Substituted 4-aminoisoindoline-1,3-dione compounds and their use for the treatment of lymphoma

Abstract

To provide pharmaceutical compositions for use in safe and effective methods of treating, preventing and managing Diffuse Large B-Cell Lymphoma (DLBCL), particularly for DLBCL that is refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and / or side effects associated with conventional therapies.SOLUTION: There are provided 4-aminoisoindoline-1,3-dione compounds having the following structure: Formula (I), compositions comprising an effective amount of a 4-aminoisoindoline-1,3-dione compounds and their use for treating lymphoma, wherein: ring A is an optionally substituted non-aromatic heterocyclyl; each R is independently substituted or unsubstituted C1-3 alkyl, or halogen; and n is 0, 1, 2, 3 or 4.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is a continuation of U.S. Provisional Application No. 62 / 661,525, filed April 23, 2018. Priority is claimed, the entire contents of which are incorporated herein by reference.

[0002] Certain 4-aminoisoindoline-1,3-dione compounds, effective amounts of such compounds and compositions containing an effective amount of such 4-aminoisoindoline-1,3-dione compounds. Diffuse large B-cell lymphoma (DLBCL), comprising administering to a subject in need thereof Provided herein are methods for treating or preventing [Background technology]

[0003] Cancer is primarily caused by an increase in the number of abnormal cells derived from a given normal tissue, and the proliferation of these abnormal cells. Infiltration of surrounding tissue by the cysts or regional lymph nodes from lymph or blood containing malignant cells Clinical data and molecular biological studies have shown that Cancer begins with subtle preneoplastic changes that, under certain conditions, can progress to neoplasia. It has been pointed out that the development of neoplastic lesions is a multi-step process. , invasion, proliferation, metastasis and heterogeneity, especially under conditions where neoplastic cells evade host immune surveillance. Current cancer therapies eradicate neoplastic cells in patients. Treatment may include surgery, chemotherapy, hormone therapy and / or radiation therapy to treat the condition. Recent advances in cancer therapy are reviewed in Nature Reviews Clinical Oncology Rajkumar et al. in Cology 11,628-630(2014) It will be reviewed by l.

[0004] All current cancer therapy approaches pose significant drawbacks to patients. The procedure may be contraindicated depending on the patient's health or may be difficult for the patient to tolerate. In addition, surgery may not completely remove the neoplastic tissue. , is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often cause serious side effects. Hormone therapy is given as a single agent. Hormonal therapy can be effective, but it is largely overlooked by other treatments. often used to prevent or delay the recurrence of cancer after removing cancer cells .

[0005] Regarding chemotherapy, there are a variety of chemotherapy agents available for the treatment of cancer. The majority of therapeutic drugs act by inhibiting DNA synthesis (deoxyribonucleotide triphosphates). It acts (either directly or indirectly) by inhibiting the biosynthesis of acid precursors. , blocking DNA replication and associated cell division. Gilman et al., Good man and Gilman's:The Pharmacological Bas is of Therapeutics,Tenth Ed.(McGraw Hill ,New York).

[0006] Despite the availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale,Medicine,vol.3,Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all The chemotherapeutic agents are toxic, and chemotherapy has side effects including severe nausea, bone marrow suppression, and immunosuppression. In addition, chemotherapy combinations can cause serious and often dangerous side effects. Even with the administration of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. Indeed, those cells that are resistant to the specific chemotherapeutic agents used in the treatment protocol The cells may be different from those of other drugs used in specific treatments, even if those drugs are different from those of other drugs used in specific treatments. Even if they act by a different mechanism, resistance to these other drugs often proves. This phenomenon is called pleiotropic drug resistance. This is also called multidrug resistance. As a result, many cancers are refractory to standard chemotherapy treatment protocols. It may become obvious or intractable.

[0007] Diffuse large B-cell lymphoma (DLBCL) is a subtype of non-Hodgkin's lymphoma (NHL). The NHL is the fifth most popular sport in the United States for both men and women. It is a common cancer. An estimated 385,700 patients were diagnosed with NHL worldwide in 2012. Approximately 199,700 patients died as a result of the disease (Torre, LA .et al.Global cancer statistics,2012;CA Cancer J.Clin.65,87-108(2015)). Most B-cell NHL DLBCL, the most common form, saw an estimated 27,650 new cases in the United States in 2016. and account for approximately 26% of all diagnosed mature B-cell NHL neoplasms (Te ras,LRet al.2016 US lymphoid malignanc y statistics by World Health Organization n subtypes;CA Cancer J.Clin.66,443-459(2 016)). Some DLBCL patients are cured with conventional chemotherapy, but the remainder experience a decline in their disease. and dies.

[0008] DLBCL, in particular, is a disease characterized by the standard treatments of surgery, radiation therapy, chemotherapy, and hormone therapy. Treatment of DLBCL refractory to conventional therapies with reduced toxicity and / or side effects associated with conventional therapies There is a significant need for safe and effective methods to treat, prevent, and manage, while avoiding, or preventing, The need still exists.

[0009] Citation or identification of any reference in this section of this application is expressly granted without prejudice to the accuracy or completeness of the information contained in the reference. Nothing contained herein should be construed as an admission that the subject matter is prior art. Summary of the Invention

[0010] A compound having the following formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof (formula wherein R, ring A, and n are as defined herein), Provided.

[0011] The compounds of formula (I) or pharmaceutically acceptable salts, tautomers, isotopic derivatives thereof, or stereoisomers (each of which is referred to herein as an "isoindolindione compound" ) is useful for the treatment or prevention of DLBCL.

[0012] In one embodiment, the isoindolinedione compounds described in this disclosure, for example, in Table 1, is provided herein.

[0013] In one embodiment, an effective amount of an isoindolinedione compound described herein, and a pharmaceutically acceptable carrier, excipient, or vehicle. In some embodiments, the pharmaceutical compositions are administered orally, parenterally, It is suitable for mucosal, transdermal or topical administration.

[0014] In one aspect, an effective amount of an isoindolinedione compound described herein to a subject in need thereof. In another embodiment, an effective amount of the compounds described herein is provided. and administering to a subject in need thereof a pharmaceutical composition comprising the compound of formula (I) or (II) to treat or treat DLBCL. In another embodiment, a method for preventing DLBCL is provided herein. The isoindolinedione compounds described herein for use in In another embodiment, the present invention provides a method for treating DLBCL. Pharmaceutical compositions as described in the specification are provided herein.

[0015] In another embodiment, the isoindolinedione compounds described herein are prepared by A method for doing so is provided herein.

[0016] The present embodiments are described in detail below with reference to the accompanying examples, which are intended to illustrate non-limiting embodiments. This can be more fully understood by reference to DETAILED DESCRIPTION OF THE INVENTION

[0017] definition As used herein, "comprising" and "in The terms "including" and "including" can be used interchangeably. The terms "g)" and "including" are used interchangeably with the express terms to which reference is made. It is interpreted as specifying the presence of a feature or component, but it does not specify the presence of one or more features or components. In addition, the use of "comprises" does not preclude the presence or addition of any component or group thereof. The terms "prising" and "including" mean "consisting of" is intended to encompass examples covered by the term "comprising of" Therefore, the term "consisting of" should be changed to "including" Instead of the words "comprising" and "including" can be used to provide more specific embodiments of the present invention.

[0018] The term "consisting of" means that the object consists of at least 90%, 95%, 97%, 98% or 99% of the expressly designated features that make up it or In another embodiment, "consists of" means "having components." The term "setting of" refers to any element except that which is not essential to the technical effect to be achieved. to exclude any other feature or component from the scope of any subsequent recitation.

[0019] As used herein, the term "or" refers to any one or any combination of It should be interpreted as an inclusive "or" meaning a combination. or C" is any of the following: "A; B; C; A and B; A and C; B and C; A, B and C" Exceptions to this definition are elements, functions, steps or This would only occur if the combination of effects were somehow inherently mutually exclusive.

[0020] As used herein and unless otherwise specified, an "alkyl" group is an alkyl group having 1 to 1 0 carbon atoms, typically 1 to 8 carbons, or in some embodiments, 1 to 6 saturated, partially saturated, or unsaturated straight-chain or or branched acyclic hydrocarbons. Representative alkyl groups include -methyl, -ethyl, , -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; On the other hand, saturated branched alkyls include -isopropyl, -sec-butyl, and -isobutyl. , -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, 2-methyl methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. An "alkenyl" group is an alkyl group having one or more carbon-carbon double bonds. An "alkynyl" group is an alkyl group containing one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include 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 —CH≡C(CH₂CH₃). The alkyl group can be substituted or unsubstituted. When the phrase "is" used herein refers to a compound that is "a compound that is capable of being produced by a method according to the present invention, it is understood that the present invention is not limited to the above-described compounds. In addition to any substituent(s) such as those found in the embodiments, halogen ;Hydroxy;Alkoxy;Cycloalkyloxy, Aryloxy, Heterocyclyloxy oxy, heteroaryloxy, heterocycloalkoxy lkyoxy), cycloalkylalkyloxy, aralkyloxy, heterocyclyl alkyloxy, heteroarylalkyloxy, heterocycloalkyloxy ( heterocycloalkyalkyloxy); oxo(=O); amino, alkyl arylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino Amino, heterocycloalkylamino; Imino; Imido; Amidino; Guanidino; Ethylene Amino; Acylamino; Sulfonylamino; Urea, Nitrourea; Oxime; Hydroxy Alkoxyamino; Aralkoxyamino; Aralkoxyamino; Hydrazino; Hydrazide; Hydrazo No; Azido; Nitro; Thio (-SH), Alkylthio; =S; Sulfinyl; Sulfonyl ;Aminosulfonyl;Phosphinyl;Acyl;Formyl;Carboxy;Ethyl ester;carbamate;amide;cyano;isocyanato;isothiocyanato;cyanato; thiocyanato; or -B(OH)2.

[0021] As used herein and unless otherwise specified, a "cycloalkyl" group means 3 to 10 optionally substituted monocyclic or polycyclic fused or bridged rings In some embodiments, the cyclic alkyl group is a saturated or partially saturated cyclic alkyl group of carbon atoms. Although cycloalkyl groups have 3 to 8 ring members, in other embodiments, the number of ring carbon atoms is in the range of 3 to 5, 3 to 6, or 3 to 7. Examples of such a cycloalkyl group include: As for the monocyclic structure (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl , 2-methylcyclooctyl, and the like), or polycyclic or bridged ring structures ( 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2 .2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like Examples of unsaturated cycloalkyl groups include, inter alia, cyclohexenyl. , cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl Cycloalkyl groups can be substituted or unsubstituted. Cycloalkyl groups include, by way of example, cyclohexanol and the like. .

[0022] As used herein and unless otherwise specified, an "aryl" group refers to a group having 6 to 1 4 carbon atoms in a single ring (e.g., phenyl) or in a polycyclic fused ring (e.g., naphthyl or aza- In some embodiments, the aryl group is an aromatic carbocyclic group having a hydroxyl group (e.g., benzotril). , 6 to 14 carbons in the ring portion of the group, and in others 6 to 12, and sometimes 6 to 1 0 carbon atoms. Particular aryl groups include phenyl, biphenyl, naphthyl Aryl groups can be substituted or unsubstituted. The phrase "aromatic group" refers to a group containing fused rings, such as a fused aromatic aliphatic ring system (e.g., indanyl). , tetrahydronaphthyl, and the like).

[0023] As used herein and unless otherwise specified, a "heteroaryl" group means A heteroaromatic ring system having 1 to 4 heteroatoms as ring atoms, with the remaining atoms being carbon atoms. In some embodiments, the heteroaryl group is an aromatic ring system in which the ring portion of the group containing 3 to 6 ring atoms, and in others 6 to 9, and sometimes 6 to 10 atoms Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include: Pyrrolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group azolyl group, isoxazolyl group, benzisoxazolyl (e.g., benzo[d]isoxazolyl) a thiazolyl group, a thiazolyl group, a pyrrolyl group, a pyridazinyl group, a pyrimidinyl group, Diphenyl group, pyrazinyl group, thiophenyl group, benzothiophenyl group, furanyl group, benzofuranyl group indolyl (e.g., indol-2-onyl) groups, isoindolin-1-onyl groups, pyrrolo[2,3-b]pyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl) ) group, indazolyl group, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl) group, azabenzimidazolyl group, imidazopyridyl (e.g., 1H-imidazo[4,5-b ]pyridyl) group, pyrazolopyridyl group, triazolopyridyl group, benzotriazolyl (e.g. For example, 1H-benzo[d][1,2,3]triazolyl) groups, benzoxazolyl (e.g. benzo[d]oxazolyl group, benzothiazolyl group, benzothiadiazolyl group, iso- Xazolopyridyl group, thianaphthalenyl group, purinyl group, xanthinyl yl), adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,4-di Hydroisoquinolin-1(2H)-onyl group, tetrahydroquinolinyl group, quinoxalinyl group Examples of heteroaryl include, but are not limited to, groups such as aryl, quinazolinyl, and heteroaryl groups. The group can be substituted or unsubstituted.

[0024] As used herein and unless otherwise specified, "heterocyclyl" refers to a ring Aromatic ring systems (heteroatoms) in which 1 to 4 of the carbon atoms are independently replaced by heteroatoms Aromatic cycloalkyl (also called aromatic aryl) or non-aromatic cycloalkyl (also called heterocycloalkyl) Suitable heteroatoms include oxygen, sulfur, and nitrogen. In some embodiments, heterocyclyl groups contain 3 to 10 ring members, while other such groups contain 3 Heterocyclyl has up to 5, 3 to 6, or 3 to 8 ring members. The heterocyclic group may be bonded to another group (i.e., at any carbon atom or heteroatom of the heterocyclic ring). Heterocyclyl groups can be substituted or unsubstituted. Heterocyclyl groups can be unsaturated, partially saturated, or and saturated ring systems, such as imidazolyl, imidazolinyl and imidazolidinyl groups (e.g. For example, imidazolidin-4-onyl group or imidazolidin-2,4-dionyl group) The term heterocyclyl encompasses fused ring species and includes both fused aromatic and fused non-aromatic groups. containing aromatic groups, such as 1-aminotetralin and 2-aminotetralin, benzotriazo aryl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl ( For example, 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxy Examples of the term include benzo[1,3]dioxolyl and benzo[1,3]dioxolyl. Bridged polycyclic ring systems (such as, but not limited to, quinuclidyl) Representative examples of heterocyclyl groups include aziridinyl groups, aziridinyl groups, and aziridinyl groups. Zetidinyl group, azepanyl group, oxetanyl group, pyrrolidyl group, imidazolidinyl (e.g. imidazolidin-4-onyl or imidazolidin-2,4-dionyl) groups, pyrazolidine a thiazolidinyl group, a tetrahydrothiophenyl group, a tetrahydrofuranyl group, Dioxolyl group, furanyl group, thiophenyl group, pyrrolyl group, pyrrolinyl group, imidazoline group a pyrazolyl group, an imidazolinyl group, a pyrazolyl group, a pyrazolinyl group, a triazolyl group, a tetrazolyl group, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[ d) isoxazolyl group, thiazolyl group, thiazolinyl group, isothiazolyl group, thiazolyl group Azolyl group, oxadiazolyl group, piperidyl group, piperazinyl (e.g., piperazine-2 -onyl) group, morpholinyl group, thiomorpholinyl group, tetrahydropyranyl (e.g., tetrahydropyranyl) group, tetrahydro-2H-pyranyl group, tetrahydrothiopyranyl group, oxathianyl group, di an oxyl group, a dithianyl group, a pyranyl group, a pyridyl group, a pyrimidyl group, a pyridazinyl group, Pyrazinyl group, triazinyl group, dihydropyridyl group, dihydrodithiinyl (dihyd rodithiinyl group, dihydrodithionyl ) group, 1,4-dioxaspiro[4.5]decanyl group, homopiperazinyl group, quinuclidyl group quinuclidyl groups, indolyl (e.g., indol-2-onyl) groups, iodo groups, isoindolin-1-onyl group, indolinyl group, isoindolyl group, isoindolinyl group , azaindolyl group, pyrrolopyridyl (e.g., 1H-pyrrolo[2,3-b]pyridyl) group , indazolyl group, indolizinyl group, benzotriazolyl (e.g., 1H-benzo[d] [1,2,3]triazolyl) groups, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl) groups, benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl group, benzo[d]imidazol-2(3H)-onyl group, phenyl group, benzothiophenyl group, benzothiazolyl group, benzoxadiazolyl group, benzo benzoxazinyl group, benzodithiinyl group benzoxathiinyl group, benzoxathiinyl group, benzoxathiinyl group Azinyl group, benzoxazolyl (e.g., benzo[d]oxazolyl) group, benzothiazo aryl group, benzothiadiazolyl group, benzo[l,3]dioxolyl group, pyrazolopyridyl group (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]-pyridyl) azabenzimidazolyl group, imidazopyridyl (e.g., 1H-imidazo[4, 5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl , xanthinyl group, adeninyl group, guaninyl group, quinolinyl group , isoquinolinyl group, 3,4-dihydroisoquinolin-1(2H)-onyl group, quinolidine quinoxalinyl group, quinazolinyl group, cinnolinyl group, phthalazinyl group, naphthyl group Lysinyl group, pteridinyl group, thianaphthalenyl group, dihydrobenzothiazinyl group, dihy dihydrobenzofuranyl group, dihydroindolyl group, dihydrobenzodioxinyl group, tetrahydrobenzofuranyl group, Hydroindolyl group, tetrahydroindazolyl group, tetrahydrobenzimidazolyl group , tetrahydrobenzotriazolyl group, tetrahydropyrrolopyridyl group, tetrahydropyridyl group Triazolopyridyl group, tetrahydroimidazopyridyl group, tetrahydrotriazolopyridyl group group, tetrahydropyrimidin-2(1H)-one group, and tetrahydroquinolinyl group. Representative non-aromatic heterocyclyl groups include, but are not limited to, fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, Azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidine-4 -onyl or imidazolidine-2,4-dionyl), pyrazolidinyl, thiazolidinyl , tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g. piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl , dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinucinyl lysyl, or tetrahydropyrimidin-2(1H)-one. Heterocyclyl groups can be monosubstituted or substituted with various substituents such as those listed below. may be multiply substituted (such as, but not limited to, pyridyl or morpholinyl groups, which are di-, tri-, tetra-, penta-, or hexa-substituted), or It may be disubstituted.

[0025] As used herein, the following heterocyclyl names refer to the structures in the table below: In some embodiments, the point of attachment is via a ring nitrogen atom. [Table 1] TIFF0007745679000003.tif243170

[0026] As used herein and unless otherwise specified, "cycloalkylalkyl" refers to a group consisting of cycloalkyl, ... The " group is a radical of the formula: -alkyl-cycloalkyl, where alkyl and cyclo Alkyl is defined above. Substituted cycloalkylalkyl groups include the alkyl portion of the group: Can be substituted at the cycloalkyl portion or at both the alkyl and cycloalkyl portions Representative cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, and cyclopropylmethyl. cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutyl ethyl ethyl, cyclopentyl ethyl, cyclohexyl ethyl, cyclopentyl propyl, These include, but are not limited to, cyclohexylpropyl, and the like.

[0027] As used herein and unless otherwise specified, an "aralkyl" group refers to a group of the formula: -alkyl-aryl radical, where alkyl and aryl are defined above. Substituted aralkyl groups are groups in which the alkyl portion, the aryl portion, or the alkyl and aryl portions of the group are substituted. Both the aryl and aryl portions may be substituted. Representative aralkyl groups include benzyl and phenyl. phenylethyl groups, and aralkyl groups in which an aryl group is fused to a cycloalkyl group (indane, Examples of suitable alkyl ethers include, but are not limited to, benzo-4-ylethyl, etc.

[0028] As used herein and unless otherwise specified, "heterocyclylalkyl" refers to a heterocyclyl group. " group is a radical of the formula: -alkyl-heterocyclyl, where alkyl and hetero Cyclyl is defined above. A "heteroarylalkyl" group is a group of the formula: -alkyl-hetero "Heteroaryl" is a radical of an aryl group, where alkyl and heteroaryl are defined above. A "heterocycloalkylalkyl" group is a radical of the formula: -alkyl-heterocycloalkyl where alkyl and heterocycloalkyl are defined above. The alkylalkyl group may be any group selected from the alkyl, heterocyclyl, or alkyl and heterocyclyl portions of the group. Both the heterocyclyl moieties may be substituted. Representative heterocyclylalkyl groups include , morpholin-4-ylethyl, morpholin-4-ylpropyl, furan-2-ylmethyl furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-yl Indol-2-ylpropyl and indol-2-ylpropyl are included, but are not limited to these.

[0029] As used herein and unless otherwise specified, "halogen" includes fluorine, It is chlorine, bromine or iodine.

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

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

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

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

[0034] As used herein and unless otherwise specified, an "aryloxy" group means -O-(aryl), where aryl is defined above.

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

[0036] As used herein and unless otherwise specified, an "amino" group refers to a group of the formula: -N H2, -NH(R # ), or -N(R # )2 radical, wherein each R # teeth, independently, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylsulfonyl ... aryl groups, aralkyl groups, heterocyclyl groups (e.g., heteroaryl groups or heterocyclyl groups) heteroarylalkyl groups), or heterocyclylalkyl groups (e.g., heteroarylalkyl groups or or heterocycloalkylalkyl groups), each of which is independently substituted or unsubstituted. be.

[0037] In one embodiment, an "amino" group has the formula: -NH-alkyl or -N(alkyl) and an "alkylamino" group, which is a radical of the formula "Cycloalkylamino", "arylamino", "heterocyclylamino" are defined as ", "heteroarylamino," "heterocycloalkylamino," or the like. Certain species include those in which the term "alkyl" is used in place of "cycloalkyl," "aryl," and "heterocycloalkyl." and the like, such as "heteroaryl," "heterocycloalkyl," or the like. Each of these reflects the above description of "alkylamino", when substituted.

[0038] As used herein and unless otherwise specified, a "carboxy" group refers to a group of the formula: It is the radical -C(O)OH.

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

[0040] As used herein and unless otherwise specified, an "amide" group is a group of the formula: -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 # ) radical, where each R # are independently defined above.

[0041] In one embodiment, an "amide" group has the formula: -C(O)-NH, -C(O)-NH( R # ), -C(O)-N(R # )2 is an "aminocarbonyl" group, which is a radical of the formula Inside, each R # are independently defined above.

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

[0043] As used herein and unless otherwise specified, a "sulfonylamino" group is , formula:-NHSO2(R # ) or -N(R # )SO2(R # ), wherein , each R # is defined above.

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

[0045] In one embodiment, an "ester" group is a radical of the formula: -C(O)-O-(alkyl) "alkoxycarbonyl" radical, where alkyl is defined above. "aryloxycarbonyl", "heterocyclyloxycarbonyl", "heterocycloalkyloxycarbonyl", "heteroaryloxycarbonyl", "heterocycloalkyloxycarbonyl", The term "carbonyl" or the like is used to refer to the term "alkoxy" as "cycloalkoxy." "aryloxy", "aryloxy", "heterocyclyloxy", "heteroaryloxy", and substituted by "oxy", "heterocycloalkyloxy" or the like, respectively. In this case, the above description of "alkoxycarbonyl" is reflected.

[0046] As used herein and unless otherwise specified, a "carbamate" group refers to a group of the formula :-OC(O)-NH2, -OC(O)-NH(R # ), -OC(O)-N(R # )2, -NH-C(O)-O-(R # ), or -N(R # )-C(O)-O-(R # ) where each R # are independently defined above.

[0047] As used herein and unless otherwise specified, a "urea" group refers to a group of 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 # )2 radical, wherein each R # are independently defined above.

[0048] As used herein and unless otherwise specified, a "sulfinyl" group refers to a group of the formula :-S(O)R #where R # is defined above.

[0049] As used herein and unless otherwise specified, a "sulfonyl" group refers to a group of the formula: -S(O)2R # where R # is defined above.

[0050] As used herein and unless otherwise specified, an "aminosulfonyl" group is , formula: -SO2NH2, -SO2NH(R # ), or -SO2N(R # )2 radical where each R # are independently defined above.

[0051] With the exception of alkyl groups, groups described herein are referred to as "substituted." When present, they may be substituted with any suitable substituent(s). Exemplary substituents include: Examples include those found in the exemplary compounds and embodiments disclosed herein. In addition to halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, Heterocyclyl, heteroaryl, heterocycloalkoxy ky), cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroaryl Heterocycloalkyl, heterocycloalkyl l) optionally hydroxy; alkoxy; cycloalkyloxy, aryloxy , heterocyclyloxy, heteroaryloxy, heterocycloalkyloxy (het erocycloalkyoxy), cycloalkylalkyloxy, aralkyloxy , heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkyl Heterocycloalkyalkyloxy; oxo(=O ); oxides (e.g., nitrogen atoms replaced by oxides are called N-oxides); amino , alkylamino, cycloalkylamino, arylamino, heterocyclylamino, Heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidinium Diamino; Ethylamino; Acylamino; Sulfonylamino; Urea, Nitrourea; Oxime; Hydroxylamino; Alkoxyamino; Aralkoxyamino; Hydrazino; Hydrazide; Hydrazono; Azido; Nitro; Thio-(SH), Alkylthio; =S; Sulfinyl; S Sulfonyl; Aminosulfonyl; Phosphonate; Phosphinyl; Acyl; Formyl; Carbo oxy; ester; carbamate; amide; cyano; isocyanato; isothiocyanato; cyano Further substituted with -anato; thiocyanato; or -B(OH)2.

[0052] As used herein, the term "isoindoledione compound" refers to a compound of the formula ( In addition to the compounds of formula I), further embodiments are provided herein. In this embodiment, the "isoindolinedione compound" is a compound described in Table 1. The term "isoindolindione compound" refers to the pharmaceutical use of the compounds provided herein. The present invention includes environmentally acceptable salts, tautomers, isotopic substitutions, and stereoisomers.

[0053] As used herein, the term "pharmaceutically acceptable salt(s)" means Pharmaceutically acceptable toxic compounds, including inorganic acids and bases, and organic acids and bases, The term "salt" refers to a salt prepared from an acid or base which is not a suitable pharmaceutically acceptable salt of the compound of formula (I). Examples of base addition salts include aluminum, calcium, lithium, magnesium, and potassium. , a metal salt made from sodium and zinc, or lysine, N,N'-dibenzylethyl Diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, Organic salts made from glutamic acid (N-methyl-glucamine) and procaine Suitable non-toxic acids include, but are not limited to, acetic acid, alginic acid, anthranil acid, and the like. Acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid Acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamine Acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, Mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid , phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid Inorganic and organic acids such as, but not limited to, tartaric acid, and p-toluenesulfonic acid Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, and sulfuric acid. , and methanesulfonic acid. Specific examples of salts include the hydrochloride and Others are known in the art, e.g., Remin gton's Pharmaceutical Sciences, 18th eds. ,Mack Publishing,Easton PA(1990) or Remin gton:The Science and Practice of Pharmac y,19th eds.,Mack Publishing,Easton PA(19 95).

[0054] As used herein and unless otherwise indicated, the term "stereoisomer" or "regioisomer" refers to a compound or a mixture of compounds. The term "enantiomerically pure" refers to the isomerization of one isoindolinedione compound. It means that the compound is a stereoisomer and is substantially free of other stereoisomers of the compound. A stereoisomerically pure compound having one chiral center is the opposite enantiomer of that compound. Stereomerically pure compounds with two chiral centers will be substantially free of mers. There will be substantially no other diastereomers of the compound. A suitable compound is one that is greater than about 80% by weight of one stereoisomer of the compound and more than about 80% by weight of another stereoisomer of the compound. less than about 20% by weight of one stereoisomer of the compound, more than about 90% by weight of one stereoisomer of the compound, and Contains less than about 10% by weight of other stereoisomers of the compound and less than about 10% by weight of one stereoisomer of the compound. More than about 95% by weight of other stereoisomers of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and about 3% by weight of the other stereoisomer of the compound The isoindolinedione compounds may have chiral centers and may be racemic, It can exist as individual enantiomers or diastereomers and as mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein. It includes mixtures of

[0055] In addition to stereomerically pure forms of such isoindolinedione compounds, their forms The use of mixtures of these modes is encompassed by the embodiments disclosed herein. For example, , mixtures containing equal or unequal amounts of the enantiomers of certain isoindolinedione compounds may be used in the methods and compositions disclosed herein. can be synthesized asymmetrically or by standard techniques such as chiral columns or chiral resolving agents. For example, Jacques, J., et al., Enantiom ers, Racemates and Resolutions(Wiley-Inte rscience, New York, 1981); Wilen, SH, et al. .,Tetrahedron 33:2725(1977);Eliel,EL,S Tereochemistry of Carbon Compounds (McGra w-Hill, NY, 1962); Wilen, SH, Tables of Res. olving Agents and Optical Resolutions p. 268(ELEliel,Ed.,Univ.of Notre Dame Pre ss, Notre Dame, IN, 1972); Todd, M., Separatio n Of Enantiomers:Synthetic Methods(Wiley -VCH Verlag GmbH & Co.KGaA,Weinheim,Germ any,2014);Toda,F.,Enantiomer Separation: Fundamentals and Practical Methods(Sprin ger Science & Business Media,2007);Subra manian,G.Chiral Separation Techniques:A Practical Approach(John Wiley & Sons,200 8);Ahuja, S., Chiral Separation Methods fo r Pharmaceutical and Biotechnological Pr Please refer to the following products (John Wiley & Sons, 2011).

[0056] The isoindolinedione compounds are E and Z isomers or mixtures thereof, and cis isomers. It should also be pointed out that the present invention may include isomeric and trans-isomers or mixtures thereof. In certain embodiments, the isoindolinedione compound is an E isomer or a Z isomer. In other embodiments, the isoindolinedione compound is isolated as either: It is a mixture of E and Z isomers.

[0057] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration will depend on the environment in which the compound is found, for example whether the compound is a solid or an organic solution. For example, in aqueous solution, pyrazole may be The compound has the following isomeric forms: [ka] and are called tautomers of each other.

[0058] As will be readily understood by those skilled in the art, various functional groups and other structures may exhibit tautomerism. and all tautomers of the compounds of formula (I) are within the scope of the invention.

[0059] The isoindolinedione compounds may contain naturally occurring atomic isotopes at one or more of the atoms. It should also be pointed out that a compound may contain proportions that are not present. lithium( 3 H), iodine-125( 125 I), sulfur 35( 35S), or carbon-14 ( 14 It can be radiolabeled with a radioisotope such as deuterium ( 2 H), carbon 13( 13 C), or nitrogen-15( 15 N) etc. are isotopically enriched As used herein, "isotopically enriched" refers to a compound that is isotopically enriched. The term "isotopically enriched" refers to an element other than the natural isotopic composition of that atom. Refers to an atom that has an isotopic composition. "Isotopically enriched" refers to the natural isotopes of that atom. It can also refer to a compound containing at least one atom having an isotopic composition other than that specified. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Labeled and isotopically enriched compounds can be used as therapeutic agents (e.g., cancer treatments), research reagents (e.g., They are useful as reagents in binding assays, and as diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of the isoindolinedione compounds described in this specification are radioactive. Regardless of whether or not the above is true, it is understood that such a method is encompassed within the scope of the embodiments provided herein. In some embodiments, the isotopic configuration of the isoindolinedione compound is Substitutions are provided, for example, isotopic substitutions enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterium" refers to a deuterium-containing isoindoledione compound. "Converted" means that at least one hydrogen (H) has been replaced with a deuterium (D or 2 (denoted by H) and replaced, i.e., the compound is enriched with deuterium in at least one position. This refers to a compound that

[0060] Each isoindolinedione compound referenced herein may be sterically or isoformally Independently of topochemical composition, any pharmaceutically acceptable salt form discussed herein Similarly, isotopic compositions may be provided in the form It is understood that the stereochemistry of each isoindolinedione compound can vary independently. Furthermore, the isotopic composition of each isoindolinedione compound or its salt is otherwise, each isoindolinedioic acid is restricted to those elements present in The selection of a pharmaceutically acceptable salt of the compound can vary independently.

[0061] If there is a discrepancy between a depicted structure and the name for that structure, the depicted structure shall be used. It should be noted that more emphasis is given to the structure.

[0062] As used herein, "treating" refers to treating a disorder, disease, or condition, or refers in whole or in part to one or more symptoms associated with a disorder, disease, or condition effectively relieve or slow or stop further progression or worsening of those symptoms or to alleviate or eradicate the cause(s) of the disorder, disease or condition itself. In one embodiment, a disorder, as described herein, is a DLBCL or its symptoms.

[0063] As used herein, "preventing" means preventing the onset of a disorder, disease or condition. , methods for preventing and / or delaying, in whole or in part, the recurrence or spread of a method for preventing an elephant from acquiring a disorder, disease or condition; or a method for preventing a subject from acquiring a disorder, disease or condition; refers to a method of reducing the risk of acquiring a pathological condition. As used herein, DLBCL or a symptom thereof.

[0064] The term "effective amount" with respect to an isoindolinedione compound is used herein to mean and an amount capable of treating or preventing the disorder, disease or condition, or a symptom thereof, of which the compound is a compound of formula (I). means.

[0065] The term "subject" includes animals, including cows, monkeys, horses, sheep, pigs, etc. , chicken, turkey, quail, cat, dog, mouse, rat, rabbit or mole In one embodiment, the mammal is a mammal, including, but not limited to, a mammal such as a hamster, a mammalian animal, a mammalian mammal, a mammalian animal ... In one embodiment, the subject is a human. In one embodiment, the subject has DLBCL or symptoms thereof. The present invention relates to a human having or at risk of having a pulmonary embolism.

[0066] In general, the technical teachings of one embodiment may be applied to other embodiments provided herein. It can be combined with those described above.

[0067] Isoindoledione compounds A compound having the following formula (I): [ka] or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof (In the formula, Ring A is an optionally substituted non-aromatic heterocyclyl (with the point of attachment on the ring nitrogen atom). can be; Each R is independently substituted or unsubstituted C 1-3 Alkyl or halogen the law of nature; n is 0, 1, 2, 3, or 4) is provided herein.

[0068] In some embodiments, the compound is a compound of formula (II) [ka] , or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof (formula wherein rings A and R are as defined herein. is.

[0069] In some embodiments, the compound is a compound of formula (III) [ka] , or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof (formula wherein rings A and R are as defined herein.

[0070] In some embodiments, the compound is a compound of formula (IV) [ka] , or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof, wherein ring A, n and R are as defined herein. is.

[0071] In some embodiments, the compound is a compound of formula (V) [ka] , or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof, and R are as defined herein.

[0072] In some embodiments, the compound is a compound of formula (VI) [ka] , or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof, and R are as defined herein. is.

[0073] In some embodiments, the compound is a compound of formula (VII) [ka] , or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof, wherein ring A, n and R are as defined herein. is.

[0074] In some embodiments, the compound is a compound of formula (VIII) [ka] , or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof, and R are as defined herein. is.

[0075] In some embodiments, the compound is a compound of formula (IX) [ka] , or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof, and R are as defined herein. is.

[0076] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is azetidyl; Peridyl; Piperazinyl; Morpholinyl; 5-Azaspiro[2,3]hexyl; 2-Aza Spiro[3.3]heptyl;2-oxa-6-azaspiro[3.3]heptyl;2-aza Spiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 6-oxa-2-azaspiro[3.4]octyl 2-Azaspiro[3.4]octyl; 2-Azaspiro[3.5]nonyl; 7-Oxa -2-Azaspiro[3.5]nonyl;Octahydrocyclopenta[c]pyrrolyl;1,2 ,3,3a,4,6a-Hexahydrocyclopenta[c]pyrrolyl; 6-Azaspiro[3 .4]octyl; 2-oxa-6-azaspiro[3.4]octyl; 6-azaspiro[2 .5]octyl; 7-azaspiro[3.5]nonyl; 1-oxa-8-azaspiro[4. 5]decanyl;2-oxa-8-azaspiro[4.5]decanyl;2,8-diazaspiro [4.5]Decan-1-onyl;3-oxa-9-azaspiro[5.5]undecanyl; 1,4-Oxazepanyl; 8-Azabicyclo[3.2.1]octyl; and isoindoli In one embodiment, the optionally substituted non-aromatic heterocyclyl is selected from aryl. wherein ring A is azetidyl; piperidyl; piperazinyl; 5-azaspiro[2,3]hexyl 2-Azaspiro[3.3]heptyl; 2-Oxa-6-azaspiro[3.3]heptyl 2-Azaspiro[3.4]octyl;5-Oxa-2-azaspiro[3.4]octyl 6-Oxa-2-azaspiro[3.4]octyl; 2-Azaspiro[3.5]noni 7-Oxa-2-azaspiro[3.5]nonyl;Octahydrocyclopenta[c]pi 1,2,3,3a,4,6a-Hexahydrocyclopenta[c]pyrrolyl;6- Azaspiro[3.4]octyl;2-oxa-6-azaspiro[3.4]octyl;6- Azaspiro[2.5]octyl;7-Azaspiro[3.5]nonyl;1-Oxa-8-a ... 2-oxa-8-azaspiro[4.5]decanyl;2,8 -diazaspiro[4.5]decane-1-onyl; 3-oxa-9-azaspiro[5.5] Undecanyl; 1,4-oxazepanyl; 8-azabicyclo[3.2.1]octyl; and and isoindolinyl. In another embodiment, Ring A is selected from the group consisting of azetidyl; piperidyl; piperazinyl; 2-azaspinylidene; 2-Azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.3]heptyl; 2-Azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl 7-oxa-2-azaspiro[3.5]nonyl; 1-oxa-8 -Azaspiro[4.5]decanyl; and 2,8-diazaspiro[4.5]decan-1-ol In another embodiment, the optionally substituted non-aromatic heterocyclyl is selected from aryl. wherein ring A is selected from azetidyl; piperidyl; piperazinyl; and morpholinyl. In another embodiment, ring A is an optionally substituted non-aromatic heterocyclyl. In another embodiment, ring A is optionally substituted azetidyl. In another embodiment, Ring A is optionally substituted piperazinyl. In another embodiment, ring A is optionally substituted morpholinyl.

[0077] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is selected from the group consisting of halogen, C1 -6 Alkyl, OR 1 , CON(R 2 )2, SO2(C 1-4 alkyl), N(R 2 )S O2(C 1-4 alkyl), -(C 0-3 alkyl)-(C 3-7 cycloalkyl), ( Non-aromatic heterocyclyl), aryl, heteroaryl, O-aryl, O-heteroaryl substituted by one or more substituents independently selected from C(O)aryl, and C(O)aryl; wherein alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl R is optionally substituted; 1 is H, optionally substituted C 1-6 Alkyl, or optionally is replaced by -(C 0-3 alkyl)-(C 3-7 cycloalkyl); each R 2 are independently H or C 1-6 In other embodiments, ring A is F, Cl, Br, CH3, CH2CH3, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH2F, CHF2 , CF3, CH2CH2F, CH2CHF2, CH2CF3, CH(CH3)CF3, C H2CH2CF3, OH, OCH3, OCH2CH3, O-Isopropyl, On-Pro Pyr, On-butyl, O-isobutyl, Ot-butyl, OCF3, O-cyclopropyl O-cyclobutyl, OCH2-cyclopropyl, OCH2-cyclobutyl, CONH 2, CONH(CH3), CON(CH3)2, SO2CH3, SO2CH2CH3, S O2 isopropyl, cyclopropyl, cyclobutyl, CH2-cyclopropyl, CH2- Cyclobutyl; Azetidyl, Pyrrolidinyl, Pyrrolidonyl, Isothiazolidyl (isothiazolidinyl) iazolidyl), isothiazolidine 1,1-dioxidyl, Piperidyl, piperazinyl, morpholinyl, 3-oxa-8-azabicyclo[3.2.1 ]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl (non-aromatic heterocyclyl) wherein heterocyclyl is CH3, CH2CH3, or is optionally substituted with one or more substituents independently selected from CF3; phenyl, O-phenyl, or C(O)-phenyl, where phenyl is selected from the group consisting of F, Cl, CH Optionally, with one or more substituents independently selected from 3, CN, or CONH2 substituted with); pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxazolyl Diazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, or is a heteroaryl selected from benzisoxazolyl, , Cl, CF3, CN, CONH2, CONH(CH3)2, or CON(CH3)2 optionally substituted with one or more substituents independently selected from substituted by one or more substituents independently selected from aryl and O-pyrimidyl; In some embodiments, ring A is selected from the group consisting of F, CH3, CH2CH3, isopropyl, t -Butyl, CH2F, CF3, CH(CH3)CF3, OH, OCH3, OCH2CH3 , O-Isopropyl, On-Propyl, O-Isobutyl, Ot-Butyl, OCF3, O-Cyclobutyl, OCH2-Cyclopropyl, CON(CH3)2, SO2CH2CH 3, SO2-isopropyl, cyclopropyl, cyclobutyl, CH2-cyclopropyl; Pyrrolidinyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, morpholinyl, 3 -oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl chloro[3.2.1]octyl (non-aromatic heterocyclyl) The cyclyl is optionally substituted with one or more substituents independently selected from CH3. phenyl, O-phenyl, or C(O)-phenyl, where phenyl is F, one or more substituents independently selected from Cl, CH3, CN, or CONH2 optionally substituted by pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl and selected from aryl, pyridyl, pyrazinyl, pyrimidyl, and benzisoxazolyl. Heteroaryl (wherein heteroaryl is F, Cl, CF3, CN, CONH2, C Optionally substituted with one or more substituents independently selected from ON(CH3)2 one or more substituents independently selected from O-pyridyl and O-pyrimidyl is replaced by

[0078] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is azetidyl. Ri, C 1-6 Alkyl, (non-aromatic heterocyclyl), aryl, heteroaryl, O- and O-heteroaryl, and one or more substituents independently selected from substituted by alkyl, cycloalkyl, heterocyclyl, aryl, or heterocyclic; In some such embodiments, ring A is an azetidiaryl. CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl, t-butyl; CF3; Pyrrolidinyl; Pyrrolidonyl piperidyl; piperazinyl; morpholinyl (optionally substituted by one or more CH3 substituted);3-oxa-8-azabicyclo[3.2.1]octyl;8-oxa-3- Azabicyclo[3.2.1]octyl; Pyrazolyl; 2-pyridyl; 3-pyridyl; 4- pyridyl, phenyl; and O-phenyl, wherein phenyl is selected from F or CN. and optionally substituted by one or more substituents selected from In another embodiment, ring A is azetidyl and C H2CH3, isopropyl, t-butyl; CF3; pyrrolidyl; pyrrolidonyl; morpholin nyl (optionally substituted by one or more CH3); 3-oxa-8-azabicyclo[4.2.1]cyclohexyl; 8-oxa-3-azabicyclo[3.2.1]octyl;8-oxa-3-azabicyclo[3.2.1]octyl; pyrazolyl; 2-pyridyl; 3-pyridyl; phenyl; and O-phenyl (wherein phenyl is optionally substituted with one or more substituents selected from F or CN and substituted with one or more independently selected substituents. A is azetidyl and is substituted with morpholinyl. In some such embodiments, In some such embodiments, the compound has the formula (II) wherein R is F. In other such embodiments, the compound has formula (I II), wherein R is F. In yet other such embodiments, the compound has the formula (IV), wherein R is F and n is 1. In other such embodiments, The compound is of formula (V) and R is F. In yet another such embodiment, The compound is of formula (VI) and R is F. In still other such embodiments, In other embodiments, the compound is of formula (VII), where R is F and n is 1. In one embodiment, the compound is of formula (VIII) and R is F. In some embodiments, the compound is a compound of formula (IX) and R is F. In such an embodiment, the compound is of formula (II) and R is CH3. In such an embodiment, the compound is of formula (III) and R is CH. In other such embodiments, the compound is a compound of formula (IV), wherein R is CH3. and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is In yet another such embodiment, the compound is a compound of formula (VI): and R is CH3. In yet other such embodiments, the compound is a compound of formula (VII) wherein R is CH3 and n is 1. In other such embodiments, the compound has the formula (VIII) wherein R is CH. In yet another such embodiment, The compound is of formula (IX), where R is CH3.

[0079] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is [ka] where R a is H and Rb is C 1-6 alkyl, non-aromatic heterocyclyl, aryl, heteroaryl, or O-aryl; or R a and R b teeth, Together with the carbon to which they are attached, they form a 3- to 6-membered cycloalkyl or a 4- to 6-membered non- Forms an aromatic heterocyclyl; alkyl, cycloalkyl, heterocyclyl, aryl , or heteroaryl may be one or more halogens, C 1-3 Alkyl or CN It is more optionally substituted.

[0080] In some such embodiments, R a is H and R b is CH2CH3, n-propanol propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl;CF3 ;pyrrolidyl;pyrrolidonyl;piperidyl;piperazinyl;morpholinyl (one or more Optionally substituted with several CH3; 3-oxa-8-azabicyclo[3.2.1]o Octyl;8-oxa-3-azabicyclo[3.2.1]octyl;Pyrazolyl;2-Pyri phenyl; or O-phenyl, where phenyl is selected from the group consisting of F and CN and optionally substituted with one or more substituents selected from In such embodiments, R a is H and R b is CH2CH3, isopropyl, t-butyl CF3, pyrrolidyl; pyrrolidonyl; piperidyl; piperazinyl; morpholinyl ( optionally substituted by one or more CH3); 3-oxa-8-azabicyclo[3 .2.1]octyl;8-oxa-3-azabicyclo[3.2.1]octyl;Pyrazolidinyl 2-pyridyl; 3-pyridyl; phenyl; or O-phenyl, where phenyl is optionally substituted with one or more substituents selected from F or CN. In some such embodiments, R a is H and R b is CH2CH3, isopropyl Pyrrolidinyl, t-butyl, CF3, pyrrolidinyl, pyrrolidinyl, morpholinyl, 2,2-dimethyl 3,3-dimethylmorpholinyl, 2,6-dimethylmorpholinyl, 3, 5-Dimethylmorpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 8 -oxa-3-azabicyclo[3.2.1]octyl, pyrazolyl, 2-pyridyl, 3- Pyridyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl In one embodiment, the aryl is 4-cyanophenyl, 4-cyanophenyl, O-phenyl, or O-4-cyanophenyl. In terms of form, R a and R b together with the carbon to which they are attached, form a cyclopropyl , cyclobutyl, 3,3-difluorocyclobutyl, cyclopentyl, cyclohexyl, Forms oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some such embodiments, the compound is of formula (II) and R is F. In such embodiments, the compound is of formula (III) and R is F. In other such embodiments, the compound is a compound of formula (IV), R is F, and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F. In yet another such embodiment, the compound is of formula (VI) and R is F. In still other such embodiments, the compound is a compound of formula (VII), wherein R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In yet another such embodiment, the compound is a compound of formula (IX): and R is F. In some such embodiments, the compound is of formula (II): In other such embodiments, the compound is represented by the formula (III): wherein R is CH3. In yet other such embodiments, the compound has the formula ( IV), where R is CH3 and n is 1. In other such embodiments, In yet another such embodiment, the compound is a compound of formula (V) and R is CH3. In yet another such embodiment, the compound is of formula (VI) and R is CH. In one embodiment, the compound is of formula (VII), R is CH3, and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH3. In yet another such embodiment, the compound is a compound of formula (IX) and R is CH It is 3.

[0081] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is piperidyl. halogen, C 1-6 Alkyl, OR 1 , CON(R 2 )2, SO2(C 1-4 Archi ru), C 3-7 cycloalkyl, non-aromatic heterocyclyl, aryl, heteroaryl, and O-heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; R 1 is H, optionally substituted C 1-6 Alkyl, or optionally substituted Converted to -(C 0-3 alkyl)-(C 3-7 cycloalkyl); each R 2 teeth, Independently H or C 1-6 In another embodiment, Ring A is piperidinyl. F, Cl, CH3, CH2CH3, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl, t-butyl, CH2F, CHF2, CF3, OH, OC H3, OCH2CH3, On-propyl, O-isopropyl, On-butyl, O-isopropyl O-butyl, Ot-butyl, OCF3, O-cyclopropyl, O-cyclobutyl, OCH 2-Cyclopropyl, OCH2-Cyclobutyl, CONH2, CONH(CH3), CO N(CH3)2, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl propyl, cyclobutyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, morpho Linyl; Tetrahydrofuranyl, Tetrahydropyranyl, Pyrazolyl; Oxadiazolyl (optionally substituted with CH3); phenyl (optionally substituted with one or more F) 2-pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl, O-3-pyridyl substituted with one or more substituents independently selected from O-4-pyridyl, O-4-pyridyl, and O-4-pyridyl; In some embodiments, ring A is piperidyl and is selected from the group consisting of F, CH3, CH2 CH3, isopropyl, t-butyl, CHF2, CF3, OH, OCH3, OCH2CH 3, O-Isopropyl, O-Isobutyl, Ot-Butyl, OCF3, O-Cyclobutyl , OCH2-cyclopropyl, CON(CH3)2, SO2CH2CH3, SO2-iso Propyl, cyclopropyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, molybdenum tetrahydropyranyl, pyrazolyl, oxadiazolyl (substituted by CH3 phenyl (substituted by one or more F); 2-pyridyl and O-2 -substituted by one or more substituents independently selected from: -pyridyl; In one such embodiment, the compound is a compound of formula (II) and R is F. In such embodiments, the compound is of formula (III) and R is F. In such embodiments, the compound is a compound of formula (IV), R is F, and n is 1 In other such embodiments, the compound is of formula (V) and R is F. In yet another such embodiment, the compound is a compound of formula (VI) and R is F. In still other such embodiments, the compound is of formula (VII) and R is F and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is F. In yet another such embodiment, the compound is a compound of formula (IX) and R is F. In some such embodiments, the compound is a compound of formula (II): In other such embodiments, the compound is of formula (III): In yet other such embodiments, the compound has the formula (I) V), wherein R is CH3 and n is 1. In other such embodiments, The compound is of formula (V) and R is CH3. In yet another such embodiment, Thus, the compound is of formula (VI) and R is CH. In the formula (VII), R is CH3 and n is 1. In such embodiments, the compound is a compound of formula (VIII) and R is CH In yet another such embodiment, the compound is a compound of formula (IX) and R is CH3 is.

[0082] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is [ka] where R c is H, halogen, OH, or (C 1-3 alkyl); R d is optionally substituted (C 1-3 alkyl), OR 1 , C(O)N(R 2 )2, SO2( C 1-4 alkyl), C 3-7 Cycloalkyl, non-aromatic heterocyclyl, aryl, or O heteroaryl; or R c and R d are the results of Together with the carbon to which it is bonded, it may be a 3- to 6-membered cycloalkyl or a 4- to 6-membered non-aromatic heterocycle. Forming a cyclocyclyl; R 1 is H, optionally substituted C 1-6 Alkyl, or optionally substituted Converted to -(C 0-3 alkyl)-(C 3-7 cycloalkyl); each R 2 teeth, Independently H or C 1-6 alkyl; alkyl, cycloalkyl, heterocyclyl The alkyl, aryl, or heteroaryl may be one or more halogens, C1-3 Alkyl or optionally substituted by CN.

[0083] In some such embodiments, R c is H, OH, F, CH3, or CH2C H3. In other such embodiments, R d are CH3, CH2CH3, n-propanol butyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, CH2F, CHF2, CF3, OCH3, OCH2CH3, On-propyl, O-isopropyl, O -n-butyl, O-isobutyl, O-t-butyl, OCF3, O-cyclopropyl, O-cyclopropyl Cyclobutyl, OCH2-cyclopropyl, OCH2-cyclobutyl, CONH2, CON H(CH3), CON(CH3)2, SO2CH3, SO2CH2CH3, SO2 isop Cyclopropyl, cyclopropyl, cyclobutyl, pyrrolidonyl, isothiazolidine 1,1-diol (xidyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl) oxadiazolyl (optionally substituted with CH3); phenyl (one or more F optionally substituted by 2-pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl In another embodiment, R d are CH3, CH2CH3, isopropyl, t-butyl, CHF2, CF3, OCH3 , OCH2CH3, O-Isopropyl, O-Isobutyl, Ot-Butyl, OCF3, O -cyclobutyl, OCH2-cyclopropyl, CON(CH3)2, SO2CH2CH3 , SO2-isopropyl, cyclopropyl, pyrrolidonyl, isothiazolidine 1,1-di Oxidyl, morpholinyl, tetrahydropyranyl, pyrazolyl, 2-methyl-1,3, 4-oxadiazolyl, 3,5-difluorophenyl, 2-pyridyl or O-2-pyridyl In one embodiment, R a and R b together with the carbon to which they are attached cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, pyrrolidonyl, 1-Methylpyrrolidonyl, tetrahydrofuranyl, 2,2-dimethyltetrahydrofuranyl In some such embodiments, the compound The compound is a compound of formula (II) wherein R is F. In other such embodiments, the compound is In yet other such embodiments, the compound is of formula (III), wherein R is F. The product is a compound of formula (IV), wherein R is F and n is 1. In other such embodiments, In yet another such embodiment, the compound is of formula (V) and R is F. In yet other such embodiments, the compound is of formula (VI) and R is F. In the compound, the compound is of formula (VII), R is F, and n is 1. In some embodiments, the compound is of formula (VIII) and R is F. In such an embodiment, the compound is of formula (IX) and R is F. In some such embodiments, the compound is of formula (II) and R is CH3. In other such embodiments, the compound is a compound of formula (III) and R is CH3 In yet other such embodiments, the compound is a compound of formula (IV) and R is CH3 and n is 1. In other such embodiments, the compound is a compound of formula (V): and R is CH3. In yet another such embodiment, the compound is a compound of formula (VI) and R is CH3. In yet other such embodiments, the compound is of formula (VII) wherein R is CH3 and n is 1. In other such embodiments, the compound The compound is a compound of formula (VIII) and R is CH3. In yet another such embodiment, wherein the compound is of formula (IX) and R is CH3.

[0084] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is piperazinyl. Yes, C 1-6 Alkyl, SO2(C 1-4 alkyl), -(C 0-3 alkyl)-(C 3-7 Independently of cycloalkyl), aryl, heteroaryl, and CO-aryl substituted by one or more selected substituents; wherein alkyl, cycloalkyl, The aryl or heteroaryl is optionally substituted. In another embodiment, Ring A is , piperazinyl, CH3, CH2CH3, n-propyl, isopropyl, n-butyl butyl, sec-butyl, isobutyl, t-butyl, CF3, CH2CF3, CH(CH3) CF3, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl, Cyclobutyl, (CH2)cyclopropyl, (CH2)cyclobutyl, phenyl (one or more optionally substituted by one or more Cl, F, CN, CH3, CONH2); pyrazolyl (optionally substituted with CH3 or CH2CH3); oxazolyl (CH3 or C oxadiazolyl (optionally substituted with CH3 or CH2CH3); thiadiazolyl (optionally substituted by CH3, CH2CH3, or CF3) optionally substituted); 2-pyridyl, 3-pyridyl, or 4-pyridyl (each of which is selected from the group consisting of Cl , F, CF3, CN, CONH2, CONH(CH3), or CON(CH3)2 pyrazinyl (optionally substituted by CH3 or CH2CH3); ); pyrimidyl (optionally substituted with OCH3); benzisoxazolyl; and C O(phenyl), wherein phenyl is optionally fluorinated; or substituted by multiple substituents. In another embodiment, Ring A is piperazinyl. Yes, CH3, isopropyl, t-butyl, CH(CH3)CF3, SO2CH2CH3 , SO2-isopropyl, cyclopropyl, cyclobutyl, (CH2)cyclopropyl, Phenyl (optionally substituted with one or more of Cl, F, CN, CH3, CONH2) pyrazolyl (optionally substituted with CH3); oxazolyl (optionally substituted with CH3) oxadiazolyl (optionally substituted with CH2CH3); thiadiazolyl zolyl (optionally substituted with CH3 or CH2CH3); 2-pyridyl (Cl, F , optionally substituted with CF3, CN, or CONH2); 3-pyridyl (CF3, optionally substituted with CN, CONH2, or CON(CH3)2); 4-pyridyl (optionally substituted with CONH2); pyrazinyl (optionally substituted with CH3) pyrimidyl (optionally substituted with OCH3); benzisoxazolyl; and CO (phenyl), wherein phenyl is optionally fluorinated; In another embodiment, A is piperazinyl. , t-butyl, or pyridyl, wherein pyridyl is substituted by C(O)NH2 In some such embodiments, R is F and n is 1. In some such embodiments, the compound is a compound of Formula (II) and R is F. In other such embodiments, the compound is of formula (III) and R is F. In still other such embodiments, the compound is a compound of formula (IV) and R is F. and n is 1. In other such embodiments, the compound is a compound of formula (V) and R is In yet another such embodiment, the compound is a compound of formula (VI) and R is F. In yet other such embodiments, the compound is a compound of formula (VII): , R is F and n is 1. In other such embodiments, the compound is of formula (VIII) wherein R is F. In yet another such embodiment, the compound has the formula (IX ) wherein R is F. In some such embodiments, the compound has the formula (I I) and R is CH3. In other such embodiments, the compound has formula (I II), wherein R is CH. In yet other such embodiments, the compound is a compound of formula (IV), where R is CH3 and n is 1. In other such embodiments, In yet another such embodiment, the compound is of formula (V) and R is CH. In one embodiment, the compound is of formula (VI) and R is CH3. In an embodiment, the compound is a compound of formula (VII), wherein R is CH3 and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH 3. In yet another such embodiment, the compound is a compound of formula (IX) and R is CH3.

[0085] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), ring A is [ka] where R e is C 1-6 Alkyl, SO2(C 1-4 alkyl), -(C 0-3 alkyl)-(C 3-7 cycloalkyl), aryl, heteroaryl, or CO-aryl alkyl, cycloalkyl, aryl, or heteroaryl is optionally will be replaced.

[0086] In some such embodiments, R e is CH3, CH2CH3, n-propyl, Isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, CH2CF3, CH(CH3)CF3, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl, cyclobutyl, (CH2)cyclopropyl, (CH2)cyclobutyl, Phenyl (optionally substituted by one or more of Cl, F, CN, CH3, CONH2) ); pyrazolyl (optionally substituted with CH3 or CH2CH3); oxazolyl ( optionally substituted by CH3 or CH2CH3; oxadiazolyl (CH3 or optionally substituted with CH2CH3; thiadiazolyl (CH3, CH2CH3, or is optionally substituted with CF3); 2-pyridyl, 3-pyridyl, or 4-pyridyl (Each is Cl, F, CF3, CN, CONH2, CONH(CH3), or CON( pyrazinyl (optionally substituted by CH3 or CH2CH3)2); Optionally substituted; pyrimidyl (optionally substituted with OCH3); benzisoxa or CO(phenyl), wherein the phenyl is optionally fluorinated. In some embodiments, R e isopropyl, t-butyl, CH(CH3)CF3 , SO2CH2CH3, SO2-isopropyl, cyclopropyl, cyclobutyl, (CH 2) Cyclopropyl, phenyl (one or more of Cl, F, CN, CH3, CONH2 pyrazolyl (optionally substituted by CH3); oxazolyl oxadiazolyl (optionally substituted by CH2CH3); substituted); thiadiazolyl (optionally substituted by CH3 or CH2CH3); 2 -pyridyl (optionally substituted with Cl, F, CF3, CN, or CONH2); 3 -pyridyl (optionally substituted with CF3, CN, CONH2, or CON(CH3)2) 4-pyridyl (optionally substituted with CONH2); pyrazinyl (optionally substituted with CH3 pyrimidyl (optionally substituted with OCH3); benzisopropyl or CO(phenyl), wherein the phenyl is optionally fluorinated. In some such embodiments, R is F or CH3 and n is 1. In some such embodiments, the compound is of Formula (II) and R is F. In other such embodiments, the compound is a compound of formula (III) and R is F. In yet other such embodiments, the compound is of formula (IV), R is F, n is 1. In other such embodiments, the compound is a compound of formula (V) and R is F In yet another such embodiment, the compound is a compound of formula (VI) and R is F. In yet other such embodiments, the compound is a compound of formula (VII): R is F and n is 1. In other such embodiments, the compound has the formula (VIII): wherein R is F. In yet another such embodiment, the compound is of formula (IX) wherein R is F. In some such embodiments, the compound has formula (II ) and R is CH3. In other such embodiments, the compound is of formula (II I) wherein R is CH3. In yet other such embodiments, the compound is In another such embodiment, R is CH3 and n is 1. In yet another such embodiment, the compound is of formula (V) and R is CH. In the present invention, the compound is of formula (VI) and R is CH3. In embodiments, the compound is of formula (VII), R is CH3, and n is 1. In other such embodiments, the compound is a compound of formula (VIII) and R is CH3 In yet another such embodiment, the compound is a compound of formula (IX) and R is It is CH3.

[0087] In some embodiments of compounds of Formula (I), (IV), or (VII), ring A is morpholinyl, R is F or CH3, and n is 1. Formula (II), (III) In other embodiments of compounds of formula (VI), (VIII), or (IX), Ring A is morpholinyl and R is F or CH3. In some such embodiments, In other such embodiments, the compound is of formula (II) and R is F. In yet other such embodiments, the compound is a compound of formula (III) and R is F. In one embodiment, the compound is of formula (IV), where R is F and n is 1. In an embodiment, the compound is of formula (V) and R is F. In an embodiment, the compound is of formula (VI) and R is F. In an embodiment, the compound is of formula (VII), R is F, and n is 1. In other such embodiments, the compound is of formula (VIII) and R is F. In yet another such embodiment, the compound is of formula (IX) and R is F. In some such embodiments, the compound is a compound of Formula (II) and R is CH In other such embodiments, the compound is a compound of formula (III) and R is C In yet other such embodiments, the compound is a compound of formula (IV): R is CH3 and n is 1. In other such embodiments, the compound is a compound of formula (V) In yet another such embodiment, the compound has formula (VI) ) wherein R is CH3. In yet other such embodiments, the compound has the formula (VII), where R is CH3 and n is 1. In other such embodiments, In another embodiment, the compound is of formula (VIII) and R is CH3. In an embodiment, the compound is of formula (IX) and R is CH3.

[0088] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In other embodiments of compounds of II) or (IX), ring A is 5-azaspiro[2, 3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3. 3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3. 4]octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3. 5]nonyl;7-oxa-2-azaspiro[3.5]nonyl;Octahydrocyclopenta [c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl 6-Azaspiro[3.4]octyl;2-Oxa-6-azaspiro[3.4]octyl 6-Azaspiro[2.5]octyl;7-Azaspiro[3.5]nonyl;1-Oxa -8-Azaspiro[4.5]decanyl;2-Oxa-8-azaspiro[4.5]decanyl ;2,8-Diazaspiro[4.5]decane-1-onyl;3-Oxa-9-azaspiro[ 5.5]undecanyl;1,4-oxazepanyl;8-azabicyclo[3.2.1]octyl and isoindolinyl (each optionally substituted with one or more CH3 or F). are selected from the following:

[0089] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), R is CH or F. In some embodiments of the compound of Formula (I), R is CH or F. In some embodiments of the compound of formula (II), R is CH or F. In some embodiments of the compound of formula (III), R is CH or F. In some embodiments of the compound of formula (V), R is CH or F. In some embodiments of the compound, R is CH or F. Compounds of Formula (VI) In some embodiments of the compound, R is CH or F. Compounds of Formula (VII) In some embodiments, R is CH or F. Compounds of Formula (VIII) In some embodiments, R is CH3 or F. In some embodiments, R is CH3 or F. In some embodiments, R is CH or F. Some of the compounds of formula (I) In some embodiments of the compound of formula (II), R is CH3. In some embodiments of the compound of Formula (III), R In some embodiments of the compound of Formula (IV), R is CH3. In some embodiments of the compound of formula (V), R is CH. In some embodiments of the compound of formula (VII), R is CH3. In some embodiments, R is CH3. Some of the compounds of formula (VIII) In some embodiments, R is CH. Some embodiments of the compound of formula (IX) In some embodiments of the compound of Formula (I), R is In some embodiments of the compound of formula (II), R is F. In some embodiments of the compound of formula (III), R is F. Compounds of formula (IV) In some embodiments of the compound of formula (V), R is F. In some embodiments, R is F. In some embodiments of the compound of Formula (VI), R is , F. In some embodiments of the compound of formula (VII), R is F. In some embodiments of the compound of formula (VIII), R is F. The compound of formula (IX) In some embodiments of the compound, R is F.

[0090] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds of II) or (IX), R is substituted or unsubstituted C 1-3 In one embodiment, R is alkyl. In one embodiment, R is methyl. wherein R is ethyl. In one embodiment, R is n-propyl. In one embodiment, R is isopropyl.

[0091] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI In some embodiments of compounds II) or (IX), R is halogen. In one embodiment, R is F. In one embodiment, R is Cl. In one embodiment, R is Br.

[0092] In some embodiments of compounds of Formula (I), (IV), or (VII), n is 0 In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 4. Formula (I) In some embodiments of the compound, n is 0. In other embodiments, n is 1 In another embodiment, n is 2. In another embodiment, n is 3. In other embodiments, n is 4. In some embodiments of the compound of formula (IV), In other embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 4. In some embodiments of the compound of formula (VII), n is 0. In other embodiments, In another embodiment, n is 1. In another embodiment, n is 2. n is 3. In other embodiments, n is 4.

[0093] In some embodiments of compounds of Formula (I), (IV), or (VII), R is C H3 or F, and n is 1. Any of the compounds of formula (I), (IV) or (VII) In some embodiments, R is CH3 and n is 1. In some embodiments of compounds of formula (VII), R is F and n is 1.

[0094] Further embodiments provided herein are any of the specific embodiments described above. It includes one or more combinations of these.

[0095] Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VI Representative compounds of II), or (IX) are listed in Table 1.

[0096] The isoindolinedione compounds described in Table 1 are DL- It was tested in a BCL assay and found to have activity therein. The isoindolinedione compound is a compound described herein, and The compound at this concentration significantly inhibits the proliferation of DLBCL cells (e.g., the proliferation of the SU-DHL-4 cell line). At the very least, it inhibits by about 50% or more.

[0097] Methods for making isoindolinedione compounds Isoindolidinedione compounds can be synthesized using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, isoindolinediones may be prepared using Compounds of formula (I) can be prepared by the methods described herein in addition to Schemes 1 and 2 shown below. The compounds can be prepared as outlined in the accompanying examples. Those skilled in the art will know how to modify the procedures used to arrive at the desired products. should be pointed out. [ka]

[0098] As shown in Scheme 1, compounds of formula (I) (wherein rings A, n, and R are as defined herein) are prepared. (as defined in the document) to a suitably derivatized and protected 4-hydroxymethyl Chilbenzaldehyde (wherein P O is a hydroxyl protecting group) with 3-aminophthalic acid acid (wherein R' is H) or dialkyl-3-aminophthalate (wherein R' is C 1-2 The solvents (MeOH, dioxane, DCM, 1,2-dichloro- A reductive aminating agent (BH3. 2-Methylpyridine, B 10 H 14 , or NaBH(OAc)3, etc.) to acetic acid or TFA), optionally at a temperature between about 0 and 25°C. In the first approach, R' can be prepared by starting with the H, the intermediate is 3-aminopiperidine-2,6-dione and a base (pyridine The cyclodehydration is carried out by treatment with a hydroxybenzoate at high temperature (for example, at about 120°C). Remove the hydroxyl protecting group (e.g., P O is a silyl ether, P O Dissolve Acid (e.g., H2SO4 or HCl) or reagent (e.g., THF or aqueous THF) in a solvent In the second approach, the The protecting group is removed (e.g., R' is C 1-2 When the alkyl group is carboxylate, e.g. For example, deprotection is performed by saponification with a base (e.g., NaOH) in a solvent (e.g., aqueous THF), and protection is performed. base P O (with simultaneous removal of silyl ethers, etc.), followed by cyclodehydration as described above. Subsequently, the leaving group LG is reacted with the resulting intermediate (where LG is OM, OT, or is a halogen such as Cl or Br) at a temperature between about 0 and 25°C. DCM, ether or toluene), for example CH3S when LG is Cl By reaction with O2Cl, SOCl2, or Ph3P-CCl4, or when LG is B By reaction with SOBr2, Ph3P-Br2, or PBr3 when r, or reaction with CH3SO2Cl or methanesulfonic anhydride when LG is OM or by reaction with TsCl when LG is OT. Solvent (DMSO, DMF, DMA, NMP, or CHCN) at temperatures between 100°C and 80°C base (DIEA, TEA, Na2CO3, K2CO3, or Cs2CO3, etc.) Displacement of leaving group LG by ring A (as defined herein) in the presence of , providing a target molecule of formula (I): [ka]

[0099] An alternative route to compounds of formula (I) is shown in Scheme 2. 4-Nitroisobenzofuran-1 ,3-dione is reacted with 3-aminopropanol at elevated temperature (e.g., 130°C) in the presence of an acid (e.g., acetic acid) to form a 3-aminopropanol. The reduction of the nitro group is carried out by treatment with piperidine-2,6-dione using a catalyst (e.g., Pd / C Reducing agents (e.g., hydrogen gas) in the presence of HCl, acetic acid, or or Fe or Zn in the presence of NH4Cl, or in a solvent (e.g., DMA, Et with SnCl2 in HCl, water, EtOAc, DMF or EtOAc / DMF mixtures This is achieved by treating the amine-containing intermediate with a solvent (MeO H or dioxane or mixtures thereof) in a reducing agent (e.g., B 10 H 14 ) in the presence of by reacting with an appropriately derivatized 4-hydroxymethylbenzaldehyde in As previously described, the leaving group LG is then added to the intermediate (L G is OM, OT, Cl or Br) at a temperature between about 0 and 25°C. dichloromethane, ether or toluene), for example, when LG is Cl by reaction with CH3SO2Cl, SOCl2, or Ph3P-CCl4, or When LG is Br, reaction with SOBr2, Ph3P-Br2, or PBr3 or CH3SO2Cl or methanesulfonic anhydride when LG is OM or by reaction with TsCl when LG is OT. As in Scheme 1, the solvent (DMSO, DMF, D Bases (DIEA, TEA, Na2CO3, K, etc.) in HCl, ... The substitution of the leaving group LG by the ring A of the heterocycle in the presence of , providing a target molecule of formula (I):

[0100] In some embodiments, chiral separation of the enantiomers of the compounds of formula (I) (standard and as described herein) to form a compound of formula (IV) and formula (V Compound II) [ka] [ka] to provide.

[0101] The term "protected" in reference to a hydroxyl group refers to a protecting group known to those skilled in the art (Pro tective Groups in Organic Synthesis,Gree ne,TW;Wuts,PGM,John Wiley & Sons,Ne w New York, NY, (5th Edition, 2014) ) refers to a form of these functional groups that are protected from undesired reactions by a protecting group. The protected hydroxyl groups can be added or removed using the procedures described in Examples include silyl ethers (hydroxyl groups are converted to t-butyldiphenylchlorosilane, t-Butyldimethylchlorosilane, trimethylchlorosilane, triisopropylchlorosilane Reacting with reagents such as, but not limited to, silane, triethylchlorosilane, etc. substituted methyl and ethyl ethers (e.g., those obtained by ethyl ether, methythiomethyl ether, benzyl Oxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether ether, tetrahydropyranyl ether, 1-ethoxyethyl ether, allyl ether, benzyl ethers, etc., but not limited to; esters (benzoyl formates, , formate, acetate, trichloroacetate, and trifluoroacetate (tr However, these include, but are not limited to, fluoracetate, etc. Not limited to.

[0102] In one embodiment, a compound of formula (I): [ka] 1. A method for preparing Compounds of formula (Ia) [ka] of, [ka] and, In the presence of a base, in a solvent, a compound of formula (I), Ring A is an optionally substituted non-aromatic heterocyclyl (with the point of attachment on the ring nitrogen atom). can be; Each R is independently substituted or unsubstituted C 1-3 Alkyl or halogen the law of nature; n is 0, 1, 2, 3 or 4; LG is OM, OT, or halogen) under conditions suitable to provide Provided herein are methods comprising contacting

[0103] In some embodiments, Ring A is selected from the group consisting of azetidyl; piperidyl; piperazinyl; 5-Azaspiro[2,3]hexyl; 2-Azaspiro[3.3]heptyl; 2 -Oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5 -Oxa-2-azaspiro[3.4]octyl; 6-Oxa-2-azaspiro[3.4] Octyl;2-Azaspiro[3.5]nonyl;7-Oxa-2-azaspiro[3.5]nonyl Octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexa Hydrocyclopenta[c]pyrrolyl;6-Azaspiro[3.4]octyl;2-Oxa- 6-Azaspiro[3.4]octyl; 6-Azaspiro[2.5]octyl; 7-Azaspiro[3.4]octyl 1-Oxa-8-azaspiro[4.5]decanyl; 2-Oxa-8 -Azaspiro[4.5]decanyl; 2,8-diazaspiro[4.5]decan-1-onyl ;3-Oxa-9-azaspiro[5.5]undecanyl;1,4-Oxazepanyl;8- azabicyclo[3.2.1]octyl; or isoindolinyl, In one embodiment, Ring A is azetidyl; Piperidyl; Piperazinyl; 2-Azaspiro[3.3]heptyl; 2-Azaspiro[3. 4]octyl;5-oxa-2-azaspiro[3.4]octyl;7-oxa-2-aza Spiro[3.5]nonyl; 1-oxa-8-azaspiro[4.5]decanyl; or 2, 8-diazaspiro[4.5]decane-1-onyl, In one embodiment, LG is Cl. In another embodiment, LG is aryl heterocyclyl. In one embodiment, the base is DIEA, TEA, NaCO 3, K2CO3, or Cs2CO3. In another embodiment, the solvent is DMSO , DMF, DMA, NMP, or CH3CN. The contacting is carried out at a temperature of about 25 to about 80°C.

[0104] In some embodiments, a further method comprises preparing a compound of formula (Ia): [ka] The method includes preparing Compound of formula (Ib) [ka] of, (a) When LG is Cl, CH3SO2Cl, SOCl2, or Ph3P-CC l4 and; (b) with SOBr2, Ph3P-Br2, or PBr3 when LG is Br; (c) with CH3SO2Cl or methanesulfonic anhydride when LG is OM; (d) TsCl and when LG is OT; in a solvent under conditions suitable to provide a compound of formula (Ia), contacting the

[0105] In one embodiment, the solvent is DCM, ether, or toluene. In embodiments, the contacting is carried out at a temperature of from about 0 to about 25°C.

[0106] In some embodiments, a further method comprises preparing a compound of formula (Ib): [ka] The method includes preparing Compound of formula (Ic) [ka] of, In a solvent, a compound of formula (Ib) O is a hydroxyl protecting group) Under conditions favorable to and deprotecting the compound.

[0107] In one embodiment, P O is a silyl ether, and deprotection is achieved by acid or TBAF. In some such embodiments, the acid is H2SO4 or HCl. In other embodiments, the solvent is THF or aqueous THF. In embodiments, the deprotection is carried out at a temperature of about 0 to about 60°C.

[0108] In some embodiments, a further method comprises preparing a compound of formula (Ic): [ka] The method includes preparing Compounds of formula (Id) [ka] of, 3-aminopiperidine-2,6-dione and a base, and a compound of formula (Ic) H), under conditions suitable to provide contacting the

[0109] In some embodiments, the base is pyridine. The contacting is carried out at a temperature of about 25 to about 130°C.

[0110] In some other embodiments, further methods include reacting a compound of Formula (Ib): [ka] The method includes preparing Compounds of formula (Ie) [ka] of, 3-aminopiperidine-2,6-dione and a base to provide a compound of formula (Ib) Under favorable conditions, contacting the

[0111] In some embodiments, the base is pyridine. The contacting is carried out at a temperature of about 25 to about 120°C.

[0112] In some such embodiments, a further method comprises reacting a compound of Formula (Ie): [ka] The method includes preparing Compounds of formula (Id) [ka] of, A compound of formula (Ie) wherein R' is C 1-2 Alkyl and P O It is preferred to provide Under suitable conditions, and deprotecting the compound.

[0113] In one embodiment, P O is a silyl ether and deprotection is achieved by base in a solvent. In one embodiment, the base is NaOH. In some embodiments, the contacting is carried out at a temperature of about 0 to about 60° C. It is carried out at a certain degree.

[0114] In some embodiments, a further method comprises preparing a compound of formula (Id): [ka] The method includes preparing Compounds of formula (If) [ka] of, Compound of formula (Ig) [ka] and, In the presence of a reductive amination agent and an acid, in a solvent, a compound of formula (Id), is H or C 1-2 under conditions suitable to provide a contacting the

[0115] In some embodiments, the reductive aminating agent is BH3. 2-methylpyridine, B 10 H 14 or NaBH(OAc). In some embodiments, the solvent is , MeOH, dioxane, DCM, 1,2-dichloroethane, CH3CN, THF, or and mixtures thereof. In other embodiments, the acid is acetic acid or TFA. In this embodiment, the contacting is carried out at a temperature of about 0 to about 25°C.

[0116] In some other embodiments, further methods include reacting a compound of Formula (Ib): [ka] The method includes preparing Compound of formula (Ih) [ka] of, Compound of formula (Ii) [ka] in the presence of a reducing agent, in a solvent, under suitable conditions to provide a compound of formula (Ib). Below, contacting the

[0117] In one embodiment, the reducing agent is B 10 H 14 In another embodiment, the solvent is , MeOH, dioxane, or a mixture thereof. is carried out at a temperature of about 0 to about 25°C.

[0118] In some embodiments, a further method comprises preparing a compound of formula (Ih): [ka] wherein the compound of formula (Ij) [ka] of, in the presence of a reducing agent, in a solvent, under conditions suitable to provide a compound of formula (Ih) , The method includes reducing

[0119] In some embodiments, the reducing agent is hydrogen gas in the presence of a catalyst. In some such embodiments, the catalyst is Pd / C, Ni, or Pt. In the form, the reducing agent is Fe or in the presence of HCl, acetic acid, or NH4Cl. In yet another embodiment, the reducing agent is SnCl. In embodiments, the solvent is DMA, EtOH, water, EtOAc, DMF, or EtOAc. c / DMF. In some embodiments, the contacting is carried out at a temperature of about 0 to about 60° C. will be done.

[0120] How to use The isoindolinedione compounds are useful for treating, preventing, or ameliorating disease states in animals or humans. Thus, it has utility as a pharmaceutical agent for the treatment of those diseases described below. Many uses of the isoindolinedione compounds are provided herein, including the prevention or treatment of The methods provided herein include administering an effective amount of one or more isoindolites. The method includes administering the dihydrodione compound(s) to a subject in need thereof.

[0121] In one aspect, an effective amount of an isoindolinedione compound described herein to a subject in need thereof. In one embodiment, an effective amount of the compounds described herein is provided. and administering to a subject in need thereof an isoindolinedione compound. Provided herein are methods for treating L. In one aspect, an effective amount of The isoindolinedione compounds described in the document are administered to a subject in need thereof. Provided herein are methods for preventing DLBCL, including administering isopropyl methyl methyl ester (MSM) to a subject in need thereof. The undrindione compounds are compounds from Table 1.

[0122] In another embodiment, an effective amount of an isoindolinedione compound is administered to a subject in need thereof. The compounds described herein are for use in the treatment or prevention of DLBCL, including administering In some embodiments, an effective amount of the compounds described herein is provided. and administering to a subject in need thereof an isoindolinedione compound. Provided herein are compounds for use in the treatment of BCL. In embodiments, an effective amount of an isoindolinedione compound described herein for use in preventing DLBCL, comprising administering to a subject in need thereof Compounds are provided herein. For example, isoindolinedione compounds are listed in Table 1. These compounds are:

[0123] In some embodiments, the DLBCL is activated B-cell-like DLBCL (ABC-D In others, DLBCL is classified as germinal center B cell-like DLBCL (GC). In still others, the DLBCL is unclassified DLBCL. In still other instances, the DLBCL is primary mediastinal B-cell DLBCL ( In another embodiment, the DLBCL is a cMyc / Bc Double-hit DLBCL (DHIT DLBCL), also known as l-2 mutant DLBCL, In some embodiments, the DLBCL is cMyc / Bcl2 / Bcl6 This is called triple-hit DLBCL (THIT DLBCL), which is a rearranged DLBCL. do.

[0124] In some embodiments, the DLBCL is newly diagnosed DLBCL. In some embodiments, the DLBCL is primary DLBCL. In some instances, the DLBCL is recurrent DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the DLBCL is relapsed or refractory. In one embodiment, the DLBCL is relapsing / refractory to rituximab. Clophosphamide, doxorubicin, vincristine, prednisone, etoposide, benzamidine one of the following: Treanda, lenalidomide, or gemcitabine; It is refractory to multiple diseases.

[0125] In some embodiments of the methods described herein, the method comprises administering rituximab to a subject. cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide , bendamustine (Treanda), lenalidomide, or gemcitabine or further comprising multiple administrations. Some embodiments of the methods described herein In the method, the method comprises administering to a subject a therapeutically effective amount of rituximab, cyclophosphamide, doxorubicin, vincristine, fluticasone, prednisone, etoposide, bendamustine (Treanda), or gemcitabine The methods described herein further include administering one or more of the following: In some embodiments, the treatment is RCHOP (rituximab plus cyclophosphamide). doxorubicin, vincristine and prednisone), R-EPOCH (etoposide , rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone ), stem cell transplant, bendamustine (Treanda) + rituximab, rituximab, Lenalidomide + rituximab, or one of the gemcitabine-based combinations The practice of some of the methods described herein further includes treatment with multiple In some embodiments, the treatment is RCHOP (rituximab plus cyclophosphamide, doxorubicin, cin, vincristine and prednisone), R-EPOCH (etoposide, rituximab + cyclophosphamide, doxorubicin, vincristine and prednisone), stem cell transplantation Bendamustine (Treanda) plus rituximab, rituximab, or gemcitabine Further included are treatments with one or more of the following bottle-based combinations:

[0126] Pharmaceutical Compositions and Routes of Administration The isoindolinedione compounds may be administered in conventional forms of preparation (capsules, microcapsules, Tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams , lotions, ointments, gels, sprays, solutions, and emulsions) to a subject orally or topically Suitable formulations may be administered orally or parenterally. Punishment, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose Hydroxymethylcellulose, Polypropylpyrrolidone, Polyvinylpyrrolidone, Ze cellulose, gum arabic, polyethylene glycol, sucrose, or starch), disintegrating agents (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, hypocalcium Hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or quercetin calcium phosphate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc , or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium sulfite, methyl paraben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate) , or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone (pyr roliclone), or aluminum stearate), dispersing agents (e.g., hydroxypropyl propyl methylcellulose), a diluent (e.g., water), and a base wax (e.g., cocoa butter). conventional organic additives such as tar, white petrolatum, or polyethylene glycol) or inorganic It can be prepared by a commonly used method using additives. An effective amount of a dringione compound is a level that achieves the desired efficacy; e.g., oral administration and For both oral and parenteral administration, the unit dosage is about 0.005 mg / kg to about 10 mg / kg of subject body weight. The dose may be g / kg subject body weight.

[0127] The dose of the isoindolinedione compound administered to a subject can vary widely. Generally, the isoindolinedione compounds are administered at a dose of about 0.001 It can be administered at a dose of 1 mg / kg to about 10 mg / kg of subject body weight, 1 to 4 times a day. The above dosage may vary depending on the age, weight and medical condition of the subject and the type of administration. In one embodiment, the dosage is from about 0.001 mg / kg to about 5 mg / kg of subject body weight. mg / kg subject body weight, approximately 0.01 mg / kg subject body weight to approximately 5 mg / kg subject body weight, approximately 0. 0.5mg / kg subject weight to approximately 1mg / kg subject weight, approximately 0.1mg / kg subject weight to approximately 0 0.75mg / kg subject body weight, or approximately 0.25mg / kg subject body weight to approximately 0.5mg / kg In one embodiment, one dose is given per day. In some instances, the amount of isoindolinedione compound administered will depend on the solubility of the active ingredient, the amount of isoindolinedione compound used, and the amount of isoindolinedione compound administered. It will depend on factors such as the formulation used and the route of administration.

[0128] In another embodiment, about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to Approx. 375mg / day, approx. 0.1mg / day ~ approx. 150mg / day, approx. 0.1mg / day ~ approx. 75m g / day, approximately 0.1 mg / day to approximately 50 mg / day, approximately 0.1 mg / day to approximately 25 mg / day, or The isoindolinedione compound is administered at a dose of about 0.1 mg / day to about 10 mg / day for patients who require it. The present invention provides a method for treating or preventing a disease or disorder, comprising administering to a subject a compound comprising the steps of: provided in the document.

[0129] In another embodiment, about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg ~ about 100 mg, between about 1 mg and about 50 mg, between about 1 mg and about 25 mg, or about 1 mg or more A unit dosage formulation containing between about 10 mg of an isoindolinedione compound is described herein. It is provided.

[0130] In certain embodiments, about 0.1 mg or 100 mg of an isoindolinedione compound Provided herein are unit dosage formulations containing the

[0131] In another embodiment, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg , 30mg, 35mg, 50mg, 70mg, 100mg, 125mg, 140mg, 1 75mg, 200mg, 250mg, 280mg, 350mg, 500mg, 560mg , 700mg, 750mg, 1000mg or 1400mg of isoindolinedionide A unit dosage formulation comprising the compound is provided herein.

[0132] The isoindolinedione compounds may be administered once, twice, three times, four or more times daily. In this embodiment, the dose of 100 mg or less is administered as a single dose per day, and the 100 mg or less dose is administered as a single dose per day. Doses greater than 1 g are given twice daily in an amount equal to half the total daily dose.

[0133] The isoindolinedione compounds may be administered orally for convenience. Therefore, when administered orally, the isoindolinedione compounds are administered with food and water. In another embodiment, the isoindolinedione compound is added to water or juice (e.g., Dispersed in a liquid such as corn or orange juice as a solution or suspension It is administered orally.

[0134] Isoindolinedione compounds are administered intradermally, intramuscularly, intraperitoneally, and transdermally (percutaneously). ously), intravenous, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal ermally), rectally, on mucous membranes, by inhalation, or into the ears, nose, eyes, or skin It may also be administered locally. The mode of administration is left to the discretion of the healthcare professional and may be administered locally at the site of the condition. may depend on

[0135] In one embodiment, the isoindolinedione isoindoline without additional carriers, excipients, or vehicles. Provided herein are capsules containing the compounds.

[0136] In another embodiment, an effective amount of an isoindolinedione compound and a pharmaceutically acceptable salt thereof is Compositions comprising a carrier or vehicle are provided herein, and pharmaceutically acceptable carriers are also The body or vehicle may comprise an excipient, a diluent, or a mixture thereof. The composition is a pharmaceutical composition.

[0137] The compositions include tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories and suspensions, and the like. The composition may be in the form of a single tablet or capsule or, preferably, The dosage unit, which may be a liquid of convenient volume, provides the daily dose, or a convenient portion of the daily dose. In one embodiment, the solution may be formulated to contain a water-soluble salt (such as the hydrochloride salt). Generally, all of the compositions are prepared according to methods known in pharmaceutical chemistry. The capsules are prepared by mixing the isoindolinedione compound with a suitable carrier or diluent and The mixture can be prepared by filling a capsule with the amount of the mixture. These include different types of starch, powdered cellulose (especially crystalline and microcrystalline cellulose), , sugars (such as fructose, mannitol, and sucrose), cereal flour, and similar edible Examples of suitable inert powder materials include, but are not limited to, inert powder-like materials such as powders.

[0138] Tablets can be prepared by direct compression, wet granulation, or dry granulation. In addition to the compound, they usually incorporate diluents, binders, lubricants and disintegrants. Examples of agents include various types of starch, lactose, mannitol, kaolin, Examples include calcium phosphate or sulfate, inorganic salts (such as sodium chloride and powdered sugar). Cellulose derivatives are also useful. Typical tablet binders are starch, gelatin, and sugars (such as cellulose). Natural rubber and and synthetic gums are also advantageous, such as acacia, alginate, methylcellulose, polyvinylpyrrolidone, and the like. Roridin, and the like. Polyethylene glycol, ethylcellulose, and The binder may also be wax.

[0139] Lubricants are necessary in tablet formulations to prevent dyes from sticking to the tablets and punches. Lubricants include talc, magnesium stearate and calcium stearate, The tablet may be selected from slippery solids such as stearic acid, and hydrogenated vegetable oils. Disintegrants are substances that expand when wet, breaking up the tablet and releasing the compound. These include starch, clay, cellulose, algin, and gums. Examples of suitable starch include corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered sponge, cation exchange resin, alginic acid, guar gum -gum, citrus juice pomace, and carboxymethylcellulose, plus sodium lauryl sulfate Tablets may be prepared with sugar as a flavoring and sealant or with fillers. The tablets may be coated with a film-forming protecting agent to modify the dissolution properties of the tablets. The composition may also be formulated as a chewable tablet, for example, by the use of substances such as mannitol in the formulation. It is possible.

[0140] When it is desired to administer the isoindolinedione compounds as a suppository, a typical Cocoa butter is a traditional suppository base; it can be made from the addition of waxes. In particular, polyethylene of various molecular weights can be modified to slightly increase its melting point. Water-miscible suppository bases, including ethylene glycol, are widely used.

[0141] The effects of isoindolinedione compounds can be delayed or prolonged by appropriate formulation For example, slowly dissolvable pellets of the isoindolinedione compounds can be prepared and packaged as tablets. Alternatively, it may be incorporated into a capsule or as a sustained-release implantable device. produced pellets with different dissolution rates and filled capsules with a mixture of the pellets. The tablet or capsule must be able to withstand dissolution for a predictable period of time. Even parenteral preparations can be coated with a film that disperses slowly in serum. The isoindolinedione compound in an oily or emulsified vehicle allows Dissolution or suspension can make it long acting. [Example]

[0142] The following examples are offered by way of illustration and not by way of limitation. Compounds are compounds that are based on a system of chemical structures. Generating the synonyms in ChemBiodraw Ultra (Cambridgesoft) Cahn-Ingold for stereochemistry using the automatic name generation tool provided in - named with the aid of the Prelog rule. Those skilled in the art will appreciate the The procedure can be modified to arrive at the desired product.

[0143] Abbreviations used: [Table 2]

[0144] Compound synthesis Example 1: 4-((4-((4-(tert-butyl)piperazin-1-yl)methyl) -3-methylbenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione [ka] 2-(2,6-dioxo-3-piperidyl)-4-nitro-isoindoline-1,3- Dione: 4-nitroisobenzofuran-1,3-dione (70.4 g, 365 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (50.0 g, 30 The mixture of 4 mmol) was stirred at 130°C for 16 hours under a nitrogen atmosphere. The remaining solid was washed with ethyl acetate (500 mL) and dried in vacuo to give 2-(2,6-Dioxo-3-piperidyl)-4-nitro-isoindoline-1,3-di The compound was obtained as a grey solid (130 g, 70.6% yield). 1 H NMR (400 MHz DMSO-d6) δ ppm 11.15 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.09 (t, J = 7.6 Hz, 1H), 5.20-5.15 (m, 1H), 2.89 -2.81 (m, 1H), 2.60-2.47 (m, 2H), 2.04 (t, J = 5.6 Hz, 1H).

[0145] 4-Amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-di On: 2-(2,6-dioxo-3-piperidyl)-4-nitro in DMA (1.5 L) -To a solution of isoindoline-1,3-dione (43.0 g, 142 mmol), Pd / C (15.0 g, 14.1 mmol, 10% Pd) was added under a blanket of N2 The mixture was degassed under vacuum and purged with H2 (3x). The purged mixture was The reaction mixture was stirred at 40°C under an atmosphere of (40 psi) for 16 hours. The reaction mixture was purged with N2. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The remaining solid was washed with ethyl acetate (200 mL). and dried under vacuum to give 4-amino-2-(2,6-dioxo-3-piperidyl)iso Indoline-1,3-dione was obtained as a yellow solid (75 g, 64.5% yield). 1 H NMR (400 MHz DMSO-d6) δ ppm 11.07 (s, 1H), 7.46 (d, J = 6.4 Hz, 1H), 7.00 (t, J = 7.0 Hz, 2H), 6.51 (br s, 2H), 5.06-5.01 (m, 1H), 2. 93-2.89 (m, 1H), 2.60-2.49 (m, 2H), 2.03-2. 00 (m, 1H).

[0146] (4-Bromo-2-methyl-phenyl)methoxy-tert-butyl-diphenyl- Run: (4-bromo-2-methyl-phenyl)methanol in CH2Cl2 (800 mL) To a solution of ethanol (80.0 g, 398 mmol), imidazole (32.5 g, 477 mmol) was added l), DMAP (2.43 g, 20.0 mmol) and tert-butyl-diphenyl- Silyl chloride (164 g, 597 mmol) was added and the mixture was stirred at ambient temperature for 16 h. The mixture was stirred and diluted with saturated ammonium chloride (1.00 L). The combined organic fractions were extracted with water (600 mL) and saturated NaCl. (500 mL). The solution was dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether). (4-bromo-2-methyl-phenyl)methoxy-tert-butyl-diphenyl The -silane (147 g, 84.1% yield) was obtained as a pale yellow oil. 1 H NMR (400 MHz CDCl3) δ ppm 7.59 (t, J = 6.4 Hz, 4H), 7. 36-7.28 (m, 9H), 4.58 (s, 2H), 2.06 (s, 3H), 1.01(s, 9H).

[0147] 4-(hydroxymethyl)-3-methyl-benzaldehyde: in THF (2.0 L) (4-Bromo-2-methyl-phenyl)methoxy-tert-butyl-diphenyl-sila A solution of 147 g (334 mmol) of ethanol was cooled to -78 °C and kept at a temperature below -65 °C. While stirring, n-BuLi (201 mL, 502 mmol, 2.5 M in hexane) was added dropwise. After the addition, the reaction mixture was stirred at -65°C for 30 minutes, keeping the temperature below -60°C. DMF (73.4 g, 1.00 mol) was added dropwise. The reaction mixture was kept at this temperature for 2 hours. The mixture was stirred for 1 hour and quenched with saturated NH4Cl (800 mL) at below -40°C. 0 mL) and ethyl acetate (800 mL) were added and the mixture was stirred for 10 minutes and allowed to cool to ambient temperature. The organic layer was removed and washed with saturated NaCl (800 mL) and NaSO The solution was dried over 4. The solution was filtered and concentrated to give crude 4-[[tert-butyl(diphenyl)methyl] [Nyl)silyl]oxymethyl]-3-methyl-benzaldehyde (130 g) was added to a pale yellow Obtained as an oil which was used in the next step without further purification.

[0148] Crude 4-[[tert-butyl(diphenyl)silyl]oxy] To a solution of methyl]-3-methyl-benzaldehyde (130 g, 334 mmol), TB AF-3H2O (52.3 g, 167 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 The reaction mixture was diluted with water (800 mL) and added with ethyl acetate (500 mL× The organic layers were combined, washed with saturated NaCl (800 mL), and The solution was filtered and concentrated, and the residue was purified by silica gel column chromatography. Purification by chromatography (10-20% petroleum ether / ethyl acetate) gave 4- (Hydroxymethyl)-3-methyl-benzaldehyde (41.0 g, 81.6% yield) ) was obtained as a pale yellow oil. 1 H NMR (400 MHz CDCl3) δ ppm 9 .97 (s, 1H), 7.73-7.60 (m, 3H), 4.78 (s, 2H) , 2.38 (s, 3H).

[0149] 4-((4-(chloromethyl)-3-methylbenzyl)amino)-2-(2,6-diamino) (3-oxopiperidin-3-yl)isoindoline-1,3-dione: 20% MeOH / dione 4-Amino-2-(2,6-dioxo-3-piperidyl)isopropyl ether in hexane (725 mL) A solution of indoline-1,3-dione (30.0 g, 110 mmol) was cooled to 0° C. 4-(hydroxymethyl)-3-methyl-benzaldehyde (33.0 g, 220 mmol) l) and B 10 H 14 (26.8 g, 220 mmol) was added in portions. The mixture was heated at ambient temperature. The reaction mixture was concentrated and the residue was dissolved in EtOH (500 mL The mixture was stirred for 1 hour and the resulting slurry was filtered. The solid cake was washed with ethyl acetate (200 mL) and dried in vacuo to give crude 2. -(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)-3 (39.0 g) of (1,3-methylbenzyl)amino)isoindoline-1,3-dione was added to the reaction vessel to obtain a yellow solid. The compound was used in the next step without further purification.

[0150] 2-(2,6-dioxopiperidin-3-yl)-4-(( 4-(hydroxymethyl)-3-methylbenzyl)amino)isoindoline-1,3-di of DIEA (25.3 g, 196 mmol) and DIEA (38.0 g, 93.3 mmol). The solution was cooled to 0°C and methanesulfonyl chloride (21.4g, 187mmol) was added in 3 The ice bath was removed and the reaction was stirred at ambient temperature for 16 hours. The mixture was added dropwise to stirred saturated NaHCO3 (800 mL) diluted with water (800 mL). The resulting slurry was filtered and the product cake was dissolved in CH2Cl2 (500 mL). The solution was washed with saturated NaCl (200 mL) and dried over Na2SO4. The residue was purified by silica gel column chromatography (20-50% The purified solid was dissolved in acetonitrile (500 mL) and dried in vacuo to give 4-((4-(chloromethyl)-3-methyl (2,6-Dioxopiperidin-3-yl)isoindole The resulting product was 1,3-dimethyl-1,4-dione (24.0 g, 60.5% yield) as a yellow solid. 1 H NMR (400 MHz DMSO-d6) δ ppm 11.08 (s, 1H), 7 .47 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.21-7.16 (m, 3H), 7.00 (d, J = 6.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.07-5.03 (m, 1H), 4.73 (s, 2H), 4.50 (d, J = 6.4 Hz, 2H), 2.87-2.61 (m, 1H), 2.60-2.47 (m, 2H), 2.33 (s, 3H), 2.05-2.04 (m, 1H). LCMS (ESI) m / z 4 26.2 [M+H] + .

[0151] 4-((4-((4-(tert-butyl)piperazin-1-yl)methyl)-3-methyl (2,6-Dioxopiperidin-3-yl)isoindole Benzene-1,3-dione: 4-((4-(chloromethyl)-3-methylbenzyl)amino)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0. 0.075g, 0.176mmol), 1-(tert-butyl)piperazine (0.025g , 0.176 mmol) and DIEA (0.092 mL, 0.528 mmol) were added to DMSO. The reaction mixture was dissolved in 1.0 mL of HCl and the resulting solution was stirred at ambient temperature for 48 hours. The mixture was purified by standard methods to give 4-((4-((4-(tert-butyl)piperazine Benzyl-1-ylmethyl-3-methylbenzylamino-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione (56.9 mg, 60.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.1 0 (s, 1 H), 8.20 (s, 1 H), 7.52 (dd, J=8.44, 7.21 Hz, 1 H), 7.08 - 7.20 (m, 4 H), 7.00 (dd , J=17.85, 7.83 Hz, 2 H), 5.07 (dd, J=12.84, 5.26 Hz, 1 H), 4.49 (d, J=6.11 Hz, 2 H), 3.3 5 (s, 3 H), 2.84 - 2.98 (m, 1 H), 2.54 - 2.63 (m, 2 H), 2.40 - 2.48 (m, 3 H), 2.32 - 2.39 (m , 3 H), 2.28 (s, 3 H), 1.96 - 2.14 (m, 1 H), 0 .98 (s, 9 H). LCMS (ESI) m / z 532.4 [M+H] + .

[0152] Example 2: 2-(2,6-dioxopiperidin-3-yl)-4-((3-((4-ethyl) (piperidine-1-yl)methyl)-4-methylbenzyl)amino)isoindoline-1 ,3-dione hydrochloride [ka] 4-((4-(chloromethyl)-3-methylbenzene) in anhydrous DMSO (0.30 mL) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (0.080 g, 0.188 mmol) (prepared as described herein) To a solution of 4-ethylpiperidine (0.040 g, 0.188 mmol), IEA (0.115 mL, 0.657 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 The reaction mixture was diluted with DMSO (1.5 mL) and filtered through a membrane syringe filter ( The solution was filtered through 0.45 μm nylon and purified by standard methods to give 2- (2,6-dioxopiperidin-3-yl)-4-((3-((4-ethylpiperidine- 1-yl)methyl)-4-methylbenzyl)amino)isoindoline-1,3-dione salt The acid salt (56.4 mg, 55.7% yield) was obtained. LCMS (ESI) m / z 503 .6 [M+H] + .

[0153] Example 3: 5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-4-yl)amino)methyl)-2-methylbenzyl)pi Perazin-1-yl)picolinamide hydrochloride [ka] 4-((4-(chloromethyl)-3-methylbenzyl) )amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (0.080 g, 0.188 mmol) (prepared as described herein ) and 5-(piperazin-1-yl)picolinamide (0.039 g, 0.188 m mol) solution, DIEA (0.115 mL, 0.657 mmol) was added to the reaction mixture. The mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (1.5 mL) and the membrane Filter the solution through a syringe filter (0.45 μm nylon) according to standard methods. The compound was purified to give 5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl )-1,3-Dioxoisoindolin-4-yl)amino)methyl)-2-methylbenzyl (1-yl)piperazin-1-yl)picolinamide hydrochloride (35.0 mg, 29.5% yield) LCMS (ESI) m / z 596.6 [M+H] + .

[0154] Example 4: 4-((4-((6-azaspiro[2.5]octan-6-yl)methyl)- 3-Methylbenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isocyanate Endrine-1,3-dione hydrochloride [ka] 4-((4-(chloromethyl)-3-methylbenzene) in anhydrous DMF (0.600 mL) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (0.080 g, 0.188 mmol) and 6-azaspiro[2.5]octane (0.021 g, 0.188 mmol) in a solution of DIEA (0.115 mL, 0.65 7 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. 1.0 mL) and filtered through a membrane syringe filter (0.45 μm nylon). The solution was filtered and purified using standard methods to give 4-((4-((6-azaspiro[2 .5]octan-6-yl)methyl)-3-methylbenzyl)amino)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (76.1mg , 75.3% yield). LCMS (ESI) m / z 501.6 [M+H]+.

[0155] Example 5: 2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-isopropyl) Propoxypiperidin-1-yl)methyl)-3-methylbenzyl)amino)isoindo Phosphorus-1,3-dione [ka] 4-((4-(chloromethyl)-3-methylbenzene) in anhydrous DMF (0.600 mL) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (0.080 g, 0.188 mmol) and 4-isopropoxypiperidine (0 To a solution of 0.027 g, 0.188 mmol) of DIEA (0.115 mL, 0.657 m mol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (1. Dilute with 0.0 mL of HCl (0.01 mL) and filter through a membrane syringe filter (0.45 μm nylon) The solution was purified using standard methods to give 2-(2,6-dioxopiperidine-3- yl)-4-((4-((4-isopropoxypiperidin-1-yl)methyl)-3-methyl (Cibenzyl)amino)isoindoline-1,3-dione (18.9 mg, 18.8%) LCMS (ESI) m / z 533.6 [M+H]+.

[0156] Example 6: 4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-4-yl)amino)methyl)-2-methylbenzyl)pi Perazin-1-yl)-3-methylbenzonitrile hydrochloride [ka] 3-Methyl-4-piperazin-1-yl-benzonitrile salt in DMF (4.0 mL) To a mixture of 1,2-dimethyl-3-oxo-2-propanol (0.100 g, 0.420 mmol), diisopropylethylamine ( 0.370 mL, 2.10 mmol), followed by 4-((4-(chloromethyl)-3-methyl (2,6-dioxopiperidin-3-yl)isoindoline The reaction mixture was stirred for 50 minutes. The mixture was stirred at 0°C for 2 hours, cooled to ambient temperature, and diluted with MeOH (1 mL). The filtrate was purified using standard methods to give 4-(4-(4-(((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )Methyl)-2-methylbenzyl)piperazin-1-yl)-3-methylbenzonitrile The hydrochloride salt (53.0 mg, 18.9% yield) was obtained. LCMS (ESI) m / z 59 1.3 [M+1] + .

[0157] Example 7: 5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine-1 -yl)picolinamide [ka] 2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl) benzyl)amino)isoindoline-1,3-dione: 20% MeOH-dioxane ( 4-Amino-2-(2,6-dioxo-3-piperidyl)isoindole in 600 mL To a solution of 4-(hydroxymethyl)-1,3-dione (25.0 g, 91.5 mmol) (I)benzaldehyde (25.0 g, 184 mmol) and B 10 H 14 (22.5g, The mixture was stirred at ambient temperature for 2 hours under venting (pressure). The residue was diluted with ethanol (500 mL) and the mixture was stirred for 1 h. The resulting suspension was filtered and the collected solid cake was dissolved in ethyl acetate (200 mL ) and dried in vacuo to give crude 2-(2,6-dioxopiperidine-3 -yl)-4-((4-(hydroxymethyl)benzyl)amino)isoindoline-1, The 3-dione (28.0 g) was obtained as a yellow-green solid, which was carried on to the next step without further purification. Used in step 1. LCMS (ESI) m / z 376.2 [MH-18] + .

[0158] 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidinyl) 2-((2-phenyl-3-yl)isoindoline-1,3-dione) in NMP (285 mL) 2,6-Dioxo-3-piperidyl)-4-[[4-(hydroxymethyl)phenyl]methyl ethylamino]isoindoline-1,3-dione (28.0 g, 71.2 mmol) and D A solution of IEA (26.1 mL, 150 mmol) was purged with nitrogen and brought to 0°C. Methanesulfonyl chloride (16.3 g, 142 mmol) was added over 5 min. The mixture was stirred at ambient temperature for 16 hours and then added with H2O (800 mL) was added dropwise to stirred saturated NaHCO3 (800 mL). The resulting suspension was filtered and the collected solid cake was dissolved in HO (500 mL) and acetonitrile. (500 mL). The solid was dried in vacuo to give 4-((4-(chloro) Methyl)benzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoin Doline-1,3-dione was obtained as a yellow solid (22.7 g, 77.5% yield). 1 H NMR (400 MHz DMSO-d6) δ ppm 11.12 (s, 1H), 7.51-7.28 (m, 6H), 7.03 (d, J = 6.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.11-5.06 (m, 1H), 4.74 (s, 2H), 4.58 (d, J = 6.0 Hz, 2H), 2.94- 2.86 (m, 1H), 2.63-2.51 (m, 2H), 2.08-2.05 (m, 1H). LCMS (ESI) m / z 412.1 [M+H] + .

[0159] 5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl) Picolinamide: 4-((4-(chloromethyl)benzyl)-2-methyl-2-pyridinyl)-1,2-diol in anhydrous DMSO (3.0 mL) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 To a solution of 5-(piperazin-1-yl)-dione (300 mg, 0.619 mmol) Picolinamide (153 mg, 0.743 mmol) and DIEA (108 μL, 0.6 The reaction mixture was stirred at ambient temperature for 16 hours and DMSO (3 The mixture was filtered through a membrane syringe filter (0.45 μm (4-(4 -(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindo phosphon-4-yl)amino)methyl)benzyl)piperazin-1-yl)picolinamide ( 255 mg (70.8%) was obtained. LCMS (ESI) m / z 582.2 [M+H] + .

[0160] Example 8: 4-(1-(4-(((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)azetidine-3 -yl)benzonitrile hydrochloride [ka] 4-((4-(chloromethyl)benzyl)amino)- in anhydrous DMF (0.30 mL) 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0. 0.062g, 0.150mmol) and 4-(azetidin-3-yl)benzonitrile hydrochloride To a solution of the salt (0.031 g, 0.180 mmol), DIEA (0.079 mL, 0.4 50 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. (1.5 mL) and filtered through a membrane syringe filter (0 The solution was filtered through a 0.45 μm nylon sieve and purified using standard methods to give 4- (1-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo Isoindolin-4-yl)amino)methyl)benzyl)azetidin-3-yl)benzo The nitrile hydrochloride salt (31.0 mg, 36.3% yield) was obtained. LCMS (ESI) m / z 534.2 [M+H] + .

[0161] Example 9: 2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-(5 -fluoropyridin-2-yl)piperazin-1-yl)methyl)benzyl)amino)i Soindoline-1,3-dione [ka] 4-((4-(chloromethyl)benzyl)amino)-2- in DMF (3.00 mL) (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.20 g, 0.487 mmol), DIEA (0.296 mL, 1.70 mmol) and 1-( 5-fluoro-2-pyridyl)piperazine (153.7 mg, 0.848 mmol) The mixture was stirred at 50 °C under N atmosphere for 24 h. The reaction mixture was diluted with H2O (30 mL). The mixture was diluted with more water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated sodium chloride. Wash with sodium hydroxide (3 x 20 mL), dry over Na2SO4, filter, and evaporate under reduced pressure. The residue was purified by standard methods to give 2-(2,6-dioxopiperidinyl) (4-((4-(5-fluoropyridin-2-yl)piperazine (1-yl)methyl)benzyl)amino)isoindoline-1,3-dione hydrochloride was obtained. (238 mg, 97.6% yield). LCMS (ESI) m / z 557.3 [M+ H] + .

[0162] Example 10: 6-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine- 1-yl)nicotinamide [ka] 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidinyl) (3-phenyl-1,3-dione)isoindoline-1,3-dione (0.216 g, 0.524 mmol) , 6-(piperazin-1-yl)nicotinamide (0.108 g, 0.524 mmol) and DIEA (0.275 mL, 1.57 mmol) were dissolved in DMF (2.9 mL). The mixture was stirred at ambient temperature for 16 hours. The mixture was purified by standard methods to give 6. -(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-diox Soyisoindolin-4-yl)amino)methyl)benzyl)piperazin-1-yl)nico The tinamide was obtained (125 mg, 41.0% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s, 1 H), 8.59 (d, J=2. 20 Hz, 1 H), 7.94 (dd, J=9.05, 2.45 Hz, 1 H), 7.74 (br d, J=1.96 Hz, 1 H), 7.44 - 7.56 (m, 1 H), 7.32 (q, J=8.23 Hz, 4 H), 7.20 (br t, J =6.24 Hz, 1 H), 7.05 - 7.15 (m, 1 H), 7.00 (d d, J=15.65, 7.83 Hz, 2 H), 6.80 (d, J=9.05 H z, 1 H), 5.07 (dd, J=12.84, 5.26 Hz, 1 H), 4. 55 (br d, J=6.36 Hz, 2 H), 3.56 (br d, J=4.65 Hz, 4 H), 3.48 (s, 2 H), 2.81 - 2.99 (m, 1 H) , 2.54 - 2.64 (m, 2 H), 2.42 (br t, J=4.77 Hz , 4 H), 1.96 - 2.10 (m, 1 H). LCMS (ESI) m / z 5 82.2 [M+H] + .

[0163] Example 11: 5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine- 1-yl)-N,N-dimethylpicolinamide [ka] 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidinyl) (3-phenyl-3-yl)isoindoline-1,3-dione (0.450 g, 1.09 mmol), N,N-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride (0.444g , 1.64 mmol) and DIEA (0.954 mL, 5.46 mmol) in DMF ( 6.0 mL) and the mixture was stirred at ambient temperature for 72 hours. and purified by 5-(4-(4-(((2-(2,6-dioxopiperidine-3-yl)methylpropional (I)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)pipera (Zin-1-yl)-N,N-dimethylpicolinamide (177 mg, 26.6% yield) obtained. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (s , 1 H), 8.22 (br d, J=1.96 Hz, 1 H), 7.42 - 7. 59 (m, 2 H), 7.27 - 7.39 (m, 5 H), 7.21 (br t, J=5.62 Hz, 1H), 7.00 (br dd, J=15.53, 7.70 Hz, 2 H), 5.07 (br dd, J=12.59, 5.01 Hz, 1 H) , 4.55 (br d, J=5.87 Hz, 2 H), 3.50 (s, 2 H), 3.27 (br s, 4 H), 2.80 - 3.10 (m, 7 H), 2.54 - 2.64 (m, 2 H), 2.39 - 2.48 (m, 4 H), 2.05 (br dd, J=10.51, 4.89 Hz, 1 H). LCMS (ESI) m / z 6 10.4 [M+H] + .

[0164] Example 12: 4-((4-((4-(1H-pyrazol-1-yl)piperidin-1-yl) (methyl)benzyl)amino)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione hydrochloride [ka] 4-((4-(chloromethyl)benzyl)amino)- in anhydrous DMF (1.50 mL) 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0. 200 g, 0.486 mmol) and 4-(1H-pyrazol-1-yl)piperidine ( To a solution of DIEA (0.297 mL, 1.70 m mol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (2. Dilute with 0.0 mL of HCl (0.01 mL) and filter through a membrane syringe filter (0.45 μm nylon) The solution was purified using standard methods to give 4-((4-((4-(1H-pyrazole -1-yl)piperidin-1-yl)methyl)benzyl)amino)-2-(2,6-diamino)- 2-(2-oxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (69.9 mg, 5.6%). LCMS (ESI) m / z 527.6 [M+H] + .

[0165] Example 13: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine- 1-yl)benzamide [ka] 4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidinyl) (3-phenyl-3-yl)isoindoline-1,3-dione (0.075 g, 0.182 mmol) , 4-(piperazin-1-yl)benzamide hydrochloride (0.044 g, 0.182 mmol) l) and DIEA (0.127 mL, 0.728 mmol) in DMF (1.0 mL) The resulting solution was stirred at ambient temperature for 16 hours. The reaction was stirred at 50° C. for an additional 5 hours. The mixture was stirred for 1 hour and cooled to ambient temperature. The mixture was purified by standard methods to give 4-(4- (4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl Benzyl-4-yl)amino)methyl)piperazin-1-yl)benzamide (71.4 mg, 67.5% yield). 1 H NMR (400 MHz, DMSO -d6) δ ppm 11.11 (s, 1 H), 7.65 - 7.79 (m, 3 H ), 7.52 (t, J=7.83 Hz, 1 H), 7.27 - 7.40 (m, 4 H), 7.21 (br t, J=6.36 Hz, 1 H), 7.01 (dd, J=15.65, 7.82 Hz, 3 H), 6.91 (d, J=8.80 Hz, 2 H), 5.08 (dd, J=12.96, 5.38 Hz, 1 H), 4.56 (br d, J=6.36 Hz, 2 H), 3.49 (s, 2 H), 3.23 ( br s, 4 H), 2.84 - 2.96 (m, 1 H), 2.55 (s, 2 H ), 2.48 (br s, 4 H), 2.06 (br dd, J=10.64, 5. 50 Hz, 1 H). LCMS (ESI) m / z 581.4 [M+H] + .

[0166] Example 14: (S)-6-(4-(4-(((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)piperidine (rhazin-1-yl)nicotinamide [ka] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxy Methyl)benzyl)amino)isoindoline-1,3-dione:anhydrous 2:1 dioxane -(S)-4-amino-2-(2,6-dioxopiperidine-) in MeOH (25 mL) 3-yl)isoindoline-1,3-dione (1.37 g, 5.00 mmol) (U.S. Patent No. (prepared as described in US Patent Publication No. US 2007 / 0004920) and 4-(hydrogen A suspension of (hydroxymethyl)benzaldehyde (0.817 g, 6.00 mmol) was heated to 0°C. Cool and add decaborane (1.34 g, 9.90 mmol) in small portions over 2 minutes. The reaction flask was fitted with a septum and needle vent and the mixture was stirred vigorously for 10 minutes. The resulting solution was allowed to reach ambient temperature and stirred for 3 hours. The mixture was concentrated to give The resulting yellow foam was then loaded onto a silica gel column (Biotage KP-Sil 50g, 0-10%). The product was purified by suspending in MTBE (75 mL). The suspension was collected, washed with MTBE, and dried in vacuo. After drying, (S)-2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxybenzoyl) (hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (1.82g, 9 3% yield) was obtained as a yellow solid. LCMS (ESI) m / z 394.0 [M+ H] + .

[0167] (S)-4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione: in anhydrous NMP (12 mL) (S)-2-(2,6-dioxopiperidin-3-yl)-4-((4-hydroxymethyl) (ethyl)benzyl)amino)isoindoline-1,3-dione (1.50g, 3.81mm A solution of methanesulfonyl chloride (0.594 mL, 7.63 m mol) and DIEA (1.33 mL, 7.63 mmol) were added successively. The mixture was stirred for 1 hour, during which time the temperature slowly reached ambient temperature over a period of 2 hours. Additional methanesulfonyl chloride (0.120 mL) and DIEA (0.260 mL) were added. The mixture was stirred for 15 hours. The reaction mixture was cooled to 0°C with vigorous mixing. The resulting yellow slurry was stirred for 10 minutes and then allowed to settle. The precipitate was collected by vacuum filtration. The collected solid was washed with H2O and Et2O and The solution was dried over MgSO4, filtered, and concentrated to give crude (S )-4-((4-(chloromethyl)benzyl)amino)-2-(2,6-dioxopiperi (Diazin-3-yl)isoindoline-1,3-dione was obtained as a yellow solid, which was further Used in the next step without further purification. LCMS (ESI) m / z 412. 0 [M+H] + .

[0168] (S)-6-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine-1 -yl)nicotinamide: crude (S)-4-((4-( Chloromethyl)benzyl)amino)-2-(2,6-dioxopiperidin-3-yl)i To a solution of 6-(pyridindoline-1,3-dione) (242 mg, 0.500 mmol), (perazin-1-yl)nicotinamide (113 mg, 0.550 mmol) was added and mixed. The mixture was stirred for 15 min. To the resulting solution was added DIEA (0.087 mL, 0.500 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The solution was diluted with 20% formic acid in 1 mL of HCl and filtered (nylon, 45 μm). (S)-6-(4-(((2-(2,6-dioxopiperidine) Lysin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl (156 mg, 54%) benzylpiperazin-1-ylnicotinamide was obtained. S (ESI) m / z 582.2 [M+H] + .88% by chiral HPLC.

[0169] Example 15: (R)-6-(4-(4-(((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)piperidine (rhazin-1-yl)nicotinamide [ka] The material obtained in Example 14 was further purified by chiral reverse phase chromatography. (S)-6-(4-(((2-(2,6-dioxopiperidin-3-yl) )-1,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine (119 mg, >99% ee) (LCMS (ESI) m / z 582.2 [M+H] + ), and (R)-6-(4-(4-(((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )Methyl)benzyl)piperazin-1-yl)nicotinamide (6 mg, >99% ee) (LCMS (ESI) m / z 582.2 [M+H] + ) was obtained.

[0170] Example 16: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine- 1-yl)picolinamide [ka] 4-((4-(chloromethyl)benzyl)amino) in anhydrous DMSO (0.30 mL) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0 0.080 g, 0.194 mmol) and 6-(piperazin-1-yl)picolinamide ( To a solution of DIEA (0.102 mL, 0.583 The reaction mixture was stirred at ambient temperature for 24 hours. Dilute with 0.5 mL of PBS and filter through a membrane syringe filter (0.45 μm nylon). The solution was purified using standard methods to give 6-(4-(4-(((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )methyl)benzyl)piperazin-1-yl)picolinamide (41.0 mg, 36.3 % yield). LCMS (ESI) m / z 582.6 [M+H] + .

[0171] Example 17: 2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-enyl) methyl)benzyl)amino)isoindoline-1,3-diol Hydrochloride [ka] 4-((4-(chloromethyl)benzyl)amino)- in anhydrous DMF (1.50 mL) 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0. 200 g, 0.486 mmol) and 4-ethylpiperidine (0.055 g, 0.486 To the solution of 1.2 mmol, DIEA (0.297 mL, 1.70 mmol) was added and the reaction mixture was The mixture was stirred at ambient temperature for 24 hours. The reaction was diluted with DMSO (2.0 mL) and the membrane Filter the solution through a syringe filter (0.45 μm nylon) using standard methods. and purified using 2-(2,6-dioxopiperidin-3-yl)-4-((4-(( 4-Ethylpiperidin-1-yl)methyl)benzyl)amino)isoindoline-1,3 -dione hydrochloride (127.4 mg, 50.0% yield). LCMS (ESI) m / z 489.6 [M+H] + .

[0172] Example 18: 4-((4-((2-azaspiro[3.3]heptan-2-yl)methyl) -2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)i Soindoline-1,3-dione [ka] (4-Bromo-3-fluorophenyl)methanol: 4-Bromo-3-fluorophenyl in THF (150 mL) A solution of bromo-3-fluoro-benzoic acid (15.0 g, 68.5 mmol) was cooled to 0°C. , borane-dimethyl sulfide complex (13.7 mL, 137 mmol, 10 M in THF) ) was added dropwise under a nitrogen atmosphere. The cooling bath was removed and the mixture was stirred at ambient temperature for 12 hours. The mixture was cooled to 0°C, quenched with MeOH (50 mL) and dissolved in water (30 mL). The mixture was concentrated in vacuo and the remaining aqueous mixture was diluted with ethyl acetate (150 mL) and The mixture was diluted with water (150 mL) and stirred for 15 minutes. The organic phase was removed and the aqueous phase was diluted with ethyl acetate. The organic fractions were combined and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography ( Purification by 2-10% ethyl acetate in petroleum ether gave 4-bromo-3-fluoro- (2-phenyl)methanol (13.1 g, 93.3% yield) was obtained as a colorless liquid. LCMS (ESI) m / z 187.0 [MH-18 + ]. 1 H NMR (400 M Hz, CDCl3) δ ppm 7.54 - 7.45 (m, 1H), 7.14 (d , J = 9.2 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 4 .64 (d, J = 4.6 Hz, 2H), 2.20 (br s, 1H).

[0173] (4-Bromo-3-fluoro-phenyl)methoxy-tert-butyl-dimethyl- Run: (4-bromo-3-fluoro-phenyl)methanol ( A solution of 13.1 g (63.9 mmol) and imidazole (12.2 g, 179 mmol) The solution was cooled to 0°C and tert-butylchlorodimethylsilane (14.4 g, 95.8 m mol) was added. The cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. Pour into cold water (30 mL) and dilute with ethyl acetate (100 mL) and water (100 mL). The organic phase was removed and the aqueous phase was diluted with ethyl acetate (150 mL × 2). The organic fractions were combined, washed with saturated NaCl (50 mL x 2), and extracted with anhydrous sodium sulfate. The mixture was dried over sodium, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. Purification by chromatography (0-10% ethyl acetate in petroleum ether) gave (4- Bromo-3-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane(1 8.6 g, 91.2% yield) was obtained as a colorless liquid. 1 H NMR (400 MHz , CDCl3) δ ppm 7.49 (dd, J = 7.1, 8.1 Hz, 1H) , 7.18 - 7.08 (m, 1H), 7.01 - 6.92 (m, 1H), 4 .69 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H).

[0174] 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluoro-benzoate aldehyde: (4-bromo-3-fluoro- -phenyl)methoxy-tert-butyl-dimethyl-silane (18.6 g, 58.3 m A solution of n-BuLi (25.6 mL, 64.0 mmol) was cooled to −78° C. and The mixture was stirred for 5 min at -78 °C and DMF (5.8 The mixture was stirred at -78°C for 2 hours and then allowed to warm to ambient temperature. The reaction mixture was cooled to 0° C. and saturated ammonium chloride (60 mL) and water (3 The mixture was quenched with ethyl acetate (2 x 150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated on silica gel. Purification was performed by column chromatography (0–2% ethyl acetate in petroleum ether). 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-fluoro-benzyl The aldehyde (11.5 g, 73.5% yield) was obtained as a yellow liquid. SI) m / z: 269.1 [M+1] + .

[0175] 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro (Benzyl)amino)phthalic acid: 1:10 acetic acid-MeOH (110 mL) 4-[[ tert-Butyl(dimethyl)silyl]oxymethyl]-2-fluoro-benzaldehyde phthalic acid (7.50 g, 27.9 mmol) and 3-aminophthalic acid (5.06 g, 27.9 mmol) A solution of 2-methylpyridinium borane (2-methylpyridinium borane) was stirred at 25°C for 30 minutes and cooled to 0°C. The methyl methyl ketone complex (4.48 g, 41.9 mmol) was added and the mixture was allowed to reach ambient temperature. The mixture was stirred at ambient temperature for 16 hours, and then the mixture was concentrated under reduced pressure. The residue was dissolved in water (25 mL). The mixture was diluted with ethyl acetate (25 mL) and stirred for 15 minutes. The organic layer was removed and the aqueous layer was The organic fractions were combined and extracted with ethyl acetate (30 mL x 2). The residue was purified by silica gel column chromatography (2 ~5% ethyl acetate in petroleum ether) to give 3-((4-(((tert -butyldimethylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (9.90 g, 81.8% yield) was obtained as a white solid. LCMS (ESI) m / z: 434.1 [M+1] + .

[0176] 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro (2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione: 3-((4-(((tert-butyldi- Methylsilyl)oxy)methyl)-2-fluorobenzyl)amino)phthalic acid (11.8 g, 27.2 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (6.72 g A solution of 40.8 mmol) was stirred at 120° C. for 12 hours under a nitrogen atmosphere. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (2-5% petroleum ether). Purification by 4-((4-(((tert-butyldimethyl Silyl)oxy)methyl)-2-fluorobenzyl)amino)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione (9.90 g, 69.2% yield) LCMS (ESI) m / z: 526.2 [M+1] + .

[0177] 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydro) (Cyclomethyl)benzyl)amino)isoindoline-1,3-dione: THF (100m L) in 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2- Fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoin To a solution of doline-1,3-dione (9.90 g, 18.8 mmol) was added concentrated sulfuric acid (20.0 mL, 368 mmol) was added and the mixture was stirred at ambient temperature for 12 hours. The mixture was evaporated in vacuo The mixture was concentrated under reduced pressure and the residue was treated with 1:5 ethyl acetate-petroleum ether (20 mL). The resulting suspension was stirred for 30 minutes and filtered. The collected solid was diluted with 1:5 ethyl acetate - Washed with petroleum ether and dried in vacuo to give 2-(2,6-dioxopiperine Zin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino ) Isoindoline-1,3-dione (6.58 g, 85.2% yield) was obtained as a yellow solid. MS (ESI) m / z: 412.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (s, 1H), 7.54 (dd, J = 7.3, 8.4 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H) ), 7.16 - 7.07 (m, 3H), 7.05 (d, J = 7.0 Hz, 1 H), 6.99 (d, J = 8.5 Hz, 1H), 5.33 - 5.25 (m, 1H), 5.07 (dd, J = 5.3, 12.9 Hz, 1H), 4.59 (d , J = 6.3 Hz, 2H), 4.47 (d, J = 5.8 Hz, 2H), 2 .95 - 2.84 (m, 1H), 2.65 - 2.52 (m, 2H), 2.09 - 2.01 (m, 1H).

[0178] 4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-di Oxopiperidin-3-yl)isoindoline-1,3-dione: dichloromethane (20 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro- 4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (6.5 A solution of thionyl chloride (20.0 mL, 27 After complete addition, the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography. Purification by filtration (1.00-1.25% MeOH in dichloromethane) gave 4- ((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione (3.80 g, 55.4% yield) LCMS (ESI) m / z: 430.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (s, 1 H), 7.54 (dd, J = 7.3, 8.4 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 1.5, 11.0 Hz, 1 H), 7.24 (dd, J = 1.6, 7.8 Hz, 1H), 7.16 (t, J = 6.3 Hz, 1H), 7.06 (d, J = 6.9 Hz, 1H), 6.9 8 (d, J = 8.5 Hz, 1H), 5.08 (dd, J = 5.3, 12.9 Hz, 1H), 4.74 (s, 2H), 4.63 (d, J = 6.3 Hz, 2 H), 2.95 - 2.85 (m, 1H), 2.66 - 2.53 (m, 2H), 2.09 - 2.02 (m, 1H).

[0179] 4-((4-((2-azaspiro[3.3]heptan-2-yl)methyl)-2-fluoro (Obenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole 4-(4-(chloromethyl)- 2-Fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (0.200 g, 0.486 mmol) and 2-azaspiro [3.3] To a solution of heptane (0.132 g, 0.931 mmol), DIEA (0.2 84 mL, 1.63 mmol) was added and the reaction mixture was stirred at ambient temperature for 24 hours. The reaction mixture was diluted with DMSO (2.0 mL) and filtered through a membrane syringe filter (0.45 μm pore size). The solution was purified using standard methods to give 2-(2,6-diisopropylmethylcellulose) xopiperidin-3-yl)-4-((4-((4-ethylpiperidin-yl)methyl) (Benzyl)amino)isoindoline-1,3-dione (18.6 mg, 8.2% yield) LCMS (ESI) m / z 491.5 [M+H] + .

[0180] Example 19: 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro- 4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindo Phosphorus-1,3-dione [ka] 4-((4-(chloromethyl)-2-fluorobenzene) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (215 mg, 0.500 mmol) (prepared as described herein ) and 4-(azetidin-3-yl)morpholine hydrochloride (107 mg, 0.600 m To a solution of 48 mol of DIEA (262 μL, 1.50 mmol) was added and the mixture was heated to 48 The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with 20% formic acid in DMSO (2.5 mL). The solution was diluted and filtered through a membrane syringe filter (0.45 μm nylon). Purification was carried out using standard methods to give 2-(2,6-dioxopiperidin-3-yl)-4- ((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl) (amino)isoindoline-1,3-dione (173 mg, 64.6% yield) was obtained. CMS (ESI) m / z 536.2 [M+H]+.

[0181] Example 20: 6-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)amino)methyl)-3-fluorobenzyl )Piperazin-1-yl)nicotinamide [ka] 4-((4-(chloromethyl)-3-fluorobenzene)- (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (60.0 mg, 0.140 mmol) and 6-(piperazin-1-yl)nicotinamide To a solution of cinnamamide (35.0 mg, 0.168 mmol), DIEA (0.12 mL, 0.698 mmol) was added and the reaction mixture was stirred at 60° C. for 5 hours. Quench with 10% formic acid in 0 (1.0 mL) and filter through a membrane syringe filter (0.45 The solution was filtered through 10 μm nylon and purified using standard methods to give 6-(4- (4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl 3-fluorobenzyl)piperazin-1-yl ) Nicotinamide (69.0 mg, 82% yield) was obtained. LCMS (ESI) m / z 600.2 [M+H]+.

[0182] Example 21: 2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-( Ethylsulfonyl)piperidin-1-yl)methyl)-2-fluorobenzyl)amino) Isoindoline-1,3-dione [ka] 4-((4-(chloromethyl)-2-fluorobenzene) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (64.5 mg, 0.150 mmol) and 4-(ethylsulfonyl)piperidin To a mixture of ethanol hydrochloride (38.5 mg, 0.180 mmol), DIEA (105 μL, 0 0.600 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hours. Dilute with 20% formic acid in 500kJ / 2000kcal (1 mL) and filter through a membrane syringe filter (0.45 μm) The solution was filtered through nylon and purified by standard methods to give 2-(2,6-dichloro-2,4-dichloro-1,4 ... xopiperidin-3-yl)-4-((4-((4-(ethylsulfonyl)piperidine- 1-yl)methyl)-2-fluorobenzyl)amino)isoindoline-1,3-dione (58.0 mg, 67.8% yield). LCMS (ESI) m / z 571.4 [M+H]+.

[0183] Example 22: 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro- 4-((3-(pyridin-2-yl)azetidin-1-yl)methyl)benzyl)amino ) Isoindoline-1,3-dione [ka] 4-((4-(chloromethyl)-2-fluorobenzene) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (64.5 mg, 0.150 mmol) and 2-(azetidin-3-yl)pyriboside To a mixture of dimethyl ether (DIEA) ( 105 μL, 0.600 mmol) was added and the reaction mixture was stirred at ambient temperature for 7 hours. The mixture was diluted with 20% formic acid in DMSO (1 mL) and filtered through a membrane syringe filter (0 The solution was filtered through a 0.45 μm nylon sieve and purified by standard methods to give 2-( 2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-(pyridinyl) Benzyl-2-yl)azetidin-1-yl)methyl)benzyl)amino)isoindoline- The 1,3-dione (34.0 mg, 43.0% yield) was obtained. LCMS (ESI) m / z 528.2 [M+H]+.

[0184] Example 23: 2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro- 4-((3-(2-oxopyrrolidin-1-yl)azetidin-1-yl)methyl)benzoate Dimethylaminoisoindoline-1,3-dione [ka] 4-((4-(chloromethyl)-2-fluorobenzene) (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (64.5 mg, 0.150 mmol) and 1-(azetidin-3-yl)pyrrolidone Lysin-2-one trifluoracetate (57. To a mixture of DIEA (105 μL, 0.600 mmol) ) was added and the reaction mixture was stirred at ambient temperature for 24 hours. Dilute with 20% formic acid and filter through a membrane syringe filter (0.45 μm nylon). The solution was purified using standard methods to give 2-(2,6-dioxopiperidine -3-yl)-4-((2-fluoro-4-((3-(2-oxopyrrolidin-1-yl )Azetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione (35.0 mg, 43.7% yield). LCMS (ESI) m / z 534.2 [M+H]+.

[0185] Example 24: 2-(2,6-dioxopiperidin-3-yl)-4-((3-fluoro- 4-((4-isopropylpiperidin-1-yl)methyl)benzyl)amino)isoin Dorine-1,3-dione [ka] ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilyl HCl: (4-Bromo-2-fluorophenyl)methanol in dichloromethane (200 mL) (30.0 g, 146 mmol) and imidazole (14.9 g, 219 mmol) The mixture was cooled to 0° C. and tert-butyl-chlorodimethylsilane (24.2 g, 161 The mixture was stirred for 5 min, the cooling bath was removed, and the mixture was allowed to stand at ambient temperature for 1 The reaction mixture was stirred for 6 hours, poured into cold water (300 mL), mixed, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (30 mL x 3), and the combined organic layer was washed with saturated NaCl. (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethyl The silane (46.0 g, 98.5%) was obtained as a yellow oil. 1 H NMR (400 MH z, CDCl3) δ ppm 7.40 - 7.34 (m, 1H), 7.31 - 7 .28 (m, 1H), 7.19 (dd, J = 1.8, 9.6 Hz, 1H), 4.74 (s, 2H), 0.97 (s, 9H), 0.16 (s, 6H).

[0186] 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorobenz Aldehyde: A solution of (4-bromo-2-fluoro-2-methyl-2-propanol) in THF (30 mL) under nitrogen atmosphere was (10.0 g, 31.3 mm) (1-(2-benzyloxy)(tert-butyl)dimethylsilane ol) was cooled to -78°C and added with n-butyllithium (15.0 mL, 37.5 mmol, The mixture was stirred at -78°C for 2 hours and then diluted with DMF (3.61 mL, 47.0 mmol) was added. The mixture was allowed to reach ambient temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride (15 mL) and water. The mixture was extracted with ethyl acetate (40 mL x 3) and the combined extracts were The organic layer was washed with saturated NaCl (30 mL × 2) and dried over anhydrous sodium sulfate. Drying, filtering, and concentrating under reduced pressure afforded the crude 4-(((tert-butyldimethylsilyl) Oxy)methyl)-3-fluorobenzaldehyde was obtained as a yellow oil (8.00 g, 95.4% yield). LCMS (ESI) m / z: 269.0 [M+1] + .

[0187] Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-3 (-fluorobenzyl)amino)phthalate: in 10:1 MeOH-acetic acid (110 mL) Crude 4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorobenzyl A mixture of benzoxaldehyde (8.00 g, 29.8 mmol) and dimethyl 3-aminobenzene-1 A mixture of 2-dicarboxylate (6.24 g, 29.8 mmol) was perfused with nitrogen. and treated with borane 2-methylpyridine complex (4.78 g, 44.7 mmol). The reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure to give MeO The H was removed and diluted with water (40 mL). The mixture was washed with ethyl acetate (30 mL × 3). The combined organic fractions were washed with saturated NaCl (20 mL x 3) and anhydrous sodium sulfate. The mixture was dried over sodium, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. Purify by chromatography (5-10% ethyl acetate in petroleum ether) to obtain dimethicone. 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro (Benzyl)amino)phthalate (6.30 g, 45.8% yield) was obtained as a yellow oil. Ta. 1 H NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J = 7.7 Hz, 1H), 7.13 - 7.09 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 10.7 Hz, 1H), 6.7 2 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H ), 4.66 (s, 2H), 4.31 (d, J = 5.6 Hz, 2H), 3. 75 (d, J = 7.7 Hz, 6H), 0.83 (s, 9H), 0.02 (s , 6H).

[0188] 3-((3-fluoro-4-(hydroxymethyl)benzyl)amino)phthalic acid:2: Dimethyl 3-((4-(((tert-) in 2:1 water-THF-MeOH (100 mL) Butyldimethylsilyl)oxy)methyl)-3-fluorobenzyl)amino)phthalate (13.3 g, 28.8 mmol) to a solution of sodium hydroxide (9.21 g, 230 m mol) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The mixture was cooled to 0°C and 6 M aqueous hydrochloric acid was added until pH = 10. The mixture was concentrated to remove MeOH and THF. The remaining aqueous mixture was cooled to 0° C. Subsequently, 6 M hydrochloric acid was added until the pH reached 5. The resulting precipitate was collected by filtration, washed with H2O, and dried in vacuo. 3-((3-fluoro-4-(hydroxymethyl)benzyl)amino)phthalic acid ( 8.90 g, 96.8% yield) as a yellow solid. LCMS (ESI) m / z : 320.0 [M+1]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br s, 2H), 7.41 (t, J = 7.8 Hz, 1H ), 7.22 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 11.2 Hz, 1H), 6.75 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.2 1 (s, 1H), 4.50 (s, 2H), 4.44 (s, 2H).

[0189] 2-(2,6-dioxopiperidin-3-yl)-4-((3-fluoro-4-(hydro) (Cyclomethyl)benzyl)amino)isoindoline-1,3-dione:pyridine (20m 3-Aminopiperidine-2,6-dione hydrochloride (6.88 g, 41.8 mmol) in 1 L ) to a solution of 3-((3-fluoro-4-(hydroxymethyl)benzyl)aminophthalic acid Acid (8.90 g, 27.9 mmol) was added and the mixture was stirred at 120° C. for 5 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL). The solution was washed with 0.5 M HCl (300 mL), dried over MgSO4, and concentrated The remaining solid was dried in vacuo to give 2-(2,6-dioxopiperidine-3- yl)-4-((3-fluoro-4-(hydroxymethyl)benzyl)amino)isoin Doline-1,3-dione (9.00 g, 78.5% yield) was obtained as a yellow solid. CMS (ESI) m / z: 394.0 [MH-18]+. 1 H NMR (400M Hz, DMSO-d6) δ ppm 11.11 (s, 1H), 7.51 (dd, J = 7.2, 8.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H) , 7.29 (br s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7 .14 ​​(d, J = 10.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 5.08 (dd, J = 5.4, ​​12.9 Hz, 1H), 4.56 (br d, J = 5.4 Hz, 2H) ), 4.50 (s, 2H), 2.93 - 2.88 (m, 1H), 2.65 - 2.54 (m, 2H), 2.10 - 2.05 (m, 1H).

[0190] 4-((4-(chloromethyl)-3-fluorobenzyl)amino)-2-(2,6-di Oxopiperidin-3-yl)isoindoline-1,3-dione:dichloromethane (12 2-(2,6-dioxopiperidin-3-yl)-4-((3-fluoro- 4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (4.0 A mixture of thionyl chloride (12.0 mL, 16.0 g, 9.72 mmol) was cooled to 0°C and 5 mmol) was added. The cooling bath was removed and the mixture was stirred at ambient temperature for 22 hours. The mixture was diluted with ethyl acetate (400 mL) and saturated aqueous sodium bicarbonate (300 mL). The mixture was poured into a 100% aqueous solution, mixed, and the organic layer was removed. The aqueous layer was diluted with saturated sodium bicarbonate to pH 5. The organic fraction was treated with ethanol and extracted with dichloromethane (300 mL x 3). The combined extracts were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography. Chromatography (1:2:8, then 1:1:5 ethyl acetate / petroleum ether / dichalcohol Purification by chloromethane yielded 4-((4-(chloromethyl)-3-fluorobenzyl )amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- The dione (3.24 g, 77.6% yield) was obtained as a yellow solid. LCMS (ESI ) m / z: 430.1 [M+1]+. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.12 (s, 1H), 7.50 (q, J = 8.1 Hz, 2 H), 7.33 (br t, J = 6.3 Hz, 1H), 7.29 - 7.18 ( m, 2H), 7.04 (d, J = 7.0 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.08 (dd, J = 5.3, 12.9 Hz, 1H) , 4.75 (s, 2H), 4.59 (br d, J = 6.2 Hz, 2H), 2 .97 - 2.82 (m, 1H), 2.69 - 2.53 (m, 2H), 2.13 - 1.98 (m, 1H).

[0191] 2-(2,6-dioxopiperidin-3-yl)-4-((3-fluoro-4-((4 -isopropylpiperidin-1-yl)methyl)benzyl)amino)isoindoline-1 ,3-dione: 4-((4-(chloromethyl)-3-fluoromethyl)-4-(4-chloromethyl)-3-fluoromethyl ... (Obenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole 1,3-dione (0.060 g, 0.140 mmol) and 4-isopropyl piperidine To a solution of dimethyl ether (DIEA) (0.073 mg, 0.140 mmol), L, 0.419 mmol) was added and the reaction mixture was stirred at 80° C. for 15 hours. The material was cooled to ambient temperature and quenched with 10% formic acid in DMSO (1.0 mL). The mixture was filtered through a membrane syringe filter (0.45 μm nylon) and the solution was diluted to standard The compound was purified using conventional methods to give 2-(2,6-dioxopiperidin-3-yl)-4-( (3-fluoro-4-((4-isopropylpiperidin-1-yl)methyl)benzyl) (amino)isoindoline-1,3-dione (56.0 mg, 77% yield) was obtained. MS (ESI) m / z 521.2 [M+H] + .

[0192] Example 25: 4-((4-((2,2-dimethyl-1-oxa-8-azaspiro[4.5 ]Decan-8-yl)methyl)-3-fluorobenzyl)amino)-2-(2,6-diol (3-oxopiperidin-3-yl)isoindoline-1,3-dione [ka] 4-((4-(chloromethyl)-3-fluorobenzene)- (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (73.0 mg, 0.170 mmol) and 2,2-dimethyl-1-oxa-8 -To a solution of azaspiro[4.5]decane (37.4 mg, 0.221 mmol), DIE A (89.0 μL, 0.510 mmol) was added and the mixture was stirred at 50° C. for 5 h. The mixture was cooled to ambient temperature, diluted with 20% formic acid in DMSO (1 mL), and applied to the membrane silica gel. The solution was filtered through a 0.45 μm nylon filter using standard methods. The compound was purified using 4-((4-((2,2-dimethyl-1-oxa-8-azaspiro[4 .5]decan-8-yl)methyl)-3-fluorobenzyl)amino)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (36.0 mg, 37 0.7%). LCMS (ESI) m / z 563.2 [M+H] + .

[0193] Example 26: (S)-6-(4-(4-(((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)-3-fluoro Benzyl)piperazin-1-yl)nicotinamide [ka] (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4 -(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione: 2:1 (S)-4-amino-2-(2,6-dioxopyrrolidone) in dioxane-MeOH (75 mL) peridin-3-yl)isoindoline-1,3-dione (5.00 g, 18.3 mmol ) and 2-fluoro-4-(hydroxymethyl)benzaldehyde (2.82 g, 18. A suspension of B (30 mmol) was cooled to 0°C and B10 H 14 (4.92g, 40.3mmol 1) was added in small portions over a 5 minute period. The reaction flask was fitted with a septum and needle vent ( The mixture was allowed to reach ambient temperature and stirred for 3 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (0-10% MeOH- DCM) to give (S)-2-(2,6-dioxopiperidin-3-yl)- 4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline- The 1,3-dione was obtained as a yellow solid (4.23 g, 56%). LCMS (ESI) m / z 411.8 [M+H] + .

[0194] (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione: anhydrous NMP( 6 mL) in (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-furan) Fluoro-4-(hydroxymethyl)benzylamino)isoindoline-1,3-dione A solution of (0.727 g, 1.77 mmol) was cooled to 0° C. and HCl (0.275 mL, 3.35 mmol) and DIEA (0.617 mL, 3.53 mmol) The reaction mixture was allowed to reach ambient temperature and stirred for 18 hours. The mixture was slowly added to H2O (60 mL) cooled to 0°C with vigorous mixing. The resulting suspension was filtered and the collected solid was washed with H2O and Et2O. The solution was dried over MgSO4, filtered, and concentrated to give (S)-4 -((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxa (isopiperidin-3-yl)isoindoline-1,3-dione was obtained as a yellow solid (0 .600g, 79%). LCMS (ESI) m / z 430.0 [M+H] + .

[0195] (S)-6-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4-yl)amino)methyl)-3-fluorobenzyl) (Piperazin-1-yl)nicotinamide: (S)-4- in anhydrous DMSO (1.0 mL) ((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxo Piperidin-3-yl)isoindoline-1,3-dione (300 mg, 0.698 mm ol), 6-(piperazin-1-yl)nicotinamide (144 mg, 1.00 To the reaction mixture was added DIEA (0.122 mL, 0.698 mmol). The mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 mL). Purification by chromatography gave (S)-6-(4-(4-(((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )Methyl)-3-fluorobenzyl)piperazin-1-yl)nicotinamide (173m g, 41%, >99%ee)(LCMS (ESI) m / z 600.2 [M+H] + ) obtained.

[0196] Example 27: (R)-6-(4-(4-(((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)-3-fluoro Benzyl)piperazin-1-yl)nicotinamide [ka] Chiral reverse phase chromatography as described in Example 26 afforded (R)-6-(4- (4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropyl 3-fluorobenzyl)piperazin-1-yl ) Nicotinamide (3 mg, >99% ee) (LCMS (ESI) m / z 600.2 [M+H] + ) was obtained additionally.

[0197] Example 28: 4-((4-((4-(tert-butyl)piperidin-1-yl)methyl )-3-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione [ka] 4-((4-(chloromethyl)-3-fluorobenzyl) )amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (0.050 g, 0.116 mmol) and 4-(tert-butyl)piperidine To a solution of the hydrochloride (0.025 mg, 0.141 mmol), DIEA (0.10 mL, 0.573 mmol) was added and the reaction mixture was stirred at 60° C. for 3 hours. The mixture was cooled to RT and quenched with 10% formic acid in DMSO (1.0 mL). Filter the solution through a ring filter (0.45 μm nylon) using standard methods. The compound was purified using 2-(2,6-dioxopiperidin-3-yl)-4-((3-fluorophenyl)- ... 4-((4-isopropylpiperidin-1-yl)methyl)benzyl)amino)iso Indoline-1,3-dione (49.0 mg, 78%) was obtained. LCMS (ESI) m / z 535.2 [M+H]+.

[0198] Example 29: 4-(1-(4-(((2-(2,6-dioxopiperidin-3-yl)- 1,3-Dioxoisoindolin-4-yl)amino)methyl)-3-methylbenzyl) Azetidin-3-yl)benzonitrile [ka] (4-Bromo-3-methyl-phenyl)methanol: 4-Br in THF (500 mL) A solution of bromo-3-methyl-benzoic acid (50.0 g, 232 mmol) was cooled to 0° C. Borane dimethyl sulfide complex (35.0 mL, 350 mmol, 10 M in THF) The reaction mixture was allowed to reach ambient temperature and stirred for 2 hours, followed by stirring at 40°C for 3 hours. The mixture was stirred for 1 hour. The mixture was cooled to 0° C. and quenched with water (200 mL). Extract with ethyl acetate (300 mL), dry the organic layer over anhydrous sodium sulfate, Filtration and concentration gave (4-bromo-3-methyl-phenyl)methanol (45.0 g, 9 6.3% yield) was obtained as a brown oil. 1 H NMR (CDCl3, 400 MHz) δ ppm 7.51 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 1 .6 Hz, 1H), 7.05 (dd, J = 1.6, 8.2 Hz, 1H), 4 .63 (s, 2H), 2.41 (s, 3H).

[0199] (4-Bromo-3-methyl-phenyl)methoxy-tert-butyl-dimethyl-sila Benzene: (4-bromo-3-methyl-phenyl)methanol in dichloromethane (500 mL) To a solution of ethanol (45.0 g, 224 mmol), imidazole (38.1 g, 559 mmol) was added l) and tert-butyldimethylsilyl chloride (40.5 g, 269 mmol) successively The mixture was added and stirred at ambient temperature for 15 hours. The mixture was washed with saturated NaCl (500 mL) and dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated to give (4-bromo-3-methyl-phenyl)methoxy-tert-butyl ether. t-Butyl-dimethyl-silane (68.0 g, 96.4% yield) was obtained as a brown oil. . 1 H NMR (CDCl3, 400 MHz) δ 7.48 (d, J = 8.2 H z, 1H), 7.19 (d, J = 1.1 Hz, 1H), 7.02 (dd, J = 1.6, 8.1 Hz, 1H), 4.67 (s, 2H), 2.40 (s, 3H) ), 0.95 (s, 9H), 0.11 (s, 6H).

[0200] 4-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-methyl-benz Aldehyde: (4-bromo-3-methyl- (phenyl)methoxy-tert-butyl-dimethyl-silane (63.0 g, 200 mmol ) was cooled to -78 °C and n-butyllithium (95.9 mL, 240 mmol, The mixture was stirred at -78°C for 2 hours and then diluted with DMF (23.1 The mixture was stirred at -78 °C for 30 min and then allowed to warm to ambient temperature. The mixture was quenched with saturated ammonium chloride (300 mL). The organic phase was diluted with saturated NaCl (300 mL) and extracted with ethyl acetate (300 mL). The residual oil was washed with hexane, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by gel column chromatography (petroleum ether) gave 4-[[tert- Butyl(dimethyl)silyl]oxymethyl]-2-methyl-benzaldehyde (45.0 g, 85.2% yield) was obtained as a brown oil. 1 H NMR (400 MHz, CDC l3) δ ppm 10.24 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 4.77 (s, 2H), 2.68 (s, 3H), 0.96 (s, 9H), 0. 12 (s, 6H).

[0201] Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)-2 -methylbenzyl)amino)phthalate: 4-[[tert -butyl(dimethyl)silyl]oxymethyl]-2-methyl-benzaldehyde (20. 0 g, 75.6 mmol) and dimethyl 3-aminobenzene-1,2-dicarboxylate To a solution of acetic acid (20.0 mL, 350 mmol) was added and the mixture was stirred at ambient temperature for 6 hours. The mixture was cooled to 0°C and borane 2-methyl The mixture was heated to 100°C for 1 hour at 4°C for 1 hour, and then 12.1 g of bismuth pyridine complex (113 mmol) was added in small portions. The mixture was allowed to reach temperature and stirred for 15 hours. The mixture was concentrated and the residue was washed with water (300 mL). The mixture was diluted and extracted with ethyl acetate (300 mL). The organic layer was washed with 0.5 M hydrochloric acid (300 mL), washed with saturated NaCl (300 mL), dried over anhydrous sodium sulfate, and The dried solution was filtered and concentrated, and the residue was purified by silica gel column chromatography. (0-10% ethyl acetate in petroleum ether) to give dimethyl 3-((4- (((tert-butyldimethylsilyl)oxy)methyl)-2-methylbenzyl)amino The phthalate (18.0 g, 43.2% yield) was obtained as a colorless oil.

[0202] 3-((4-(hydroxymethyl)-2-methylbenzyl)amino)phthalic acid: 1:1 of dimethyl 3-((4-(((tert-butyldimeth- yl 3-( ... Methylsilyl)oxy)methyl)-2-methylbenzyl)amino)phthalate (18.0 g, 32.7 mmol) in water (50 mL) 27 mmol) was added and the mixture was stirred at ambient temperature for 15 hours. OH and THF were removed and the remaining aqueous mixture was cooled to 0° C. Then 6 M hydrochloric acid was added The resulting precipitate was collected by filtration, washed with water, and vacuum and dried at 3-((4-(hydroxymethyl)-2-methylbenzyl)amino ) Phthalic acid (5.30 g, 51.4% yield) was obtained as a yellow solid. 1 H NMR ( 400 MHz, DMSO-d6) δ 8.41 (br t, J = 5.3 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 7 .04 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.38 (br d, J = 7.4 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 5.07 (br s, 1H), 4.43 (br s, 2H) ), 4.19 (br d, J = 5.1 Hz, 2H), 2.31 (s, 3H).

[0203] 2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl) -2-Methylbenzyl)amino)isoindoline-1,3-dione: Pyridine (60 mL) ) solution of 3-((4-(hydroxymethyl)-2-methylbenzyl)amino)phthalic acid (5.30 g, 16.8 mmol) to 3-aminopiperidine-2,6-dione hydrochloride ( 4.15 g, 25.2 mmol) was added and the mixture was stirred at 120° C. for 10 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (300 mL). The solution was diluted with 0.5 M hydrochloric acid ( 300 mL), dried over sodium sulfate, filtered, and 2-(2,6-dichloro-2,4-dichloro-1,4 ... Oxopiperidin-3-yl)-4-((4-(hydroxymethyl)-2-methylbenzyl) to (4.80 g, 70.1% yield) Concentrated as a colored solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.1 0 (s, 1H), 7.52 (dd, J = 7.2, 8.4 Hz, 1H), 7. 20 - 7.12 (m, 2H), 7.10 - 7.01 (m, 2H), 6.98 - 6.87 (m, 2H), 5.06 (dd, J = 5.4, 12.9 Hz, 1 H), 4.50 (br d, J = 5.5 Hz, 2H), 4.42 (s, 2H) , 2.95 - 2.79 (m, 1H), 2.64 - 2.52 (m, 2H), 2 .33 (s, 3H), 2.08 - 1.99 (m, 1H).

[0204] 4-((4-(chloromethyl)-2-methylbenzyl)amino)-2-(2,6-diamino) 1,3-dichloromethane (200 2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxy) Methyl)-2-methylbenzyl)amino)isoindoline-1,3-dione (9.10g To a solution of thionyl chloride (32.4 mL, 447 mmol) was added The mixture was stirred at ambient temperature for 15 hours. The mixture was diluted with dichloromethane (300 mL). The mixture was diluted with water, poured into saturated sodium bicarbonate (300 mL), cooled to 0°C, and mixed. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was slurried in dichloromethane-petroleum ether (20 mL) and the solid was collected by filtration. The collected solid was purified by silica gel column chromatography (1:1 petroleum ether -20 to 100% ethyl acetate in dichloromethane) to give 4-((4-( Chloromethyl)-2-methylbenzyl)amino)-2-(2,6-dioxopiperidine- 3-yl)isoindoline-1,3-dione (7.40 g, 70.8% yield) was obtained as a yellow Obtained as a solid. LCMS (ESI) m / z: 426.1 [M+1] + . 1 HNM R (400 MHz, DMSO-d6) δ 11.12 (m, 1H), 7.52 ( dd, J = 7.3, 8.4 Hz, 1H), 7.27 (s, 1H), 7.20 (d, J = 1.0 Hz, 2H), 7.07 - 7.01 (m, 2H), 6.9 0 (d, J = 8.5 Hz, 1H), 5.07 (dd, J = 5.5, 12.9 Hz, 1H), 4.69 (s, 2H), 4.53 (d, J = 6.0 Hz, 2 H), 2.94 - 2.79 (m, 1H), 2.64 - 2.52 (m, 2H), 2.34 (s, 3H), 2.09 - 2.00 (m, 1H).

[0205] 4-(1-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-4-yl)amino)methyl)-3-methylbenzyl)azetidine 4-((4-(chloromethyl)-3-yl)benzonitrile) in anhydrous DMF (1.0 mL) (2-methylbenzyl)amino)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (0.060 g, 0.141 mmol) and 4-(azepine) A mixture of 3-(dithiazin-3-yl)benzonitrile hydrochloride (0.027 mg, 0.141 mmol) To the mixture was added DIEA (0.074 mL, 0.423 mmol) and the reaction mixture was stirred for 80 The reaction was stirred at 0°C for 15 hours. The reaction was cooled to ambient temperature and diluted with 10% DMSO (1.0 mL). The mixture was quenched with 100 ml of formic acid. The mixture was filtered through a membrane syringe filter (0.45 μm nylon). and the eluted solution was purified using standard methods to give 2-(2,6-dichloro-2,4 ... 4-((3-fluoro-4-((4-isopropylpiperidin-3-yl)-4-((3-fluoro-4-((4-isopropylpiperidin-3-yl) Dibenzoyl)methyl)benzyl)amino)isoindoline-1,3-dione (49. 0 mg, 59.9% yield). LCMS (ESI) m / z 548.2 [M+H ] + .

[0206] Example 30: 4-((4-((4-(tert-butyl)piperidin-1-yl)methyl )-2-methylbenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)i Soindoline-1,3-dione [ka] 4-((4-(chloromethyl)-2-methylbenzyl) Amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-di ion (0.050 g, 0.117 mmol), 4-(tert-butyl)piperidine (0 0.0249 mL, 0.176 mmol) and DIEA (0.102 mL, 0.585 mmol) A solution of 1.0 ml of DMSO (1.0 ml) was stirred at 60° C. under an atmosphere of N for 3 h. The solution was quenched with 10% formic acid in 1 mL of PBS and filtered through a membrane syringe filter (0.45 μm). The solution was purified using standard methods to give 4-((4-((4- (tert-butyl)piperidin-1-yl)methyl)-2-methylbenzyl)amino -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4 3.0 mg, 69.0%) was obtained. LCMS (ESI) m / z 531.3 [M+H] + .

[0207] Example 31: 4-((4-((4-(2,4-difluorophenyl)piperazine-1-yl) (methyl)-2-methylbenzyl)amino)-2-(2,6-dioxopiperidine-3 -yl)isoindoline-1,3-dione [ka] 4-((4-(chloromethyl)-2-methylbenzyl)azoline) in DMF (1.00 mL) (amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-diol (0.060 g, 0.141 mmol), 1-(2,4-difluorophenyl)piperazine dine (0.031 g, 0.155 mmol) and DIEA (0.074 mL, 1.73 m A solution of 1000 mg of DMSO (1 mol) was stirred at 80 °C under an atmosphere of N for 15 h. Quench with 10% formic acid in 0.0 mL of PBS and filter through a membrane syringe filter (0.45 μm Nylon) and the solution was purified using standard methods to give 4-((4-(( 4-(2,4-difluorophenyl)piperazin-1-yl)methyl)-2-methylbenzyl (2,6-dioxopiperidin-3-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (34.0 mg, 40.9%) was obtained. LCMS (ESI) m / z 588 .2 [M+H] + .

[0208] Example 32: (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-furan) Fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)i Soindoline-1,3-dione [ka] (S)-4-((4-(chloromethyl)-2-fluoro- (2,6-dioxopiperidin-3-yl)isoindoline To a solution of 4-(azetidine-3-yl)-1,3-dione (300 mg, 0.698 mmol), -yl)morpholine hydrochloride (125 mg, 0.698 mmol) and DIEA (0.12 2 mL, 0.698 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The solution was purified by chiral reversed-phase chromatography. and (S)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro- 4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindo Phosphorus-1,3-dione (89 mg, 24%, 97% ee) (LCMS (ESI) m / z 536.2 [M+H] + ) was obtained.

[0209] Example 33: (R)-2-(2,6-dioxopiperidin-3-yl)-4-((2-furan) Fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)i Soindoline-1,3-dione [ka] (R)-2-(2, 6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholino Azetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione( 16mg, 97%ee)(LCMS (ESI) m / z 535.6 [M+H] + ) added obtained through addition.

[0210] Example 34: (S)-5-(4-(4-(((2-(2,6-dioxopiperidine-3- yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)piperidine (rhazin-1-yl)picolinamide [ka] (S)-4-((4-(chloromethyl)benzyl)azoline) in anhydrous DMSO (3.0 mL) (amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-diol To a solution of 5-(piperazin-1-yl)picolinone (300 mg, 0.619 mmol), amide (153 mg, 0.743 mmol) and DIEA (0.108 mL, 0.61 9 mmol) was added and the mixture was stirred at ambient temperature for 16 h. L) and the solution was purified by reverse phase chromatography to give (S)-5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1, 3-Dioxoisoindolin-4-yl)amino)methyl)benzyl)piperazine-1- (yl)picolinamide (255 mg, 71%, 95% ee) (LCMS (ESI) m / z 582.2 [M+H] + ) was obtained.

[0211] Example 35: ((R)-5-(4-(4-(((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)pi Perazin-1-yl)picolinamide [ka] Chirality of the solution obtained in Example 34 or the racemic material obtained in Example 7 Purification by column chromatography yielded ((R)-5-(4-(4-(((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)a (amino)methyl)benzyl)piperazin-1-yl)picolinamide (LCMS (ESI ) m / z 582.2 [M+H] + ) was obtained.

[0212] Assay Cell-based assays SU-DHL-4 cell proliferation assay. The following was performed using DLBCL cell lines, e.g. SU-DHL-4 cell line (Deutsche Sammlung von Mikroo rganismen und Zellkulturen GmbH[DSMZ]:Kata Antiproliferative activity of isoindolinedione compounds in the treatment of rhodopsin (Log No. ACC-495) This is an example of an assay that can be used to determine the effect of SU-DHL-4 on the IL-1 receptor agonist (IL-1) at 120 hours after IL-1 activation. Optimize seeding density in 1536-well plates to ensure assay linearity in 1536-well plates It is possible.

[0213] Increasing concentrations (0.5 nM to 10 μM) of test compound were added to the wells of an empty 1536-well plate. Into a 20-point dilution format (unequal) via an ultrasonic dispenser (EDC ATS-100) The DMSO concentration was 0.1 The final assay concentration of DMSO was kept constant at 100%. The cells were cultured in RPMI-1640 (Ros) containing 10% FBS (fetal bovine serum: HyClone). Grown in Well Park Memorial Institute-1640 medium The cells were then cultured in 5 μL of PBS and amplified in culture flasks to provide sufficient starting material. Compounds were spotted onto a 1536-well plate diluted to 500 cells per well in a volume of 1000 μL. The cells were grown for 120 hours at 37°C in 5% CO2. At the time of starting exposure to the compound (t0), the initial number of viable cells was calculated based on the amount of ATP present in the viable cells. By quantifying the level of luminescence generated by adenosine-5'-triphosphate (ATP) and according to the manufacturer's (Promega Corporation, Madison, WI) instructions. Cell Titer-Glo® Lumin Evaluated by Scent Cell Viability Assay. After a period of time, cell viability of the treated cells was assessed by Cell Titer-Glo®. All growth inhibition curves were assessed using the Activity Baseline method and luminescence was read. (IDBS, Alameda, CA) for processing and evaluation. Rate IC 50 The values ​​were compared using a four-parameter logistic model (sigmoidal dose-response model): y=(A+((BA) / (1+((C / x)^D)))) Calculate using During the ceremony, A=Y Min B=Y Max C=EC 50 D = curve slope I C 50 = Compound concentration where Y is 50% of DMSO control Y = cell viability measured as luminescence units, and x = concentration of compound It was.

[0214] In vivo assay WSU-DLCL2 (GCB subtype) triple hit (Myc, Bcl2, Bcl 6) Reconstitution of DLBCL xenograft model. WSU-DLCL2 cells are diffuse large cell type Derived from B-cell lymphoma (a type of non-Hodgkin's lymphoma). Severe combined T-cell and B-cell immunity Female SCID mice (Fox Chase SCID) characterized by deficiency (trademark), CB17 / Icr-Prkdcscid, Charles River) are research On day 1 of the study, the mice were 10 weeks old with a weight ranging from 15.4 to 24.2 g. 6 W SU-DLCL2 cells are inoculated subcutaneously into the flank of female CB17 SCID mice. Mice were randomized to treatment groups (n=9 / group) at the start of treatment and tumors were approximately 350 mm 3 Treatment begins on day 18, which is 0.01 mg / kg / day. Test compounds (at four dose levels) are administered once daily. MCT (0.5% methylcellulose, 0.25% Tween 1 in PBS) was administered QD. QD administration of 80 mM citrate and 50 mM citrate (pH 7.0) was used as a vehicle control. A single cycle of CHOP therapy (single dose of cyclophosphamide on day 1, Doxorubicin single dose, vincristine single dose on day 1, and QD x 5 on days 1-5 Prednisone) caused significant weight loss and was used as a positive control. The two endpoints in this study were tumor volume reduction (TVR) and The vehicle group was approximately 1400 mm 3 The predetermined end At the end of the study, tumor-free animals were determined as those without palpable tumors, at which point the TVR was reached. or <50 mm 3 30 mg / kg QD treatment group: The patients were followed for TTP and tumor growth delay (TGD) (which is the difference between treated tumors and control tumors) was calculated. For tumors, 1000mm 3 The difference in the number of days required to reach the specified volume of Multiple dosing schedules can be tested. Mean tumor volume in the vehicle group is approximately 1400mm 3At the end of the study, when the predetermined endpoint is reached, the final tumor Reduction in tumor volume is determined.

[0215] SU-DHL-6 (GCB subtype) double-hit DLBCL xenograft model. -DHL-6 cells are derived from diffuse large B-cell lymphoma (a type of non-Hodgkin's lymphoma). The SU-DHL-6 cell line is a GCB-type "double hit" (Bcl2 rearrangement and combination It is characterized by severe combined T-cell and B-cell immunodeficiency. Female SCID mice (Fox Chase SCID®, CB17) were mated. / Icr-Prkdcscid, Charles River) on day 1 of this study. , weighing between 15.4 and 24.2 g and aged 10 weeks. 10 x 10 6 SU-DHL- 6 cells are inoculated subcutaneously into the flank of female CB17 SCID mice. Mice are treated. At 14 days, patients were randomized to treatment groups (n=7 / group) and tumors were approximately 170 mm 3 The 28th day Treatment begins on day 49 of the 3-week oral dosing period. The tumor volume was approximately 1400 mm 3 At the end of the study, the pre-determined endpoint of The final tumor volume reduction was determined. 0.25% Tween 80 and 50 mM citrate pH) were administered QDs to the vehicle. A single cycle of R-CHOP therapy (a single dose of rituximab on day 1) was used as a control. dose, single dose of cyclophosphamide on day 1, single dose of doxorubicin on day 1, A single dose of vincristine and a combination of prednisone QD x 5 on days 1-5) This induces significant weight loss and serves as a positive control. Results include tumor volume reduction (TVR). 3 of Upon reaching the predetermined endpoint, TVR is determined. Tumor-free animals are palpable. No significant tumor or <50 mm 3 A tumor-bearing animal is defined as a tumor-bearing animal.

[0216] OCI-LY10 (ABC subtype) DLBCL xenograft model. OCI-LY10 The cells originate from diffuse large B-cell lymphoma (a type of non-Hodgkin's lymphoma). Female SCID mice (Fox C) characterized by combined T-cell and B-cell immunodeficiency hase SCID®, CB17 / Icr-Prkdcscid, Charl On day 1 of the study, 10 hamsters weighing between 15.4 and 24.2 g were Weeks old. 10 x 10 6 OCI-LY10 cells were cultured in female CB17 SCID mice. Mice were randomized into treatment groups (n=9 / group) at the start of treatment. , tumor is approximately 100 mm 3 Treatment begins on day 9, when the mean Tumor volume is approximately 1400mm 3 At the end of the study, the pre-determined endpoint of The final tumor volume reduction was determined. Rituximab (at one dose level, administered intraperitoneally every other week) The study endpoints included tumor volume, The vehicle group is approximately 1400 mm 3 Predetermined endpoints of At the end of the study, when the tumor was reached, the TVR was determined. Tumor-free animals were classified as having no palpable tumors or or <50mm3 A tumor-bearing animal is defined as a tumor-bearing animal.

[0217] Cell lines that can be used in the xenograft assays described herein GCB DLBCL cell lines (e.g., Karpas-422, WSU-DLBCL) 2, SU-DHL-1, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU -DHL-8, SU-DHL-10, HT, Farage, Pfeifer, or OC I-Ly7), ABC DLBCL cell lines (e.g., OCI-Ly10, U2932, OC I-Ly3, or RC-K8), or DHIT (double hit, i.e., cMyc and and Bcl-2 mutation) or THIT (triple hit, i.e., Myc, Bcl-2 , Bcl6-reconstituted) cell lines.

[0218] Isoindolinedione compounds have been tested in DLBCL xenograft models or will be tested and shown to be effective in models for the treatment of DLBCL. has been or will be shown.

[0219] Activity Table Each of the isoindolinedione compounds in Table 1 was shown to be effective in DLBCL cell proliferation assays. Test in one or more of these (e.g., SU-DHL-4 cell proliferation assay) and were found to have activity therein, all of the compounds being at concentrations below 1 μM in the assay. Mitsu IC 50 with some compounds having an IC of less than 200 nM 50 (Activity level D) some have IC values ​​between 200 nM and 500 nM 50 (activity level C), some 50 IC from 1nM to 750nM 50(activity level B), and others between 751 nM and 1 μM I C 50 (activity level A). Table 1 [Table 3] TIFF0007745679000079.tif236170TIFF0007745679000080.tif230170TIFF0007745679000081.tif230170TIFF0007745679000082.tif245170TIFF0007745679000083.tif220170TIFF0007745679000084.tif241170TIFF0007745679000085.tif245170TIFF0007745679000086.tif233170TIFF0007745679000087.tif233170TIFF0007745679000088.tif234170TIFF0007745679000089.tif231170TIFF0007745679000090.tif242170TIFF0007745679000091.tif230170TIFF0007745679000092.tif231170TIFF0007745679000093.tif214170TIFF0007745679000094.tif248170TIFF0007745679000095.tif219170TIFF0007745679000096.tif249170TIFF0007745679000097.tif225170TIFF0007745679000098.tif249170TIFF0007745679000099.tif225170TIFF0007745679000100.tif241170TIFF0007745679000101.tif249170TIFF0007745679000102.tif232170TIFF0007745679000103.tif240170TIFF0007745679000104.tif223170TIFF0007745679000105.tif230170TIFF0007745679000106.tif247170TIFF0007745679000107.tif246170TIFF0007745679000108.tif248170TIFF0007745679000109.tif215170TIFF0007745679000110.tif242170TIFF0007745679000111.tif225170TIFF0007745679000112.tif249170TIFF0007745679000113.tif232170TIFF0007 745679000114.tif249170TIFF0007745679000115.tif238170TIFF0007745679000116.tif22 0170TIFF0007745679000117.tif237170TIFF0007745679000118.tif234170TIFF000774567 9000119.tif249170TIFF0007745679000120.tif232170TIFF0007745679000121.tif104170.

[0220] Numerous references are cited, the disclosures of which are incorporated herein by reference in their entireties. It is used as a reference.

[0221] The above described embodiments are intended to be merely exemplary and those skilled in the art will appreciate that they are readily apparent to those skilled in the art through routine implementation. By using only experimental work, one can recognize numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are within the scope of this invention. It is determined that the invention is covered by the appended claims. The present application provides the following aspects of the invention. (Aspect 1) Compounds of formula (I): (chemical 1) TIFF0007745679000122.tif35170, or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof (In the formula, Ring A is an optionally substituted non-aromatic heterocyclyl; Each R is independently substituted or unsubstituted C 1-3 Alkyl or halogen the law of nature; n is 0, 1, 2, 3 or 4). (Aspect 2) The compound is a compound of formula (II): (chemical 2) TIFF0007745679000123.tif37170, or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof 2. The compound of embodiment 1, wherein (Aspect 3) The compound is a compound of formula (III): (C3) TIFF0007745679000124.tif32170, or a pharmaceutically acceptable salt, tautomer, isotopically substituted derivative, or stereoisomer thereof 2. The compound of embodiment 1, wherein (Aspect 4) The compound is a compound of formula (IV): (C4) TIFF0007745679000125.tif34170, or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof 2. The compound of embodiment 1, wherein (Aspect 5) The compound is a compound of formula (V): (C5) TIFF0007745679000126.tif36170, or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof 5. The compound of embodiment 4, wherein (Aspect 6) The compound is a compound of formula (VI): (6) TIFF0007745679000127.tif31170, or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof 5. The compound of embodiment 4, wherein (Aspect 7) The compound is a compound of formula (VII): (C7) TIFF0007745679000128.tif35170, or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof 2. The compound of embodiment 1, wherein (Aspect 8) The compound is a compound of formula (VIII): (8) TIFF0007745679000129.tif40170, or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof 8. The compound of embodiment 7, wherein (Aspect 9) The compound is a compound of formula (IX): (9) TIFF0007745679000130.tif31170, or a pharmaceutically acceptable salt, tautomer, or isotopic substitution thereof 8. The compound of embodiment 7, wherein (Aspect 10) Ring A is (C10) TIFF0007745679000131.tif20170 (in the formula, R a is H and R b is C 1-6 Alkyl, non-aromatic heterocyclyl, aryl aryl, heteroaryl, or O-aryl; or R a and R b are those together with the carbon to which it is attached form a 3- to 6-membered cycloalkyl or a 4- to 6-membered non-aromatic forming a heterocyclyl; said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be one or more halogens, C 1-3 Alkyl or CN (optionally replaced) 10. The compound according to any one of aspects 1 to 9, wherein: (Aspect 11) Ring A is (Chem.11) TIFF0007745679000132.tif22170 (in the formula, R c is H, halogen, OH, or (C 1-3 alkyl); R d is (C 1-3 alkyl), OR 1 , C(O)N(R 2 )2, SO2(C 1- 4 alkyl), C 3-7 Cycloalkyl, non-aromatic heterocyclyl, aryl, heteroaromatic or O is heteroaryl; or R is c and R d are combined Together with the carbon atom, a 3- to 6-membered cycloalkyl or a 4- to 6-membered non-aromatic heterocyclic Forming a rill;R 1 is H, optionally substituted C 1-6 alkyl, or optionally substituted Ru-(C 0-3 alkyl)-(C 3-7 cycloalkyl); each R 2 is independent H or C 1-6 alkyl; the alkyl, cycloalkyl, heterocyclyl , aryl, or heteroaryl may be one or more halogens, C 1-3 Alkyl or CN) 10. The compound according to any one of aspects 1 to 9, wherein: (Aspect 12) Ring A is (C12) TIFF0007745679000133.tif21170 (in the formula, R e is C 1-6 Alkyl, SO2(C 1-4 alkyl), -(C 0-3 Archi (C 3-7 cycloalkyl), aryl, heteroaryl, or CO-aryl wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted. (to be exchanged) 10. The compound according to any one of aspects 1 to 9, wherein: (Aspect 13) Ring A is azetidyl; piperidyl; piperazinyl; morpholinyl; 5-azaspiro[2 ,3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3 .3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3 .4]octyl;6-oxa-2-azaspiro[3.4]octyl;2-azaspiro[3 .5]nonyl;7-oxa-2-azaspiro[3.5]nonyl;Octahydrocyclopenta[2.5]nonyl 1,2,3,3a,4,6a-Hexahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-Hexahydrocyclopenta[c]pyrrolyl 6-Azaspiro[3.4]octyl;2-Oxa-6-azaspiro[3.4]octyl 6-Azaspiro[2.5]octyl;7-Azaspiro[3.5]nonyl;1-Oxy 2-oxa-8-azaspiro[4.5]decanyl; 2-oxa-8-azaspiro[4.5]decanyl 2,8-Diazaspiro[4.5]decane-1-onyl;3-Oxa-9-azaspiro [5.5]undecanyl;1,4-oxazepanyl;8-azabicyclo[3.2.1]o an optionally substituted non-aromatic heterocyclyl selected from: octyl; and isoindolinyl; 10. The compound according to any one of aspects 1 to 9, wherein (Aspect 14) Ring A is halogen, C 1-6 Alkyl, OR 1 , CON(R 2 )2, SO2(C 1-4 alkyl), N(R 2 )SO2(C 1-4 alkyl), -(C 0-3 Alkyl)-(C3 -7 Cycloalkyl) (non-aromatic heterocyclyl), aryl, heteroaryl, O-aromatic heterocyclyl one or more independently selected from C(O)aryl, O-heteroaryl, and C(O)aryl; substituted by a plurality of substituents; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted; R 1 H, optionally substituted C 1-6 alkyl, or optionally substituted -(C 0-3 alkyl)-(C 3-7 Cycloa Each R 2 independently H or C 1-6 alkyl. The compound described in (Aspect 15) Ring A is F, Cl, Br, CH3, CH2CH3, n-propyl, isopropyl, n- Butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH 2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH(CH 3) CF3, CH2CH2CF3, OH, OCH3, OCH2CH3, O-Isopropyl , On-propyl, On-butyl, O-isobutyl, Ot-butyl, OCF3, O -cyclopropyl, O-cyclobutyl, OCH2-cyclopropyl, OCH2-cyclobutene Chill, CONH2, CONH(CH3), CON(CH3)2, SO2CH3, SO2C H2CH3, SO2 isopropyl, cyclopropyl, cyclobutyl, CH2-cyclopropyl Pyr, CH2-cyclobutyl; Azetidyl, Pyrrolidyl, Pyrrolidonyl, Isothiazolidine isothiazolidine 1,1-dioxidyl (diio xidyl), piperidyl, piperazinyl, morpholinyl, 3-oxa-8-azabicyclo[4.2.1] 8-oxa-3-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl (non-aromatic heterocyclyl) wherein said heterocyclyl is selected from CH3, Optionally with one or more substituents independently selected from CH2CH3, or CF3 phenyl, O-phenyl, or C(O)-phenyl (wherein the phenyl is substituted with Nyl is one or more independently selected from F, Cl, CH3, CN, or CONH2. optionally substituted by multiple substituents); pyrazolyl, imidazolyl, oxazolyl, iridium Thioxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl heteroaryl selected from aryl, pyrimidyl, or benzisoxazolyl, , wherein the heteroaryl is F, Cl, CF3, CN, CONH2, CONH(CH3)2 or CON(CH3)2, optionally with one or more substituents independently selected from substituted with); one or more independently selected from O-pyridyl and O-pyrimidyl 14. The compound of embodiment 13, wherein the compound is substituted with a number of substituents. (Aspect 16) Ring A is F, CH3, CH2CH3, isopropyl, t-butyl, CH2F, CF3, CH(CH3)CF3, OH, OCH3, OCH2CH3, O-Isopropyl, On- Propyl, O-isobutyl, Ot-butyl, OCF3, O-cyclobutyl, OCH2- Cyclopropyl, CON(CH3)2, SO2CH2CH3, SO2-isopropyl, cyclopropyl Cyclopropyl, cyclobutyl, CH2-cyclopropyl; pyrrolidyl, pyrrolidonyl, iridium Sothiazolidine 1,1-dioxidyl, morpholinyl, 3-oxa-8-azabicyclo[ 3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl (non-aromatic heterocyclyl) wherein said heterocyclyl is independently selected from CH optionally substituted by one or more substituents selected from the group consisting of phenyl, O-phenyl, phenyl, or C(O)-phenyl, wherein the phenyl is selected from the group consisting of F, Cl, CH3, CN, or CONH2, optionally substituted by one or more substituents independently selected from pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazolyl heteroaryl selected from pyrimidinyl, pyrimidyl, or benzisoxazolyl (formula wherein the heteroaryl is F, Cl, CF3, CN, CONH2, CON(CH3)2 optionally substituted with one or more substituents independently selected from substituted by one or more substituents independently selected from aryl and O-pyrimidyl; 14. The compound of embodiment 13. (Aspect 17) Ring A is azetidyl, and C 1-6 Alkyl, (non-aromatic heterocyclyl), aryl aryl, heteroaryl, O-aryl, and O-heteroaryl; and wherein the alkyl, cycloalkyl, heterocyclic, The compound of embodiment 13, wherein the aryl, aryl, or heteroaryl is optionally substituted. . (Aspect 18) Ring A is azetidyl, CH2CH3, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl, t-butyl; CF3; pyrrolidyl; pyrrolidonyl (py rolidonyl); piperidyl; piperazinyl; morpholinyl (one or more C optionally substituted by H3); 3-oxa-8-azabicyclo[3.2.1]octyl ;8-Oxa-3-azabicyclo[3.2.1]octyl;Pyrazolyl;2-Pyridyl; 3-pyridyl; 4-pyridyl, phenyl; and O-phenyl, wherein the phenyl is F or CN), independently 14. The compound of embodiment 13, wherein the compound is substituted with one or more substituents selected from the following: (Aspect 19) Ring A is piperidyl, halogen, C 1-6 Alkyl, OR 1 , CON(R 2 )2 , SO2(C 1-4 alkyl), C 3-7 Cycloalkyl, non-aromatic heterocyclyl, one or more independently selected from aryl, heteroaryl, and O-heteroaryl; substituted by any number of substituents; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted; R 1 H, optionally substituted C1 -6 alkyl, or optionally substituted -(C 0-3 alkyl)-(C 3-7 Cycloal Kill); each R 2 independently H or C 1-6 In accordance with embodiment 13, The compound described. (Aspect 20) Ring A is piperidyl and is substituted with F, Cl, CH3, CH2CH3, n-propyl, isopropyl propyl, n-butyl, sec-butyl, isobutyl, t-butyl, CH2F, CHF2, CF3, OH, OCH3, OCH2CH3, On-propyl, O-isopropyl, O- n-Butyl, O-Isobutyl, Ot-Butyl, OCF3, O-Cyclopropyl, O-Cyclopropyl Cyclobutyl, OCH2-cyclopropyl, OCH2-cyclobutyl, CONH2, CON H(CH3), CON(CH3)2, SO2CH3, SO2CH2CH3, SO2-iso Propyl, cyclopropyl, cyclobutyl, pyrrolidonyl, isothiazolidine 1,1-di Oxidyl, morpholinyl; tetrahydrofuranyl, tetrahydropyranyl, pyrazolyl oxadiazolyl (optionally substituted with CH3); phenyl (one or more F optionally substituted by 2-pyridyl, 3-pyridyl, 4-pyridyl, O-2-pyridyl one or more independently selected from O-pyridyl, O-3-pyridyl, and O-4-pyridyl 14. The compound of embodiment 13, wherein the compound is substituted with a substituent of (Aspect 21) Ring A is piperidyl and is selected from the group consisting of F, CH3, CH2CH3, isopropyl, t-butyl, CHF2, CF3, OH, OCH3, OCH2CH3, O-isopropyl, O-isobutyl OCF3, Ot-butyl, OCF3, O-cyclobutyl, OCH2-cyclopropyl, CON (CH3)2, SO2CH2CH3, SO2-isopropyl, cyclopropyl, pyrrolide nyl, isothiazolidine 1,1-dioxidyl, morpholinyl; tetrahydropyranyl, Pyrazolyl, oxadiazolyl (substituted by CH3); phenyl (one or more substituted by F; 1 independently selected from 2-pyridyl and O-2-pyridyl 14. The compound of embodiment 13, wherein the compound is substituted with one or more substituents. (Aspect 22) Ring A is piperazinyl, and C 1-6 Alkyl, SO2(C 1-4 alkyl), -( C 0-3alkyl)-(C 3-7 cycloalkyl), aryl, heteroaryl, and C substituted by one or more substituents independently selected from O-aryl; The alkyl, cycloalkyl, aryl, or heteroaryl may be optionally substituted. 14. The compound of embodiment 13. (Aspect 23) Ring A is piperazinyl, CH3, CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, CF3, CH2CF3, CH( CH3)CF3, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl propyl, cyclobutyl, (CH2)cyclopropyl, (CH2)cyclobutyl, phenyl (optionally substituted by one or more of Cl, F, CN, CH3, CONH2); azolyl (optionally substituted with CH3 or CH2CH3); oxazolyl (CH3 or CH2CH3 optionally substituted; oxadiazolyl (CH3 or CH2 optionally substituted with CH3; thiadiazolyl (CH3, CH2CH3, or CF 2-pyridyl, 3-pyridyl, or 4-pyridyl (respectively is Cl, F, CF3, CN, CONH2, CONH(CH3), or CON(CH3 )2 optionally substituted); pyrazinyl (optionally substituted by CH3 or CH2CH3 substituted); pyrimidyl (optionally substituted with OCH3); benzisoxazolyl and CO(phenyl), wherein said phenyl is optionally fluorinated. 14. The compound of embodiment 13, wherein the compound is substituted with one or more substituents selected from the group consisting of: (Aspect 24) Ring A is piperazinyl, CH3, isopropyl, t-butyl, CH(CH3)C F3, SO2CH2CH3, SO2-isopropyl, cyclopropyl, cyclobutyl, ( CH2) cyclopropyl, phenyl (one or more of Cl, F, CN, CH3, CON optionally substituted with H2); pyrazolyl (optionally substituted with CH3); oxazolyl oxadiazolyl (optionally substituted by CH3); oxadiazolyl (optionally substituted by CH2CH3) thiadiazolyl (optionally substituted by CH3 or CH2CH3) 2-pyridyl (optionally substituted with Cl, F, CF3, CN, or CONH2) 3-pyridyl (optionally substituted by CF3, CN, CONH2, or CON(CH3)2) substituted); 4-pyridyl (optionally substituted with CONH2); pyrazinyl (CH3 pyrimidyl (optionally substituted with OCH3); benzoyl and CO(phenyl), wherein the phenyl is optionally fluorinated. The compound according to embodiment 13, substituted with one or more substituents independently selected from Compound. (Aspect 25) The compound according to embodiment 13, wherein ring A is morpholinyl, R is F or CH3, and n is 1. Compound. (Aspect 26) Ring A is 5-azaspiro[2,3]hexyl; 2-azaspiro[3.3]heptyl; 2 -Oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5 -Oxa-2-azaspiro[3.4]octyl; 6-Oxa-2-azaspiro[3.4] Octyl;2-Azaspiro[3.5]nonyl;7-Oxa-2-azaspiro[3.5]nonyl Nil; octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexa hydrocyclopenta[c]pyrrolyl; 6-azaspiro[3.4]octyl; 2-oxa- 6-azaspiro[3.4]octyl; 6-azaspiro[2.5]octyl; 7-azaspi ro[3.5]nonyl; 1-oxa-8-azaspiro[4.5]decanyl; 2-oxa-8 -azaspiro[4.5]decanyl; 2,8-diazaspiro[4.5]decan-1-onyl ; 3-oxa-9-azaspiro[5.5]undecanyl; 1,4-oxazepanyl; 8- (2) azabicyclo[3.2.1]octyl; and isoindolinyl (each of which is optionally substituted by one or more CH3 or F), a compound according to embodiment 13. (Embodiment 27) A compound according to any one of embodiments 1 to 26, wherein R is F. (Embodiment 28) A compound according to any one of embodiments 1 to 26, wherein R is CH3. (Embodiment 29) A compound according to any one of embodiments 1 to 28, wherein n is 1. (Embodiment 30) A compound according to embodiment 1, wherein the compound is selected from Table 1. (Embodiment 31) A pharmaceutical composition comprising an effective amount of a compound according to any one of embodiments 1 to 30, or a pharmaceutically acceptable salt, tautomer, isotope-substituted form, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle. (Embodiment 32) An effective amount of a compound according to any one of embodiments 1 to `30, or a pharmaceutical composition according to embodiment 31, administered to a subject in need thereof, diffuse large B-cell lymphoma (DLBCL) treatment method. (Embodiment 33) 33. The method of claim 32, wherein the DLBCL is relapsed or refractory DLBCL. How to do it. (Aspect 34) The DLBCL is treated with rituximab, cyclophosphamide, doxorubicin, vincristine, tin, prednisone, etoposide, bendamustine, lenalidomide, or gemcitabine 34. The method of embodiment 33, wherein the patient is refractory to one or more of: (Aspect 35) The method of embodiment 32, wherein the DLBCL is newly diagnosed DLBCL. (Aspect 36) Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone , etoposide, bendamustine, lenalidomide, or gemcitabine or 36. The method of any one of aspects 32-35, further comprising administering a plurality of (Aspect 37) For use in methods for the treatment of diffuse large B-cell lymphoma (DLBCL) The compound according to any one of Aspects 1 to 30 or the pharmaceutical composition according to Aspect 31. The method comprises administering an effective amount of the compound or the pharmaceutical composition to a subject in need thereof. administering said compound or said pharmaceutical composition. (Aspect 38) 38. The method of claim 37, wherein the DLBCL is relapsed or refractory DLBCL. Compound or pharmaceutical composition for use. (Aspect 39) The DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, tin, prednisone, etoposide, bendamustine, lenalidomide, or gemcitabine 39. The compound or compounds for use according to embodiment 38, wherein the patient is refractory to one or more of or pharmaceutical compositions. (Aspect 40) 38. The use according to aspect 37, wherein the DLBCL is newly diagnosed DLBCL. A compound or pharmaceutical composition of (Aspect 41) Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone , etoposide, bendamustine, lenalidomide, or gemcitabine or 41. The use according to any one of aspects 37 to 40, further comprising administering a plurality of Compound or pharmaceutical composition. (Aspect 42) Compounds of formula (I): (C13) TIFF0007745679000134.tif35170, a method for preparing the Compounds of formula (Ia): (C14) TIFF0007745679000135.tif35170, (C15) TIFF0007745679000136.tif16170 and In the presence of a base, in a solvent, a compound of formula (I), Ring A is an optionally substituted non-aromatic heterocyclyl; Each R is independently substituted or unsubstituted C 1-3 Alkyl or halogen the law of nature; n is 0, 1, 2, 3 or 4; LG is OM, OT, or halogen) Under conditions suitable to provide The method comprising contacting.

Claims

1. Compounds of formula (I): 【Chemical 1】 1. A method for preparing Compounds of formula (Ia): 【Chemistry 2】 of, 【Chemistry 3】 and, In the presence of a base, in a solvent, a compound of formula (I), Ring A is an optionally substituted non-aromatic heterocyclyl; Each R is independently substituted or unsubstituted C １－３ is alkyl or halogen; n is 0, 1, 2, 3, or 4; and LG is OM, OT, or halogen. Under conditions suitable to provide The method comprising contacting.

2. Ring A is azetidyl; piperidyl; piperazinyl; morpholinyl; 5-azaspiro[2,3]hexyl; 2-azaspiro[3.3]heptyl; 2-oxa-6-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 6-oxa-2-azaspiro[3.4]octyl; 2-azaspiro[3.5]nonyl; 7-oxa-2-azaspiro[3.5]nonyl; octahydrocyclopenta[c]pyrrolyl; 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrolyl; 6-azaspiro[c]pyrrolyl; 2,8-diazaspiro[4.5]decane-1-onyl; 3-oxa-9-azaspiro[5.5]undecanyl; 1,4-oxazepanyl; 8-azabicyclo[3.2.1]octyl; or isoindolinyl.

3. 2. The method of claim 1, wherein Ring A is an optionally substituted non-aromatic heterocyclyl selected from azetidyl; piperidyl; piperazinyl; 2-azaspiro[3.3]heptyl; 2-azaspiro[3.4]octyl; 5-oxa-2-azaspiro[3.4]octyl; 7-oxa-2-azaspiro[3.5]nonyl; 1-oxa-8-azaspiro[4.5]decanyl; or 2,8-diazaspiro[4.5]decan-1-onyl.

4. The method of any one of claims 1 to 3, wherein LG is Cl.

5. The method of any one of claims 1 to 3, wherein LG is Br.

6. The base is DIEA, TEA, Na ２ CO ３ , K. ２ CO ３ , or Cs ２ CO ３ The method according to any one of claims 1 to 5, wherein

7. The solvent is DMSO, DMF, DMA, NMP, or CH ３ 7. The method according to claim 1, wherein the compound is CN.

8. The method of any one of claims 1 to 7, wherein the contacting is carried out at a temperature of from 25 to 80°C.

9. preparing a compound of formula (Ia) Compound of formula (Ib) 【Chemistry 4】 of, (a) When LG is Cl, CH ３ SO ２ Cl, SOCl ２ , or Ph ３ P-CCl ４ and; (b) When LG is Br, SOBr ２ , Ph ３ P-Br ２ , or PBr ３ and; (c) If LG is OM, then CH ３ SO ２ Cl or methanesulfonic anhydride; (d) with TsCl when LG is OT; in a solvent under conditions suitable to provide said compound of formula (Ia), The method of any one of claims 1 to 8, comprising contacting

10. 10. The method of claim 9, wherein the solvent is DCM, ether, or toluene.

11. 11. The method of claim 9 or 10, wherein the contacting is carried out at a temperature of 0 to 25°C.

12. preparing a compound of formula (Ib) Compound of formula (Ic) 【Chemistry 5】 of, In a solvent, the compound of formula (Ib) Ｏ is a hydroxyl protecting group), The method of any one of claims 9 to 11, comprising deprotecting.

13. P Ｏ 13. The method of claim 12, wherein is a silyl ether and the deprotection is by treatment with an acid or TBAF.

14. The acid is H ２ SO ４ or HCl.

15. The method according to any one of claims 12 to 14, wherein the solvent is THF or an aqueous THF solution.

16. The method of any one of claims 12 to 15, wherein the deprotection is carried out at a temperature of 0 to 60°C.

17. preparing a compound of formula (Ic) Compound of formula (Id) 【Chemistry 6】 of, 3-aminopiperidine-2,6-dione and a base under conditions suitable to provide the compound of formula (Ic) wherein R' is H; The method of any one of claims 12 to 16, comprising contacting

18. 18. The method of claim 17, wherein the base is pyridine.

19. 19. The method of claim 17 or 18, wherein the contacting is carried out at a temperature of from 25 to 130°C.

20. preparing a compound of formula (Ib) Compound of formula (Ie) 【Chemistry 7】 of, 3-aminopiperidine-2,6-dione and a base under conditions suitable to provide the compound of formula (Ib), The method of any one of claims 9 to 11, comprising contacting

21. 21. The method of claim 20, wherein the base is pyridine.

22. 22. The method of claim 20 or 21, wherein the contacting is carried out at a temperature of from 25 to 120°C.

23. preparing a compound of formula (Ie), Compound of formula (Id) 【Chemistry 8】 of, The compound of formula (Ie) １－２ alkyl, and P Ｏ is a hydroxyl protecting group), The method of any one of claims 20 to 22, comprising deprotecting.

24. P Ｏ 24. The method of claim 23, wherein: is a silyl ether and the deprotection is by treatment with a base in a solvent.

25. 25. The method of claim 24, wherein the base is NaOH.

26. 26. The method of claim 24 or 25, wherein the solvent is aqueous THF.

27. 27. The method of any one of claims 23 to 26, wherein the deprotection is carried out at a temperature of 0 to 60°C.

28. preparing a compound of formula (Id) Compound of formula (If) 【Chemistry 9】 of, Compound of formula (Ig) 【Chemistry 10】 and, In the presence of a reductive amination agent and an acid, in a solvent, the compound of formula (Id) (wherein R' is H or C １－２ under conditions suitable to provide a methyl group, 28. The method of any one of claims 23 to 27, comprising contacting

29. The reductive aminating agent is BH ３ 2-methylpyridine, B １０ H １４ , or NaBH(OAc) ３ 29. The method of claim 28, wherein:

30. The solvents are MeOH, dioxane, DCM, 1,2-dichloroethane, CH ３ 30. The method of claim 28 or 29, wherein the solvent is CN, THF, or a mixture thereof.

31. The method of any one of claims 28 to 30, wherein the acid is acetic acid or TFA.

32. 32. The method of any one of claims 28 to 31, wherein the contacting is carried out at a temperature of 0 to 25°C.

33. preparing a compound of formula (Ib) Compound of formula (Ih) 【Chemistry 11】 of, Compound of formula (Ii) 【Chemistry 12】 in the presence of a reducing agent, in a solvent, under conditions suitable to provide the compound of formula (Ib), The method of any one of claims 9 to 11, comprising contacting

34. The reducing agent is B １０ H １４ 34. The method of claim 33, wherein:

35. 35. The method of claim 33 or 34, wherein the solvent is MeOH, dioxane, or a mixture thereof.

36. 36. The method of any one of claims 33 to 35, wherein the contacting is carried out at a temperature of 0 to 25°C.

37. preparing a compound of formula (Ih), 【Chemistry 13】 of, in the presence of a reducing agent, in a solvent, under conditions suitable to provide the compound of formula (Ih), 37. The method of any one of claims 33 to 36, comprising reducing.

38. 38. The method of claim 37, wherein the reducing agent is hydrogen gas in the presence of a catalyst.

39. 39. The method of claim 38, wherein the catalyst is Pd / C, Ni, or Pt.

40. The reducing agent is HCl, acetic acid, or NH ４ 38. The method of claim 37, wherein the metal is Fe or Zn in the presence of Cl.

41. The reducing agent is SnCl ２ 38. The method of claim 37, wherein:

42. 42. The method of any one of claims 37 to 41, wherein the solvent is DMA, EtOH, water, EtOAc, DMF, or EtOAc / DMF.

43. 43. The method of any one of claims 37 to 42, wherein the reduction is carried out at a temperature of from 0 to 60°C.

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