranging from approximately 0.5 mg / kg (subject's body weight) to approximately 20 mg / kg (subject's body weight), although these doses may be appropriately adjusted depending on the subject's age, body weight, medical condition, and type of administration. In one embodiment, the dose is approximately 0.1 mg / kg (subject's body weight) to approximately 3 mg / kg (subject's body weight), approximately 0.5 mg / kg (subject's body weight) to approximately 2 mg / kg (subject's body weight), approximately 1 mg / kg (subject's body weight) to approximately 2 mg / kg (subject's body weight), or approximately 1.5 mg / kg (subject's body weight) to approximately 2 mg / kg (subject's body weight). In one embodiment, the dose is approximately 1 mg / kg (body weight of the subject) to approximately 3 mg / kg (body weight of the subject). In one embodiment, the dose is approximately 0.5 mg / kg (body weight of the subject) to approximately 1 mg / kg (body weight of the subject). In one embodiment, the dose is approximately 1 mg / kg (body weight of the subject) to approximately 2 mg / kg (body weight of the subject). In one embodiment, the dose is approximately 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, 3.0 mg / kg (body weight of the subject). In one embodiment, one dose is given per day. In any given case, the amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or compound from Table 1 administered depends 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 approximately 0.01 to 10 μM.

[0170] In another embodiment, a method for treating or preventing a disease or disorder is provided herein, characterized by administering formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1 to a subject suffering from an abnormal hemoglobinosis in an amount ranging from about 1 mg / day to about 1200 mg / day. In yet another embodiment, a method for treating or preventing a disease or disorder is provided herein, characterized by administering formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1 to a subject suffering from an abnormal hemoglobinosis in an amount ranging 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. In one embodiment, a method for treating a disease or disorder is characterized by administering formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1 to a subject suffering from an abnormal hemoglobin disorder at a dose of approximately 0.375 mg / day to approximately 750 mg / day. In one embodiment, a method for treating a disease or disorder is characterized by administering formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1 to a subject suffering from an abnormal hemoglobin disorder at a dose of approximately 3.75 mg / day to approximately 75 mg / day.

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

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

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

[0174] Formulas (I), (I'), (II), (II'), (III), or those listed in Table 1 may be administered once, twice, three times, four times, or more times per day. In certain embodiments, doses of 600 mg or less are administered once daily, and doses greater than 600 mg are administered twice daily in amounts equal to half of the total daily dose.

[0175] Formulas (I), (I'), (II), (II'), (III), or those listed in Table 1 may be administered orally for convenience. In one embodiment, when administered orally, formulas (I), (I'), (II), (II'), (III), or those listed in Table 1 are administered with food and water. In another embodiment, formulas (I), (I'), (II), (II'), (III), or those listed in Table 1 are dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.

[0176] Formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 may be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, transdermally, transdermally, rectally, mucous membrane, by inhalation, or topically to the ear, nose, eye, or skin, or topically to the eye (i.e., subconjunctival, intravitreal, retrobulbar, anterior chamber). The method of administration is left to the discretion of the healthcare provider and may be partially dependent on the site of the disease.

[0177] In one embodiment, a capsule containing formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound from Table 1 is provided herein, without additional carriers, excipients, or vehicles.

[0178] In another embodiment, compositions comprising an effective amount of formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1 and a pharmaceutically acceptable carrier or vehicle are provided herein, wherein the pharmaceutically acceptable carrier or vehicle may include excipients, diluents, 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, injections, lozenges, suppositories, suspensions, gels, ruminant devices (e.g., for prolonged prophylaxis or controlled release), implants, topical pore-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 a suitable portion of a daily dose in a dosing unit which may be one tablet, one capsule, or an appropriate amount of liquid. In one embodiment, the solution is prepared from a water-soluble salt such as hydrochloride. Generally, all compositions are prepared according to methods known in pharmacochemistry. Capsules may be prepared by mixing formula (I), formula (I'), formula (II), formula (II'), formula (III), or a compound of Table 1 with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powders (e.g., various types of starch), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (e.g., fructose, mannitol, and sucrose), grain flour, and similar edible powders.

[0180] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations typically 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 calcium sulfate, inorganic salts (e.g., sodium chloride), and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like). Natural and synthetic rubbers 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 the formulation of tablets to prevent the tablet and punch from sticking in the dye. Lubricants can be selected from slippery solids such as talc, magnesium stearate 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 rubber. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethylcellulose, as well as sodium lauryl sulfate may be used. Tablets may be coated with sugars as flavoring and fillers, or with film-forming protective agents, to modify the tablet's solubility. Compositions may also be formulated as chewable tablets, for example, by using substances such as mannitol in formulation.

[0182] The effects of formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 may be delayed or prolonged by appropriate formulations. For example, gradually dissolving pellets of formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 may be prepared and incorporated into tablets or capsules, or as sustained-release implantable devices. Techniques also include creating pellets with multiple different dissolution rates and filling capsules with mixtures of pellets. Tablets or capsules may be coated with a membrane that resists dissolution over a predictable period of time. Even parenteral formulations may be made long-acting by dissolving or suspending them in an oily or emulsified vehicle that allows for slow dispersion of formulas (I), (I'), (II), (II'), (III), or the compounds in Table 1 in serum, or by adding a certain amount of PLGA.

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

[0184] 2. [ka] However, the compound described in Embodiment 1 has a single bond.

[0185] 3. [ka] However, the compound described in Embodiment 1 has a double bond.

[0186] 4. The compound according to any one of Embodiments 1 to 3, wherein A1 is NR1.

[0187] 5. The compound according to any one of Embodiments 1 to 4, wherein A2 is NR1.

[0188] 6. The compound according to any one of Embodiments 1 to 5, wherein A3 is NR1.

[0189] 7. The compound according to any one of Embodiments 1 to 6, wherein R1 is CH3.

[0190] 8. The compound according to any one of Embodiments 1 to 6, wherein A2 is CR2.

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

[0192] 10. A compound according to any one of Embodiments 1 to 8, wherein R2 is CH3.

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

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

[0195] 13.R 3 but, [ka] And here, R5 is H, a substituted or unsubstituted alkyl group, or an alkoxy group; R6 is H, a halogen, or a substituted or unsubstituted alkyl group. 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 to 14, wherein R6 is a haloalkyl group.

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

[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 to 18, wherein R7 is CH3.

[0202] 20.R 10 However, the compound is CH3, as described in any one of embodiments 16 to 18.

[0203] 21.R 10 The compound according to any one of embodiments 16 to 18, wherein the compound is an aryl compound.

[0204] 22.R 10 The compound described in any one of embodiments 16 to 18, wherein the compound is phenyl.

[0205] 23.R 10 However, the compound is a substituted phenyl compound as described in any one of Embodiments 16 to 18.

[0206] 24.Formula (III): [ka] [In the formula, Q is either H or CH3; R 12[These are substituted or unsubstituted pyridyls, substituted or unsubstituted alkyls, substituted or unsubstituted heterocyclyls, or substituted or unsubstituted C3-C6 cycloalkyls.] Compounds thereof, as well as their pharmaceutically acceptable salts, tautomers, isotopologs, and stereoisomers.

[0207] 25. The compound according to Embodiment 24, wherein Q" is H.

[0208] The compound according to Embodiment 24, wherein "Q" is CH3.

[0209] 27.R 12 However, the compound is CH3, as described in any one of embodiments 24 to 26.

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

[0211] 29.R 12 However, the compound according to any one of Embodiments 24 to 26, selected from substituted or unsubstituted thiazoles, or substituted or unsubstituted pyrazoles.

[0212] 30.R 12 but, [ka] And here, 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 to 31, wherein Q5 is OCH3.

[0215] 33. The compound according to any one of embodiments 30 to 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 described in any one of Embodiments 1 to 42 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0226] 44. A method for inducing HbF expression in cells, comprising contacting cells with a compound or pharmaceutical composition described in any one of Embodiments 1 to 43.

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

[0228] 46. ​​A method for reducing ZBTB7A expression in cells, comprising contacting cells with a compound or pharmaceutical composition described in any one of Embodiments 1 to 43.

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

[0230] 48. A method for treating abnormal hemoglobin disorders, characterized by administering a compound or pharmaceutical composition described in any one of Embodiments 1 to 43 to a subject in need of treatment.

[0231] 49. The method according to embodiment 48, wherein the abnormal hemoglobin disorder is anemia.

[0232] 50. The method according to Embodiment 48, wherein the abnormal hemoglobin disorder is sickle cell disease.

[0233] 51. The method according to Embodiment 48, wherein the abnormal hemoglobin disorder is thalassemia.

[0234] 52. The method according to Embodiment 48, wherein the abnormal hemoglobin disorder is alpha-thalassemia.

[0235] 53. The method according to Embodiment 48, wherein the abnormal hemoglobin disorder is beta-thalassemia.

[0236] 54. Use of the compound or pharmaceutical composition described in any one of Embodiments 1 to 43 for the treatment of abnormal hemoglobin disorders.

[0237] 55. The use described in Embodiment 54, wherein the abnormal hemoglobin disorder is anemia.

[0238] 56. The use according to Embodiment 54, wherein the abnormal hemoglobin disorder is sickle cell anemia.

[0239] 57. The use according to Embodiment 54, wherein the abnormal hemoglobin disorder is thalassemia.

[0240] 58. The use according to Embodiment 54, wherein the abnormal hemoglobin disorder is alpha-thalassemia.

[0241] 59. The use according to Embodiment 54, wherein the abnormal hemoglobin disorder is beta-thalassemia. [Examples]

[0242] The following examples are presented as illustrative examples, not as limitations. The compounds were named using an automated name generation tool provided in Chemdraw Ultra 20.1 (Cambridgesoft), which generates systematic names of chemical structures while adhering to the Kahn-Ingold-Prelogue order rule for stereochemistry. Those skilled in the art may modify the procedures described in the illustrative examples to arrive at the desired product.

[0243] Compounds of formulas (I), (II), and (III) are provided herein, as shown 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 prepared using conventional organic synthesis and commercially available starting materials. Certain compounds of formulas (I), (I'), (II), (II'), and (III) are prepared as described in the following examples.

[0246] Example 1: 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-phenoxy-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka]

[0247] 6-bromo-1-methyl-5-nitro-1H-indazole [ka] Potassium carbonate (0.420 g, 3.04 mmol) was added 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). 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), lyophilized, and obtained 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] In 5 mL of N,N-dimethylformamide, a solution of 6-bromo-1-methyl-5-nitro-1H-indazole (0.470 g, 1.84 mmol) was added to 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 resulting crude residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain 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-indazole-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), dried palladium carbon (0.070 g, 0.66 mmol) was added. 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 reduced pressure using a water pump. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 1-methyl-6-phenoxy-1H-indazole-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-dioxopiperidine-3-yl)-4-((1-methyl-6-phenoxy-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka] To 5 mL of 1,4-dioxane, a solution of 1-methyl-6-phenoxy-1H-indazole-5-amine (0.120 g, 0.50 mmol) was added, to which 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-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) were added. 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 obtain the crude product (0.100 g). The crude product was dissolved in 2 mL of N,N-dimethylformamide and filtered. The mixture was purified by preparative HPLC (ACN / water) to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-phenoxy-1H-indazole-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-dioxopiperidine-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-yl)amino)isoindorin-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-indazole-5-amine [ka] Iron (0.117 g, 2.09 mmol) was added 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). The mixture was stirred at 40°C for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative silica gel TLC (petroleum ether: ethyl acetate) to obtain 6-(4-fluorophenoxy)-1-methyl-1H-indazole-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-dioxopiperidine-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] 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) were added to a solution of 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.060 g, 0.18 mmol) and 6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-amine (0.046 g, 0.18 mmol) in 1 mL of 1,4-dioxane. The mixture was stirred under nitrogen at 110°C for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC. The organic solvent was removed, and the preparative liquid phase was freeze-dried to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-yl)amino)isoindorin-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 preparative liquid phase was freeze-dried to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-yl)amino)isoindorin-1,3-dione (28 mg, 0.054 mmol, 55% yield) and 2-(2,6-dioxopiperidine-3-yl)-4-((6-(4-fluorophenoxy)-1-methyl-1H-indazole-5-yl)amino)isoindorin-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-dioxopiperidine-3-yl)-4-((6-methoxy-4-phenylpyridine-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), 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) were added. 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 x 3). The combined organic layers were dried over sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) to obtain 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] Sodium methoxide (0.13 g, 2.56 mmol) was added to a solution of 2-chloro-5-nitro-4-phenylpyridine (0.20 g, 0.8500 mmol) in methanol (10 mL). The solution was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (8:1-4:1 petroleum ether:ethyl acetate) to obtain 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-phenylpyridine-3-amine [ka] A solution of 2-methoxy-5-nitro-4-phenylpyridine (0.150 g, 0.6500 mmol) in methanol (10 mL) was mixed with 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 hours. The suspension was filtered, and the filtrate was concentrated to obtain 6-methoxy-4-phenylpyridine-3-amine (130 mg, 0.64 mmol, 99% yield). MS (ESI) m / z: 269.5 [M+1] +

[0259] 2-(2,6-dioxopiperidine-3-yl)-4-((6-methoxy-4-phenylpyridine-3-yl)amino)isoindoline-1,3-dione [ka] 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 to a solution of 6-methoxy-4-phenylpyridine-3-amine (0.10 g, 0.50 mmol) and 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindorin-1,3-dione (0.168 g, 0.500 mmol) in 1,4-dioxane (5 mL). The suspension was degassed under vacuum and purged several times with nitrogen. The reaction mixture was stirred at 110°C for 12 hours. The suspension was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC. The resulting solution was then freeze-dried, and the crude product was purified by preparative TLC to obtain 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-dioxopiperidine-3-yl)-4-((6-methyl-4-phenoxypyridine-3-yl)amino)isoindoline-1,3-dione [ka]

[0261] 5-Bromo-2-methyl-4-phenoxypyridine [ka] In a solution of phenol (0.040 g, 0.43 mmol) in N-methylpyrrolidone (1.5 mL), cesium carbonate (0.345 g, 1.06 mmol) and 5-bromo-4-chloro-2-methylpyridine (0.105 g, 0.51 mmol) were added. 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 x 3). The combined organic layer was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative silica gel TLC (petroleum ether: ethyl acetate) to obtain 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 mL of 1,4-dioxane, 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) were added. The mixture was stirred under nitrogen at 110°C for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative TLC (petroleum ether: ethyl acetate) of silica gel to obtain 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-phenoxypyridine-3-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0264] 2-((4-chloro-5-nitropyridine-2-yl)oxy)-N,N-dimethylethaneamine [ka] To a solution of 4-chloro-5-nitropyridine-2-ol (1.50 g, 8.59 mmol) in tetrahydrofuran (30 mL), 2-chloro-N,N-dimethylethaneamine hydrochloride (1.857 g, 12.89 mmol) and silver carbonate (7.11 g, 25.78 mmol) were added. 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 obtain 2-((4-chloro-5-nitropyridine-2-yl)oxy)-N,N-dimethylethaneamine (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-phenoxypyridine-2-yl)oxy)ethaneamine [ka] A solution of 2-((4-chloro-5-nitropyridine-2-yl)oxy)-N,N-dimethylethaneamine (0.090 g, 0.37 mmol) was added dropwise to 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 hours. 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 freeze-dried to obtain N,N-dimethyl-2-[(5-nitro-4-phenoxy-2-pyridyl)oxy]ethaneamine (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-phenoxypyridine-3-amine [ka] A solution of N,N-dimethyl-2-[(5-nitro-4-phenoxy-2-pyridyl)oxy]ethaneamine (0.013 g, 0.04 mmol) in methanol (5 mL) was mixed with a palladium-activated carbon catalyst (0.010 g, 0.05 mmol) under nitrogen. The suspension was degassed under vacuum and purged several times with nitrogen. The mixture was stirred under hydrogen (15 Psi) at 15°C for 12 hours. 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-phenoxypyridine-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-phenoxypyridine-3-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To a solution of 6-[2-(dimethylamino)ethoxy]-4-phenoxypyridine-3-amine (0.010 g, 0.04 mmol) in 1,4-dioxane (3 mL), 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindorin-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 several times with nitrogen. The mixture was stirred at 110°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 4-((6-(2-(dimethylamino)ethoxy)-4-phenoxypyridine-3-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-dioxopiperidine-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka]

[0269] 6-Fluoro-5-nitro-1H-indazole [ka] Potassium nitrate (7.4 g, 7.35 mmol) was added at 0°C to a solution of 6-fluoro-1H-indazole (10,000 g, 73.50 mmol) in concentrated sulfuric acid (220 mL). The resulting mixture was stirred at 25°C for 12 hours. The mixture was added dropwise to ice water (1000 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were 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 (ethyl acetate in 40-50% petroleum ether) to obtain 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), sodium hydride (6.34 g, 26.50 mmol) was added at 0°C, and the mixture was stirred for 0.5 hours. 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 under vacuum. The resulting crude substance was purified by silica gel column chromatography (ethyl acetate in 20-25% petroleum ether) to obtain 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] In 10 mL of N,N-dimethylformamide, a solution of 6-fluoro-5-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.00 g, 3.20 mmol) was added, to which 3-fluorophenol (0.432 g, 0.39 mmol) and potassium carbonate (0.668 g, 0.48 mmol) were added. 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 phases were washed with saturated saline solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The obtained crude substance was purified by silica gel column chromatography (ethyl acetate in 20-25% petroleum ether) to obtain 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), trifluoroacetic acid (0.5 mL, 0.10 mmol) was added, and the mixture was stirred at 25°C for 12 hours. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated saline solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate in 10-20% petroleum ether) to obtain 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), 4-iodotetrahydro-2H-pyran (0.093 g, 0.44 mmol) and potassium carbonate (0.151 g, 1.10 mmol) were added. The mixture was stirred at 110°C for 12 hours. The mixture was filtered. The filtrate was purified by preparative HPLC to obtain 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-indazole-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), iron powder (0.007 g, 0.13 mmol) and ammonium chloride (0.022 g, 0.42 mmol) were added. The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-amine (0.008 g, 0.024 mmol, 58% yield). MS (ESI) m / z: 328.1 [M+1] +

[0275] 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] To a solution of 6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-amine (0.008 g, 0.03 mmol) in 1,4-dioxane (2 mL), 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-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 under nitrogen at 110°C for 12 hours. The solution was filtered, concentrated, and purified by preparative HPLC to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluorophenoxy)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka]

[0277] 1-Methyl-6-(2-methylpyridine-4-yl)-5-nitro-1H-indazole [ka] In 3 mL of 1,4-dioxane, 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) was added, to which cesium carbonate (1.14 g, 3.51 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) (0.096 g, 0.120 mmol) were added. The resulting mixture was stirred under nitrogen 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 obtain 1-methyl-6-(2-methylpyridine-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-methylpyridine-4-yl)-1H-indazole-5-amine [ka] Ammonium chloride (0.503 g, 9.32 mmol) and ferrous iron powder (0.520 g, 9.32 mmol) were added to a solution of 1-methyl-6-(2-methylpyridine-4-yl)-5-nitro-1H-indazole (0.250 g, 0.930 mmol) in ethanol (3 mL) and water (1 mL). 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 obtain 1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-amine (0.145 g, 0.638 mmol, 96% yield). MS (ESI) m / z: 239.1[M+1] +

[0279] 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione. [ka] To a solution of 1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-amine (0.070 g, 0.290 mmol) and 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.099 g, 0.290 mmol), 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 to 1,4-dioxane (2 mL). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. 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 obtain 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-indazole-4-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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 mixture was stirred at 0°C for 1 hour. The reaction mixture was poured over ice water (1000 mL), the precipitate was collected by filtration, washed with water (300 mL), and dried under reduced pressure to obtain 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-indazole-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), sodium hydride (1.9 g, 48.59 mmol) was added at 0°C and the mixture was 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 layers were 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 obtain the product 2-[(5-fluoro-4-nitroindazole-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-nitroindazole-1-yl]methoxy]ethyltrimethylsilane [ka] In dimethylformamide (4 mL), a solution of 2-chlorophenol (0.136 g, 1.06 mmol) was mixed with cesium carbonate (0.626 g, 1.93 mmol) and 2-[(5-fluoro-4-nitroindazole-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 obtain the residue. The residue was purified by preparative TLC (ethyl acetate) to obtain the product 2-[[5-(2-chlorophenoxy)-4-nitroindazole-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] In 2 mL of dichloromethane, a solution of 2-[[5-(2-chlorophenoxy)-4-nitroindazole-1-yl]methoxy]ethyltrimethylsilane (0.370 g, 0.88 mmol) was added to 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 obtain 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] Potassium carbonate (0.048 g, 0.35 mmol) was added 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). 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 the 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-ylindazole-4-amine [ka] A solution of 5-(2-chlorophenoxy)-4-nitro-1-tetrahydropyran-4-yl-indazole (0.023 g, 0.06 mmol) was added to ethanol (1 mL) and water (0.30 mL) with 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 obtain the product 5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazole-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-ylindazole-4-yl]amino]benzene-1,2-dicarboxylate [ka] 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) were added under nitrogen to a solution of 5-(2-chlorophenoxy)-1-tetrahydropyran-4-yl-indazole-4-amine (0.013 g, 0.04 mmol) and dimethyl 3-bromobenzene-1,2-dicarboxylate (0.011 g, 0.04 mmol) in 1 mL of 1,4-dioxane. The suspension was degassed under vacuum and purged several times with nitrogen. 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 obtain the product dimethyl 3-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-ylindazole-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-ylindazole-4-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ka] Lithium iodide (0.01 mL, 0.11 mmol) was added to a solution of dimethyl 3-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-ylindazole-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). The suspension was degassed under vacuum and purged several times with nitrogen. 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 obtain the product 4-[[5-(2-chlorophenoxy)-1-tetrahydropyran-4-ylindazole-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-dioxopiperidine-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka]

[0290] 6-bromo-1-methyl-5-nitro-1H-indazole [ka] 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) were added to a 250 mL three-necked flask. 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 x 3) and filtered. The solid was dried under reduced pressure to obtain 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] In 3 mL of dioxane, 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) was prepared by adding 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 under nitrogen at 110°C for 12 hours. The reaction product was filtered, and the filtrate was concentrated under reduced pressure using a water pump. The residue was purified by preparative HPLC to obtain 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-indazole-5-amine [ka] Ammonium chloride (0.143 g, 2.66 mmol) and ferrous iron powder (0.148 g, 2.66 mmol) were added 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). 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 obtain 6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-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-dioxopiperidine-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka] 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) were added to a solution of 6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-5-amine (0.070 g, 0.260 mmol) and 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.091 g, 0.270 mmol) in dioxane (2 mL). The resulting mixture was stirred under nitrogen 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 and preparative TLC (petroleum ether:ethyl acetate 1:1) to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((6-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-indazole-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-dioxopiperidine-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazole-4-yl)amino)isoindorin-1,3-dione [ka]

[0295] 5-(2-fluoro-6-methylphenoxy)-1-methyl-4-nitro-1H-indazole [ka] In 3 mL of N,N-dimethylformamide, a solution of 2-fluoro-6-methyl-phenol (0.1 g, 0.79 mmol) was added to 5-fluoro-1-methyl-4-nitroindazole (0.154 g, 0.79 mmol) and cesium carbonate (0.515 g, 1.59 mmol). The mixture was stirred at 90°C for 12 hours. The mixture was diluted with water and extracted with ethyl acetate (10 ml x 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 obtain 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-indazole-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), iron (0.176 g, 3.15 mmol) and ammonium chloride (0.34 g, 6.31 mmol) were added, 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 (ethyl acetate in 40% petroleum ether) to obtain 5-(2-fluoro-6-methylphenoxy)-1-methylindazole-4-amine (50 mg, 0.184 mmol, 29% yield).

[0297] 2-(2,6-dioxopiperidine-3-yl)-4-((5-(2-fluoro-6-methylphenoxy)-1-methyl-1H-indazole-4-yl)amino)isoindorin-1,3-dione [ka] To 3 mL of 1,4-dioxane, a solution of 5-(2-fluoro-6-methylphenoxy)-1-methylindazole-4-amine (0.05 g, 0.18 mmol) was added, along with 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindorin-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). 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 obtain 2-(2,6-dioxo-3-piperidyl)-4-[[5-(2-fluoro-6-methylphenoxy)-1-methylindazole-4-yl]amino]isoindorin-1,3-dione (13 mg, 0.025 mmol, 13% yield) and 2-(2,6-dioxo-3-piperidyl)-4-[[5-(2-fluoro-6-methylphenoxy)-1-methylindazole-4-yl]amino]isoindorin-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-dioxopiperidine-3-yl)-4-((4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-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), cesium carbonate (0.924 g, 2.84 mmol) and 4-iodotetrahydropyran (0.6 g, 2.84 mmol) were added, 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 layers were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by preparative silica gel TLC (ethyl acetate in 50% petroleum ether) to obtain 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-dioxopiperidine-3-yl)-4-((4-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] In 3 mL of 1,4-dioxane, a solution of 5-bromo-4-methyl-1-tetrahydropyran-4-yl-indazole (0.1 g, 0.34 mmol) was mixed with 4-amino-2-(2,6-dioxo-3-piperidyl)isoindorin-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 obtain 2-(2,6-dioxo-3-piperidyl)-4-[(4-methyl-1-tetrahydropyran-4-ylindazole-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-ylindazole-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-dioxopiperidine-3-yl)-4-((6-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka]

[0302] 5-bromo-6-methoxy-1-tetrahydropyran-4-yl-indazole TIFF0007852160000131.tif4247 In dimethylformamide (4 mL), a solution of 5-bromo-6-methoxy-1H-indazole (0.3 g, 1.32 mmol) was added to 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 x 3), the combined organic layer was washed with saturated saline (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 obtain 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-ylindazole-5-yl)amino]isoindoline-1,3-dione [ka] 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)isoindorin-1,3-dione (0.08 g, 0.29 mmol) were added 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). 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 obtain 2-(2,6-dioxo-3-piperidyl)-4-[(6-methoxy-1-tetrahydropyran-4-ylindazole-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)indazole-6-yl]amino]isoindoline-1,3-dione [ka]

[0305] 5-bromo-1-methyl-6-nitroindazole [ka] Sodium hydride (0.363 g, 9.09 mmol) was added at 0°C to a solution of 5-bromo-6-nitro-1H-indazole (2.0 g, 8.26 mmol) in DMF (20 mL). The mixture was stirred at 0°C for 0.5 hours. Iodomethane (1.17 g, 8.26 mmol) was added to the mixture. 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 x 3). The combined organic layers were washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by semi-preparative reverse-phase HPLC to obtain 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), 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) were added. 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 (ethyl acetate in 50% petroleum ether) to obtain 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)indazole-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), iron powder (0.182 g, 3.24 mmol) and ammonium chloride (0.286 g, 5.41 mmol) were added. 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 obtain 1-methyl-5-(2-methyl-4-pyridyl)indazole-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)indazole-6-yl]amino]benzene-1,2-dicarboxylate [ka] To 1,4-dioxane (2 mL), a solution of 1-methyl-5-(2-methyl-4-pyridyl)indazole-6-amine (0.120 g, 0.50 mmol) was added, along with 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 obtain dimethyl 3-[[1-methyl-5-(2-methyl-4-pyridyl)indazole-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)indazole-6-yl]amino]isoindoline-1,3-dione [ka] To a solution of dimethyl 3-[[1-methyl-5-(2-methyl-4-pyridyl)indazole-6-yl]amino]benzene-1,2-dicarboxylate (0.100 g, 0.23 mmol) in pyridine (1 mL), 3-aminopiperidine-2,6-dione hydrochloride (0.042 g, 0.26 mmol) and lithium iodide (0.091 g, 0.70 mmol) were added. 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 obtain the product 2-(2,6-dioxo-3-piperidyl)-4-[[1-methyl-5-(2-methyl-4-pyridyl)indazole-6-yl]amino]isoindorin-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-dioxopiperidine-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-6-yl)amino)isoindoline-1,3-dione [ka]

[0311] 5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-nitro-1H-benzo[d]imidazole [ka] Potassium carbonate (0.096 g, 0.70 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene) palladium(II) (0.018 g, 0.03 mmol) were added 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). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. 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 obtain 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]imidazole-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), ferrous iron powder (0.050 g, 0.90 mmol) and ammonium chloride (0.090 g, 1.67 mmol) were added. 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 obtain 5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-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]imidazole-6-yl)amino)phthalate [ka] In 2 mL of dioxane, a solution of 5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-6-amine (0.041 g, 0.15 mmol) and dimethyl 3-bromophthalate (0.045 g, 0.16 mmol) was prepared by adding 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 under nitrogen at 110°C for 12 hours. 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 obtain dimethyl 3-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-6-yl)amino)phthalate (0.041 g, 0.088 mmol, 58% yield). MS (ESI) m / z: 464.2[M+1] +

[0314] 2-(2,6-dioxopiperidine-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-6-yl)amino)isoindoline-1,3-dione [ka] Lithium iodide (0.049 mg, 0.38 mmol) was added to a solution of dimethyl 3-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-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). 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 obtain 2-(2,6-dioxopiperidine-3-yl)-4-((5-(3-fluoro-4-methoxyphenyl)-1-methyl-1H-benzo[d]imidazole-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-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka]

[0316] 6-bromo-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] Potassium carbonate (1.7 g, 12.4 mmol) and 4-iodotetrahydropyran (1.05 g, 4.96 mmol) were added to a solution of 6-bromo-5-nitro-1H-indazole (1.0 g, 4.13 mmol) in N,N-dimethylacetamide (10 mL). 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 obtain 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-methylpyridine-4-yl)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To 1,4-dioxane (10 mL), a solution of 6-bromo-5-nitro-1-tetrahydropyran-4-yl-indazole (0.220 g, 0.670 mmol) was added, along with 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 obtain 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-methylpyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-amine [ka] To a solution of 6-(2-methyl-4-pyridyl)-5-nitro-1-tetrahydropyran-4-ylindazole (0.160 g, 0.4700 mmol) in ethanol (10 mL), iron powder (0.265 g, 4.73 mmol) and ammonium chloride (0.255 g, 4.73 mmol) were added 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 saline (50 ml), dried over sodium sulfate, and filtered. The filtrate was concentrated to obtain 6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-ylindazole-5-amine (100 mg, 0.324 mmol, 68% yield). MS (ESI) m / z 309.4 [M+1] +

[0319] Dimethyl-3-((6-(2-methylpyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)phthalate [ka] To 5 mL of 1,4-dioxane, a solution of 6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-yl-indazole-5-amine (0.10 g, 0.320 mmol) was added, along with 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 hours. The solution was concentrated, and the residue was purified by preparative HPLC to obtain dimethyl 3-[[6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-ylindazole-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-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] To a solution of dimethyl 3-[[6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-ylindazole-5-yl]amino]benzene-1,2-dicarboxylate (0.10 g, 0.200 mmol) in pyridine (2 mL), 3-aminopiperidine-2,6-dione hydrochloride (0.036 g, 0.220 mmol) and lithium iodide (0.053 g, 0.400 mmol) were added. 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 obtain 2-(2,6-dioxo-3-piperidyl)-4-[[6-(2-methyl-4-pyridyl)-1-tetrahydropyran-4-ylindazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0322] 6-bromo-5-nitro-1H-benzoimidazole [ka] Potassium nitrate (5.18 g, 60.90 mmol) was added in several portions at 0°C to a solution of 5-bromo-1H-benzimidazole (10.0 g, 50.75 mmol) in sulfuric acid (50 mL, 2967.60 mmol). The mixture was stirred at 25°C for 1 hour. 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 adding 6 N sodium hydroxide aqueous solution. The resulting precipitate was filtered and purified by preparative HPLC to obtain 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-benzoimidazole [ka] To a solution of 6-bromo-5-nitro-1H-benzimidazole (0.600 g, 2.48 mmol) in dichloroethane (20 mL), 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) were added. The mixture was stirred under air at 70°C for 12 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (ethyl acetate in 50% petroleum ether) to obtain 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-methylpyridine-4-yl)-6-nitro-1H-benzoimidazole [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), 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) were added. 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 preparative TLC of silica gel (ethyl acetate in 80% petroleum ether) to obtain 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-methylpyridine-4-yl)-1H-benzimidazole-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), iron (0.189 g, 3.40 mmol) and ammonium chloride (0.367 g, 6.80 mmol) were added. 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 obtain 3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)phthalate [ka] To 1,4-dioxane (4 mL), a solution of 3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazole-5-amine (0.050 g, 0.19 mmol) was added, along with 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 obtain dimethyl 3-[[3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To a solution of dimethyl 3-[[3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazole-5-yl]amino]benzene-1,2-dicarboxylate (0.030 g, 0.07 mmol) in pyridine (2 mL), 3-aminopiperidine-2,6-dione hydrochloride (0.016 g, 0.10 mmol) and lithium iodide (0.044 g, 0.33 mmol) were added. 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 obtain 4-[[3-cyclopropyl-6-(2-methyl-4-pyridyl)benzimidazole-5-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindorin-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-benzoxazole-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), concentrated nitric acid (1.26 mL, 28.30 mmol) was added dropwise at 0°C. The mixture was stirred at 25°C for 2 hours. 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 (ethyl acetate in 20-25% petroleum ether) to obtain 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 1,4-dioxane (5 mL), a solution of 6-bromo-3-methyl-5-nitro-1,2-benzoxazole (0.360 g, 1.40 mmol) was added, along with 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 several times with nitrogen. The mixture was stirred at 80°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 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-benzoxazole-5-amine [ka] 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 mixed with 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 hour. The mixture was concentrated under reduced pressure. The mixture was basicized to pH 7-8 with ammonium hydroxide. The residue was purified by preparative TLC (ethyl acetate) to obtain 3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazole-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-benzoxazole-5-yl]amino]isoindoline-1,3-dione [ka] In 5 mL of 1,4-dioxane, a solution of 3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazole-5-amine (0.060 g, 0.25 mmol) was added, to which 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindorin-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) were added. The suspension was degassed under vacuum and purged several times with nitrogen. The mixture was stirred at 80°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and preparative TLC (methanol in 9% dichloromethane) to obtain 2-(2,6-dioxo-3-piperidyl)-4-[[3-methyl-6-(2-methyl-4-pyridyl)-1,2-benzoxazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0334] 6-bromo-2-methyl-5-nitro-1H-benzimidazole [ka] Nitric acid (1.27 mL, 28.43 mmol) was added dropwise to a solution of 6-bromo-2-methyl-1H-benzimidazole (2.0 g, 9.48 mmol) in sulfuric acid (20 mL, 373.47 mmol) 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 obtain 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] Sodium hydride (0.117 g, 2.93 mmol) was added to a solution of 6-bromo-2-methyl-5-nitro-1H-benzimidazole (0.500 g, 1.95 mmol) in tetrahydrofuran (10 mL) 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 obtain 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), 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) were added. The suspension was degassed and purged several times with nitrogen. The mixture was stirred at 110°C for 12 hours. 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 obtain 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)benzimidazole-5-amine [ka] Iron powder (0.395 g, 7.08 mmol) and ammonium chloride (0.765 g, 14.17 mmol) were added 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). 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 obtain a mixture of 2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazole-5-amine and 2,3-dimethyl-5-(2-methyl-4-pyridyl)benzimidazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)phthalate [ka] 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) were added to a solution of a mixture of 2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazole-5-amine and 2,3-dimethyl-5-(2-methyl-4-pyridyl)benzimidazole-6-amine (0.200 g, 0.79 mmol) in 2 mL of 1,4-dioxane. 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 obtain dimethyl 3-[[2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-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-methylpyridine-4-yl)-1H-benzo[d]imidazole-6-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To a solution of dimethyl 3-[[2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazole-5-yl]amino]benzene-1,2-dicarboxylate (0.100 g, 0.220 mmol) in pyridine (2 mL), 3-aminopiperidine-2,6-dione (0.057 g, 0.450 mmol) and lithium iodide (50 mg) were added. 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 obtain 4-[[2,3-dimethyl-6-(2-methyl-4-pyridyl)benzimidazole-5-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindorin-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-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0341] 6-Cyclopropyl-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole [ka] To 4 mL of tert-amyl alcohol, a solution of 6-bromo-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.300 g, 0.92 mmol) was prepared by adding cyclopropylboronic acid (0.095 g, 1.11 mmol), cesium carbonate (0.900 g, 2.77 mmol), and methanesulfonate (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 hours. 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 obtain 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-indazole-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), ferrous iron powder (0.136 g, 2.44 mmol) and ammonium chloride (0.132 g, 2.44 mmol) were added. 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 obtain 6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-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-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To a solution of 6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-amine (0.060 g, 0.23 mmol) and 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.083 g, 0.24 mmol), 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) were added to dioxane (2 mL). The resulting mixture was stirred under nitrogen 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 obtain 4-((6-cyclopropyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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] 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.295 g, 1.10 mmol) was added to a solution of 6-bromo-1,3-dimethyl-5-nitro-1H-indazole (0.190 g, 0.80 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting substance was purified by silica gel column chromatography (ethyl acetate in 5-15% petroleum ether) to obtain 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-methylpyridine-4-yl)-1H-indazole-5-amine [ka] In ethanol (0.6 mL), a solution of 1,3-dimethyl-6-(2-methyl-4-pyridyl)-5-nitroindazole (0.080 g, 0.28 mmol) was added to ammonium chloride (0.153 g, 2.83 mmol) and ferrous iron powder (0.079 g, 1.42 mmol). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 1,3-dimethyl-6-(2-methylpyridin-4-yl)-1H-indazole-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-methylpyridine-4-yl)-1H-indazole-5-yl)amino)phthalate [ka] To 0.60 mL of 1,4-dioxane, a solution of 1,3-dimethyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-amine (0.040 g, 0.16 mmol) was added, along with 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 mixture 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 obtain dimethyl 3-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To a solution of dimethyl 3-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)phthalate (0.05 g, 0.11 mmol) in pyridine (1 mL), 3-aminopiperidine-2,6-dione (0.021 g, 0.17 mmol) and lithium iodide (0.030 g, 0.22 mmol) were added. The reaction mixture was stirred at 130°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to obtain 4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0351] 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] In 5 mL of 1,4-dioxane, a solution of 4-bromo-2-(difluoromethyl)pyridine (0.530 g, 2.55 mmol) was added, to which 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) were added. The suspension was degassed under vacuum and purged several times with nitrogen. The mixture was stirred at 100°C for 12 hours. The reaction product was diluted with water (60 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude substance was purified by silica gel column chromatography (ethyl acetate in 5-15% petroleum ether) to obtain 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)pyridine-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), 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) were added. The suspension was degassed and purged several times with nitrogen. The mixture was stirred at 110°C for 12 hours. The reaction product was filtered, the filtrate was concentrated, and purified by preparative HPLC to obtain 6-(2-(difluoromethyl)pyridine-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)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-amine [ka] In ethanol (6 mL), a solution of 6-(2-(difluoromethyl)pyridine-4-yl)-5-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (0.140 g, 0.37 mmol) was added, to which ammonium chloride (0.202 g, 3.74 mmol) and ferrous iron powder (0.104 g, 1.87 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 6-(2-(difluoromethyl)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-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)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] 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) were added to a solution of 6-(2-(difluoromethyl)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-amine (0.080 g, 0.23 mmol) and 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindorin-1,3-dione (0.082 g, 0.24 mmol). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. The reaction product was filtered, the filtrate was concentrated, and purified by preparative HPLC to obtain 4-((6-(2-(difluoromethyl)pyridine-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-dioxopiperidine-3-yl)isoindorin-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), hydroxylamine hydrochloride (3.2 g, 47.3 mmol) and pyridine (4.9 g, 61.9 mmol, 5 mL) were added. The reaction mixture 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 saline (50 mL), dried over sodium sulfate, and filtered. The solvent was removed under reduced pressure to obtain 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-iddene-1-amine [ka] To a solution of 6-bromoindan-1-one oxime (4.6 g, 20.35 mmol) in methyl alcohol (100 mL), molybdenum trioxide (3.51 g, 24.42 mmol) and sodium borohydride (3.85 g, 101.74 mmol) were added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with 1N hydrochloric acid aqueous solution (200 mL) and ethyl acetate (200 mL). The aqueous solution was made basic and subsequently extracted with dichloromethane (3 × 200 mL). The combined organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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-iddene-1-amine [ka] To a solution of 6-bromoindan-1-amine (2.3 g, 10.8 mmol) in formic acid (4 mL), formaldehyde (45.5 g, 500.9 mmol, 41.8 mL) was added in water. The reaction mixture was stirred at 100°C for 12 hours. The aqueous solution was made basic, then extracted with dichloromethane (3 × 100 mL), and dried over sodium sulfate. The extract was then filtered, concentrated under reduced pressure, and 6-bromo-N,N-dimethylindan-1-amine (1.1 g, 4.58 mmol, 42%) was obtained. 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-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To 3 mL of 1,4-dioxane, 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-idene-1-amine (0.100 g, 0.42 mmol) were added to a solution of (S)-4-amino-2-(3-methyl-2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.100 g, 0.42 mmol). The resulting mixture was stirred under nitrogen at 100°C 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 obtain 4-((3-(dimethylamino)-2,3-dihydro-1H-inden-5-yl)amino)-2-((S)-3-methyl-2,6-dioxopiperidine-3-yl)isoindorin-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione and (R)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka]

[0361] 6-bromo-1-methyl-5-nitro-1H-indazole [ka] 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) were added to a 500 ml three-necked flask. 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 reduced pressure to obtain 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-methylpyridine-4-yl)-5-nitro-1H-indazole [ka] In 30 mL of dioxane, cesium carbonate (7.62 g, 23.43 mmol) and dichloro(1,1'-bis(diphenylphosphanyl)ferrocene) palladium(II) (0.319 g, 0.39 mmol) were added 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). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-methyl-6-(2-methylpyridine-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-methylpyridine-4-yl)-1H-indazole-5-amine [ka] Ammonium chloride (1.51 g, 27.96 mmol) and ferrous iron powder (1.56 g, 27.96 mmol) were added to a solution of 1-methyl-6-(2-methylpyridine-4-yl)-5-nitro-1H-indazole (1.50 g, 5.59 mmol) in ethanol (15 mL) and water (5 mL). 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 phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka] 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) were added to a solution of 1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-amine (1.300 g, 5.46 mmol) and 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (1.931 g, 5.73 mmol) in dioxane (30 mL). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse-phase preparative HPLC (5-35% acetonitrile in water, 0.1% 2,2,2-trifluoroacetic acid additive). The separated substance was freeze-dried to obtain crude 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindorin-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione (0.600 g, 1.21 mmol) was purified by chiral preparative SFC (ethanol in 70% acetonitrile). The separated substance was concentrated under reduced pressure to obtain (S)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione (0.600 g, 1.21 mmol) was purified by chiral preparative SFC (ethanol in 70% acetonitrile). The separated substance was concentrated under reduced pressure to obtain (R)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione and (S)-4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0368] 5-Bromo-1,3-dimethylbenzimidazole-2-one [ka] In 100 mL of N,N-dimethylformamide, a solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (5.00 g, 22.02 mmol) was added to a solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one. Sodium hydride (1.590 g, 66.06 mmol) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Iodomethane (15.63 g, 110.10 mmol) was added. The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with 60 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated saline solution (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-1,3-dimethylbenzimidazole-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]imidazole-2-one [ka] To a solution of 5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (5.00 g, 20.74 mmol) in acetic anhydride (83 mL), fuming nitric acid (1.85 mL, 41.48 mmol) was slowly added 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 hour. The reaction mixture was quenched with water (300 mL). The resulting solution was extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-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-methylpyridine-4-yl)-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one [ka] In 40 mL of 1,4-dioxane, a solution of 5-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (4.00 g, 13.98 mmol) was added to 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 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated saline solution (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol in 5-15% dichloromethane) to obtain 1,3-dimethyl-5-(2-methylpyridine-4-yl)-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-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-methylpyridine-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one [ka] In ethanol (60 mL) and water (20 mL), 1,3-dimethyl-5-(2-methylpyridine-4-yl)-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (4.00 g, 13 mmol) was dissolved, to which ammonium chloride (7.24 g, 134 mmol) and iron powder (3.74 g, 67 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 5-amino-1,3-dimethyl-6-(2-methylpyridine-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-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-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To a solution of 5-amino-1,3-dimethyl-6-(2-methylpyridine-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (2.60 g, 9.69 mmol) in 1,4-dioxane (50 mL), 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-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) were added. The resulting suspension was degassed and purged with nitrogen. The mixture was stirred at 115°C for 12 hours. The reaction product was filtered, and the filtrate was concentrated under reduced pressure. The resulting substance was purified by semi-preparative reverse-phase HPLC (added with 15-45% acetonitrile in water and 0.1% trifluoroacetic acid). The relevant fractions were lyophilized to obtain 4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] 4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (1.00 g, 1.91 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 70-70% acetonitrile). Peak 1 was concentrated under reduced pressure and extracted with sodium bicarbonate (50 mL × 2) and dichloromethane (60 mL × 3). The combined organic layers were 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 obtain (S)-4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] 4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (1.00 g, 1.91 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 70-70% acetonitrile). Peak 2 was concentrated under reduced pressure and extracted with sodium bicarbonate (50 mL × 2) and dichloromethane (60 mL × 3). The combined organic layers were 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 obtain (R)-4-((1,3-dimethyl-6-(2-methylpyridine-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione and (S)-4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0376] 5-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one [ka] To 1,4-dioxane (0.5 mL), a solution of 5-bromo-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (0.230 g, 0.80 mmol) was added, to which 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) were added. The suspension was degassed and purged with nitrogen. The mixture was stirred at 110°C for 12 hours. The reaction product was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol in 5-15% dichloromethane) to obtain 5-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-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-dimethylpyridine-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazole-2-one [ka] In a solution of 5-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-6-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one (0.180 g, 0.58 mmol) in ethanol (3 mL) and water (1 mL), ammonium chloride (0.156 g, 2.88 mmol) and ferrous iron powder (0.322 g, 5.76 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 5-amino-6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (0.130 g, 0.46 mmol, 79% yield). MS (ESI) m / z: 283.1[M+1] +

[0378] 4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] To 3 mL of 1,4-dioxane, a solution of 5-amino-6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (0.130 g, 0.42 mmol) was added, along with 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-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 product was filtered, and the filtrate was concentrated. The resulting residue was purified by semi-preparative reverse-phase HPLC (added with 13-43% acetonitrile in water and 0.1% trifluoroacetic acid). The recovered fraction was freeze-dried to obtain 4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-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-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] 4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.120 g, 0.22 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 70-70% acetonitrile). After separation, one of the two separated peaks was concentrated under reduced pressure to obtain (R)-4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-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-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka] 4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (0.120 g, 0.22 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 70-70% acetonitrile). After separation, one of the two separated peaks was concentrated under reduced pressure to obtain (S)-4-((6-(2,6-dimethylpyridine-4-yl)-1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)-2-(2,6-dioxopiperidine-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-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione and 2-((S)-2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-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 dried 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) was added to tetrahydrofuran (20 mL), 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 separated target substance was freeze-dried to obtain (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-methylpyridine-4-yl)-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole [ka] 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) were added 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). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain (R)-6-(2-methylpyridine-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-methylpyridine-4-yl)-1-(tetrahydrofuran-3-yl)-1H-indazole-5-amine [ka] To a solution of (R)-6-(2-methylpyridine-4-yl)-5-nitro-1-(tetrahydrofuran-3-yl)-1H-indazole (3.00 g, 9.25 mmol) in ethanol (30 mL) and water (10 mL), ferrous iron powder (2.58 g, 46.25 mmol) and ammonium chloride (4.99 g, 92.5 mmol) were added. 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 obtain crude (R)-6-(2-methylpyridine-4-yl)-1-(tetrahydrofuran-3-yl)-1H-indazole-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-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] In 40 mL of dioxane, a solution of (R)-6-(2-methylpyridine-4-yl)-1-(tetrahydrofuran-3-yl)-1H-indazole-5-amine (2.730 g, 9.27 mmol) and 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione (3.130 g, 9.27 mmol) was prepared by adding 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 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 separated substance was freeze-dried to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-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-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] 2-(2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione (0.75 g, 1.36 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 70-70% acetonitrile). One of the two separated peaks was concentrated under reduced pressure to obtain 2-((R)-2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-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-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione [ka] 2-(2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-1,3-dione (0.75 g, 1.36 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 70-70% acetonitrile). One of the two separated peaks was concentrated under reduced pressure to obtain 2-((S)-2,6-dioxopiperidine-3-yl)-4-((6-(2-methylpyridine-4-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-indazole-5-yl)amino)isoindorin-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione [ka]

[0389] 7-amino-6-bromo-3,4-dihydroquinoline-2(1H)-one [ka] A mixture of 7-amino-3,4-dihydroquinoline-2(1H)-one (5.00 g, 30.83 mmol) suspended in dichloromethane (100 mL) and methanol (25 mL) was mixed with 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 with 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 obtain 7-amino-6-bromo-3,4-dihydroquinoline-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-dihydroquinoline-2(1H)-one [ka] 7-amino-6-bromo-3,4-dihydroquinoline-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 at 25°C for 12 hours. The reaction product was quenched with saturated ammonium chloride solution (10 mL), followed by partitioning with ethyl acetate and saturated brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to obtain 7-amino-6-bromo-1-methyl-3,4-dihydroquinoline-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); MS (ESI) m / z: 255.1[M]

[0391] 7-amino-1-methyl-6-(2-methylpyridine-4-yl)-3,4-dihydroquinoline-2(1H)-one [ka] To a solution of 1,4-dioxane (10 mL) and water (1 mL) containing a mixture of 7-amino-6-bromo-1-methyl-3,4-dihydroquinoline-2(1H)-one (0.80 g, 3.14 mmol), 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) were added. The suspension was degassed and purged with nitrogen. The mixture was stirred at 110°C for 12 hours. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 7-amino-1-methyl-6-(2-methylpyridine-4-yl)-3,4-dihydroquinoline-2(1H)-one (0.60 g, 2.24 mmol, 71% yield). MS (ESI) m / z: 268.0[M+1] +

[0392] 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione [ka] To a solution of 7-amino-1-methyl-6-(2-methylpyridine-4-yl)-3,4-dihydroquinoline-2(1H)-one (0.60 g, 2.24 mmol) in 10 mL of 1,4-dioxane, 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-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) were added. The suspension was degassed and purged with nitrogen. The mixture was stirred at 115°C for 12 hours. The reaction product was filtered, the filtrate was concentrated, and purified by semi-preparative reverse-phase HPLC. The recovered fraction was freeze-dried to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione [ka] 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione (0.60 g, 1.15 mmol) was separated by chiral preparative SFC (isopropyl alcohol in 40-40% acetonitrile). After separation, the peak (S)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(4-methylthiazole-2-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-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-dihydroquinoline-2(1H)-one [ka] Potassium acetate (0.57 g, 5.88 mmol) was added to a solution of 7-amino-6-bromo-1-methyl-3,4-dihydroquinoline-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). The mixture was degassed and purged with nitrogen. (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.16 g, 0.20 mmol) was added to the mixture, 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 obtain 7-amino-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-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-methylthiazole-2-yl)-3,4-dihydroquinoline-2(1H)-one [ka] Sodium carbonate (0.21 mg, 1.99 mmol) was added to a solution of 7-amino-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-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). The mixture was degassed and purged with nitrogen. (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.06 mg, 0.07 mmol) was added to the mixture, 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 obtain 7-amino-1-methyl-6-(4-methylthiazole-2-yl)-3,4-dihydroquinoline-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(4-methylthiazole-2-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)isoindoline-1,3-dione [ka] To a solution of 7-amino-1-methyl-6-(4-methylthiazole-2-yl)-3,4-dihydroquinoline-2(1H)-one (0.05 g, 0.18 mmol) in 1,4-dioxane (2 mL), 4-bromo-2-(2,6-dioxopiperidine-3-yl)isoindorin-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) were added. The suspension was degassed and purged with nitrogen. The mixture was stirred at 115°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude residue was purified by semi-preparative reverse-phase HPLC, and the recovered fraction was freeze-dried to obtain 2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(4-methylthiazole-2-yl)-2-oxo-1,2,3,4-tetrahydroquinoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindorin-1,3-dione [ka]

[0399] 7-amino-6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one [ka] To a solution of 1,4-dioxane (4 mL) and water (1 mL) containing a mixture of 7-amino-6-bromo-1-methyl-3,4-dihydroquinoline-2-one (0.20 g, 0.78 mmol), 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) were added. 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 subsequently filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (methanol in 5-15% dichloromethane) to obtain 7-amino-6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-3,4-dihydroquinoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalate [ka] In 5 mL of 1,4-dioxane, 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) were added to a solution of 7-amino-6-(1-cyclopropylpyrazole-4-yl)-1-methyl-3,4-dihydroquinoline-2-one (0.197 g, 0.70 mmol) and dimethyl 3-bromobenzene-1,2-dicarboxylate (0.226 g, 0.83 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 crude product obtained was purified by preparative TLC to obtain dimethyl 3-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalic acid [ka] To a solution of dimethyl 3-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalate (0.170 g, 0.36 mmol) in water (1 mL) and methanol (3 mL), sodium hydroxide (0.043 g, 1.07 mmol) was added. 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 obtain crude 3-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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-cyclopropylpyrazole-4-yl)-1-methyl-2-oxo-3,4-dihydroquinoline-7-yl]amino]-1,3-dioxoisoindoline-2-yl]-5-oxopentanoate [ka] To a solution of 3-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalic acid (0.088 g, 0.20 mmol) in toluene (1.5 mL) and triethylamine (0.34 mL, 1.97 mmol), tert-butyl rac-(4S)-4,5-diamino-5-oxopentanoate (0.040 g, 0.20 mmol) was added. 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 obtain tert-butyl rac-(4S)-5-amino-4-[4-[[6-(1-cyclopropylpyrazole-4-yl)-1-methyl-2-oxo-3,4-dihydroquinoline-7-yl]amino]-1,3-dioxoisoindoline-2-yl]-5-oxopentanoate (0.069 g, 0.11 mmol, 57.1% yield).

[0403] (S)-4-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione [ka] In acetonitrile (1 mL), a solution of tert-butyl rac-(4S)-5-amino-4-[4-[[6-(1-cyclopropylpyrazole-4-yl)-1-methyl-2-oxo-3,4-dihydroquinoline-7-yl]amino]-1,3-dioxoisoindoline-2-yl]-5-oxopentanoate (0.069 g, 0.11 mmol) was added to benzenesulfonic acid (0.018 g, 0.11 mmol). The mixture was stirred at 60°C for 12 hours. The reaction product was extracted with dichloromethane (30 mL x 3) and saturated sodium bicarbonate solution (30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to obtain (S)-4-((6-(1-cyclopropyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione [ka]

[0405] 7-amino-6-(1,3-dimethylpyrazole-4-yl)-1-methyl-3,4-dihydroquinoline-2-one [ka] Potassium carbonate (0.27 g, 2.00 mmol) was added to a solution of 7-amino-6-bromo-1-methyl-3,4-dihydroquinoline-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). 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 obtain 7-amino-6-(1,3-dimethylpyrazole-4-yl)-1-methyl-3,4-dihydroquinoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalate [ka] 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 to a solution of 7-amino-6-(1,3-dimethylpyrazole-4-yl)-1-methyl-3,4-dihydroquinoline-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). The mixture was stirred at 110°C for 12 hours. The suspension was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC to obtain dimethyl 3-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalic acid [ka] To a solution of dimethyl 3-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalate (0.15 g, 0.32 mmol) in methanol (3 mL), sodium hydroxide (0.06 g, 1.63 mmol) was added 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 precipitate was filtered, washed with water (20 mL), and dried under reduced pressure to obtain 3-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-1,3-dioxoisoindoline-2-yl)-5-oxopentanoate [ka] Triethylamine (0.44 mL, 2.53 mmol) was added 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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalic acid (0.110 g, 0.25 mmol) in toluene (2.5 mL). 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 obtain tert-butyl (S)-5-amino-4-(4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-1,3-dioxoisoindoline-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-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione [ka] In acetonitrile (1.5 mL), a solution of tert-butyl (S)-5-amino-4-(4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-1,3-dioxoisoindoline-2-yl)-5-oxopentanoate (0.09 g, 0.15 mmol) was added, to which benzenesulfonic acid (0.047 g, 0.30 mmol) was added. 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 x 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The separated product was freeze-dried to obtain (S)-4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-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-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione [ka]

[0411] 7-amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-3,4-dihydroquinoline-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), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.048 g, 0.06 mmol), 7-amino-6-bromo-1-methyl-3,4-dihydroquinoline-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)pyridine-2(1H)-one (0.293 g, 1.18 mmol) were added. The suspension was degassed and purged with nitrogen. The mixture was stirred at 110°C for 12 hours. The reaction product was concentrated under reduced pressure and purified by silica gel column chromatography (methanol in 5-15% dichloromethane) to obtain 7-amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-3,4-dihydroquinoline-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-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalate [ka] In 1 mL of 1,4-dioxane, 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) were added to a solution of 7-amino-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-3,4-dihydroquinoline-2(1H)-one (0.150 g, 0.50 mmol) and dimethyl 3-bromophthalate (0.165 g, 0.61 mmol). The mixture was degassed and purged with nitrogen. The resulting mixture was stirred under nitrogen at 110°C for 12 hours. The reaction product was filtered, the filtrate was concentrated, and purified by semi-preparative reverse-phase HPLC (with 45-65% acetonitrile in water and 0.1% trifluoroacetic acid). The separated fraction was lyophilized to obtain dimethyl 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalic acid [ka] A solution of dimethyl 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)phthalate (0.050 g, 0.10 mmol) was added to 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 resulting solid was dried under reduced pressure. The filtrate was extracted with dichloromethane (20 mL x 3) and water (20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-1,3-dioxoisoindoline-2-yl)-5-oxopentanoate [ka] Triethylamine (0.15 mL, 0.87 mmol) was added to a solution of 3-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-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). 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 obtain tert-butyl (S)-5-amino-4-(4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-1,3-dioxoisoindoline-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-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione [ka] In acetonitrile (2 mL), a solution of tert-butyl (S)-5-amino-4-(4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-1,3-dioxoisoindoline-2-yl)-5-oxopentanoate (0.040 g, 0.06 mmol) was added to benzenesulfonic acid (0.023 g, 0.14 mmol). The resulting mixture was stirred under nitrogen 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 (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, followed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was re-purified by chiral preparative SFC (isopropyl alcohol in 40-40% acetonitrile). After separation, the main peak was freeze-dried to obtain (S)-4-((6-(1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-7-yl)amino)-2-(2,6-dioxopiperidine-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka]

[0417] 6-bromo-1-methyl-5-nitro-1H-indazole [ka] 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) were added to a 500 ml three-necked flask. 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 reduced pressure to obtain 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-methylpyridine-4-yl)-5-nitro-1H-indazole [ka] 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) were added 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). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-methyl-6-(2-methylpyridine-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-methylpyridine-4-yl)-1H-indazole-5-amine [ka] Ammonium chloride (9.0 g, 168.2 mmol) and ferrous iron powder (6.0 g, 107.1 mmol) were added to a solution of 1-methyl-6-(2-methylpyridine-4-yl)-5-nitro-1H-indazole (9.0 g, 33.5 mmol) in ethanol (90 mL) and water (30 mL). 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 phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-methylpyridine-4-yl)-1H-indazole-5-yl)amino)phthalate [ka] In 60 mL of dioxane, 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) were added to a solution of 1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-amine (5.3 g, 22.2 mmol) and dimethyl 3-bromophthalate (6.2 g, 22.7 mmol). The resulting mixture was stirred under nitrogen at 110°C for 12 hours. 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-methylpyridine-4-yl)-1H-indazole-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-methylpyridine-4-yl)-1H-indazole-5-yl)amino)phthalic acid [ka] A solution of dimethyl 3-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)phthalate (8.0 g, 18.58 mmol) was added to 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 resulting solid was dissolved in methanol (800 mL), and then the pH was adjusted to 4 with aqueous HCl (6 M). The solution was concentrated under reduced pressure. The filtrate was adjusted to 4 with aqueous HCl (6 M). The resulting precipitate was separated by suction filtration and dried under reduced pressure. The separated substances were combined to obtain 3-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-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-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-1,3-dioxoisoindorin-2-yl)-5-oxopentanoate [ka] To a solution of 3-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)phthalic acid (4.0 g, 9.94 mmol) in toluene (60 mL), tert-butyl (S)-4,5-diamino-5-oxopentanoate (2.01 g, 9.94 mmol) and triethylamine (17 mL, 99.4 mmol) were added. 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 obtain tert-butyl (S)-5-amino-4-(4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-1,3-dioxoisoindorin-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-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindoline-1,3-dione [ka] In 30 mL of acetonitrile, a solution of tert-butyl (S)-5-amino-4-(4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)-1,3-dioxoisoindorin-2-yl)-5-oxopentanoate (2.83 g, 4.98 mmol) was added to 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 x 3) and sodium bicarbonate (200 mL). The combined organic layers were 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 freeze-dried to obtain (S)-2-(2,6-dioxopiperidine-3-yl)-4-((1-methyl-6-(2-methylpyridine-4-yl)-1H-indazole-5-yl)amino)isoindorin-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 assay HbF induction assay Using a two-step 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), GCSF-mobilized human CD34 + (STEMCELL Technologies Inc.) Cells were proliferated, differentiated, and matured into erythroid cells. In the first step, StemSpan cells were treated 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 using XF (STEMCELL Technologies Inc.) medium + Cells were cultured and maintained in a logarithmic growth phase for 7 days at 37°C and 5% CO2 to support proliferation and progenitor cell differentiation before the second step and compound treatment. In the second step, the medium was changed to StemSpan with 1X BIT 9500, penicillin-streptomycin (50 U / mL), 50 ng / mL rh SCF, and 40 ng / mL rh EPO added. TM The medium was changed to XF medium to promote further differentiation and maturation of erythrocytes, and treatment with the compound was initiated. The compound was distributed in two duplicates at a final concentration of 1 μM and a final DMSO content of 0.1%. Fresh compound was applied again to maintain a constant cell density every two days. After 7 days, cells were evaluated for viability and fetal hemoglobin expression using flow cytometry. For viability analysis, see eBioscience. TM Fixable Viability Dye eFluor TMCells were treated with 780 (1:1000, eBioscience; Cat# 65-0865-14) and left 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 process, cells were stained with PE-labelled Mouse Anti-Human Fetal Hemoglobin (1:10, clone 2D12; BD Biosciences, Cat# BDB560041), incubated at room temperature for 20 minutes, and protected from light. PE-labelled Mouse anti-IgG k (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 the data were analyzed using FCS express software (De Novo Software). Table 1 below shows the % viable cells, viable cell count, the effects of compounds (I), (I'), (II), (II'), and (III) on % 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 isotype-negative controls. Baseline % HbF-positive cells in DMSO-treated control cells were 15%. Compounds (I), (I'), (II), (II'), and (III) that induce 66% to 100% HbF are classified as level A. Compounds of formulas (I), (I'), (II), (II'), and (III) with HbF induction of 33% to 66% are classified as Level B. Compounds of formulas (I), (I'), (II), (II'), and (III) with HbF induction of less than 33% are classified as Level C. For specific compounds of formulas (I), (I'), (II), (II'), and (III), the %HbF induction values ​​for 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 were performed on WIZ and ZBTB7A in HUDEP-2 cells as follows. HUDEP-2 cells, engineered to express the HiBiT tag in either the WIZ (Widely interspaced zinc finger) protein or the ZBTB7A (Zinc Finger And BTB Domain Containing 7A) protein, 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). Before starting the assay, cell number and viability were measured using a Vi-cell XR cell viability analyzer by trypan blue exclusion method. 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 placed 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) in a 1.0x10⁶ cell range. 6The cells were resuspended at a density of cells / ml. 40 microliters of cell suspension were distributed using a VIAFLO 384 liquid hander into 384-well Low Flange White Flat Bottom Polystyrene TC-treated Microplates containing pre-distributed compounds, and the plates were placed in a 37°C, 5% CO2 incubator. Each compound was distributed in two replicates to achieve a final DMSO concentration of 0.1%. 24 hours after treatment, 40 μL of Nano-Glo HiBiT Lytic Detection System reagent was distributed into each well using a VIAFLO 384 liquid hander. The plates were incubated at room temperature for 25 minutes, and luminescence was read as relative luminescence using an EnVision plate reader. EC50 and Y-min values ​​were calculated using curves generated by dotmatics software after normalizing the data to 10 different concentrations of DMSO control (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 count and viability were measured using a Vi-cell XR cell viability analyzer by trypan blue exclusion method. The cells were then transferred to a 50 mL conical beaker and centrifuged at 500 g for 5 minutes. The cells were resuspended in a low-adhesion flask 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. This was then placed in an incubator at 37°C and 5% CO2. After 48 hours, cell count and viability were measured using the Vi-cell XR cell viability analyzer by trypan blue exclusion method. HUDEP-2 ZBTB7A cells were transferred to a 50 mL conical beaker, centrifuged at 500 g for 5 minutes, and then transferred to 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 (1.0 x 10⁶ cells). 6The cells were resuspended at a density of cells / ml. 40 microliters of cell suspension were distributed using a VIAFLO 384 liquid hander into 384-well Low Flange White Flat Bottom Polystyrene TC-treated Microplates containing pre-distributed compounds, and the plates were placed in a 37°C, 5% CO2 incubator. Each compound was distributed in two replicates to achieve a final DMSO concentration of 0.1%. 24 hours after treatment, 40 μL of Nano-Glo HiBiT Lytic Detection System reagent was distributed into each well using a VIAFLO 384 liquid hander. The plates were incubated at room temperature for 25 minutes, and luminescence was read as relative luminescence using an EnVision plate reader. EC50 and Y-min values ​​were calculated using curves generated by dotmatics software after normalizing the data to 10 different concentrations of DMSO control (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 formulas (I), (I'), (II), (II'), and (III) with a WIZ EC50 < 0.01 μM are level D. Compounds of formulas (I), (I'), (II), (II'), and (III) with a WIZ EC50 > 0.01 μM to 0.1 μM are level E. Compounds of formulas (I), (I'), (II), (II'), and (III) with a WIZ EC50 > 0.1 μM are level F. Specific compounds of formulas (I), (I'), (II), (II'), and (III) with WIZ EC50 values ​​< 0.01 μM (activity level D), WIZ EC50 > 0.01 μM to 0.1 μM (activity level E), and < 0.01 μM (activity level F) are shown in Table 2 below.

[0429] Compounds of formula (I), (I'), (II), (II'), and (III) with ZBTB7A EC50 < 0.03 μM are level G. Compounds of formula (I), (I'), (II), (II'), and (III) with ZBTB7A EC50 > 0.03 μM to 0.1 μM are level H. Compounds of formula (I), (I'), (II), (II'), and (III) with ZBTB7A EC50 > 0.1 μM are level I. Specific compounds of formulas (I), (I'), (II), (II'), and (III) having ZBTB7A EC50 values ​​of <.01 μM (activity level G), ZBTB7A EC50 >.01 μM-0.1 (activity level H), and <.01 μM (activity level I) are shown in Table 2 below. [Table 29] [Table 30]

[0430] Although multiple references are cited, their disclosures are incorporated herein by reference as a whole.

Claims

1. The following equation (III): 【Chemistry 1】 [In the formula, Q is H or CH ３ And; R １２ This includes substituted or unsubstituted pyridyls, substituted or unsubstituted alkyls, substituted or unsubstituted heterocyclyls, or substituted or unsubstituted C ３ -C ６ It is a cycloalkyl group. Compounds thereof or their pharmaceutically acceptable salts, tautomers, isotopologs, or stereoisomers.

2. The compound according to claim 1, wherein Q'' is H, or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

3. Q is CH ３ The compound described in claim 1 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

4. R １２ However, CH ３ A compound according to claim 1, selected from cyclopropyl, substituted or unsubstituted thiazole, or substituted or unsubstituted pyrazole, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer thereof.

5. R １２ but, 【Chemistry 2】 And here, Q ３ is selected from H, Cl, or F; Q ４ H, CH ３ , or CH(F) ２ Selected from; Q ５ H, CH ３ , or OCH ３ Selected from; Q ６ This is selected from H or F. The compound described in claim 1 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

6. Q ３ However, F is and / or Q ５ However, OCH ３ Or CH ３ The compound according to claim 5 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

7. Q ３ However, H is Q ４ However, H is Q ５ However, CH ３ Q ６ However, it is H; Q ３ However, H is Q ４ However, CH(F) ２ Q ５ However, H is Q ６ However, it is H; Q ３ However, it is F and Q ４ However, CH ３ Q ５ However, H is Q ６ However, it is H; Q ３ However, it is F and Q ４ However, H is Q ５ However, CH ３ Q ６ However, it is H; Q ３ However, it is Cl and Q ４ However, CH ３ Q ５ However, H is Q ６ However, it is H; Q ３ However, H is Q ４ However, CH ３ Q ５ However, CH ３ Q ６ However, it is H; Q ３ However, H is Q ４ However, CH ３ Q ５ However, OCH ３ Q ６ However, it is H; Q ３ However, it is F and Q ４ However, H is Q ５ However, OCH ３ Q ６ However, H is; or Q ３ However, H is Q ４ However, H is Q ５ However, OCH ３ Q ６ However, it is F. The compound described in claim 5 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

8. A compound selected from the following, or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof. 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Request Item 9】 【Chemistry 9】 The compound according to claim 8, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer. 【Request Item 10】 【Chemistry 10】 The compound according to claim 8, or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer.

11. A compound with the following structure. 【Chemistry 11】

12. A compound with the following structure. 【Chemistry 12】

13. pharmaceutically acceptable salts of the following compounds. 【Chemistry 13】

14. pharmaceutically acceptable salts of the following compounds. 【Chemistry 14】

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, isotopolog, 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 composition for inducing HbF expression in cells and / or reducing ZBTB7A expression in cells and / or reducing WIZ expression in cells, comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, tautomer, isotopolog, or stereoisomer, a compound according to claim 11 or 12, or a pharmaceutically acceptable salt according to claim 13 or 14.

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

18. The composition according to claim 17, wherein the abnormal hemoglobin disorder is anemia, sickle cell disease, thalassemia, alpha-thalassemia, or beta-thalassemia.

19. A composition for treating an abnormal hemoglobin disorder, comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, a compound according to claim 11 or 12, or a pharmaceutically acceptable salt according to claim 13 or 14, characterized in that it is used to be administered in combination with a second active agent and / or therapy.

20. The composition according to claim 19, wherein the second active agent and / or therapy is ruspatercept, voxerotol, chryzanlizumab-tmca, hydroxyurea, L-glutamine, etavo pivat, mita pivat, osivelotol, incrumab, blood transfusion, stem cell transplantation, bone marrow transplantation, or gene therapy.

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

22. The composition according to claim 19, wherein the abnormal hemoglobin disorder is anemia, sickle cell disease, thalassemia, alpha-thalassemia, or beta-thalassemia.

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