Spirocycloalkyl compounds that modulate IKZF2 and pharmaceutical compositions

Abstract

Disclosed are compounds and salts thereof that bind to and modulate the activity of cereblon. In some embodiments, the binding and modulation of cereblon results in the degradation of IKAROS family zinc finger proteins (e.g., IKZF2). The compounds are represented by Formula I: TIFF2026502995000081.tif43170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 478,449, filed January 4, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure provides compounds and salts thereof that bind to cereblon and thereby modulate its activity. In some embodiments, certain compounds described herein bind to cereblon, thereby reducing cellular IKAROS family zinc finger (IKZF) protein levels. In some embodiments, certain compounds described herein bind to cereblon but do not thereby reduce cellular IKZF protein levels. In some embodiments, compounds disclosed herein bind to cereblon, thereby initiating degradation of IKZF proteins (e.g., IKZF2). Also disclosed are pharmaceutical compositions comprising the above-described compounds or salts thereof (e.g., pharmaceutically acceptable salts thereof), as well as methods of using such compounds and / or salts thereof to treat various diseases or disorders mediated by IKZF2. [Background technology]

[0003] IKAROS family zinc finger 2 (IKZF2) (also known as Helios) is one of five members of the Ikaros transcription factor family found in mammals. IKZF2 is a key regulator of T cell activity and function. Genetic deletion of Helios enhanced antitumor immune responses (Kim et al., Science 350:334-339 (2015)). In particular, Helios is highly expressed in regulatory T cells (Tregs) (Elkord et al., Expert Opin. Biol. Ther. 12:1423-1425 (2012)), a subpopulation of T cells that limit the activity of effector T cells. Selective deletion of Helios in regulatory T cells resulted in both loss of suppressive activity and acquisition of effector T cell function (Najagawa et al., Proc. Natl. Acad. Sci. USA 113:6248-6253 (2016); Yates et al., Proc. Natl. Acad. Sci. USA 115:2162-2167 (2018)). Thus, Helios is a key factor limiting T cell effector function in Tregs.

[0004] Helios expression has also been reported to be upregulated in "exhausted" T cells in the context of two types of chronic viral infection (Crawford et al., Immunity 40:289-302 (2014), Doering et al., Immunity 371130-1144 (2012); Scott-Browne et al., Immunity 45:1327-1340 (2016)) and tumors (Martinez et al., Immunity 42:265-278 (2015); Mognol et al., Proc. Natl. Acad. Sci. USA 114:E2776-E2785 (2017); Pereira et al., J. Leukoc. Biol. 102:601-615 (2017); Singer et al., Cell 166:1500-1511 (2016); Schietinger et al., Immunity 45:389-401 (2016)), and dysfunctional chimeric antigen receptor (CAR) T cells (Long et al., Nat. Med. 21:581-590 (2015)). Overexpression or aberrant expression of Helios and various splice isoforms has been reported in several hematological malignancies, including T-cell leukemia and lymphoma (Nakase et al., Exp. Hematol. 30:313-317 (2002); Tabayashi et al., Cancer Sci. 98:182-188 (2007); Asanuma et al., Cancer Sci. 104:1097-1106 (2013)). Furthermore, knockdown of Helios in a mixed lineage leukemia (MLL)-induced myeloid leukemia model effectively suppressed proliferation and increased cell death (Park et al., J. Clin. Invest. 125:1286-1298 (2015); Park et al., Cell Stem Cell 24:153-165 (2019)).

[0005] Anti-CTLA4 antibodies are currently used clinically to target Tregs in tumors. However, targeting CTLA4 often leads to systemic activation of T effector cells, resulting in excessive toxicity and limiting the effectiveness of the treatment. Grade 3 or higher adverse events have been reported in up to 75% of patients treated with anti-PD1 and anti-CTLA4 combination therapy (National Cancer Institute, Division of Cancer Treatment and Diagnosis, Common Terminology for Adverse Events (CTCAE), https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm).

[0006] There is a need for therapies that can target Tregs in tumors without causing systemic activation of T effector cells. Thus, IKZF2-specific modulators or degraders may focus enhanced immune responses in tumor or peritumoral regions, potentially providing better-tolerated and less toxic therapies for the treatment of IKZF2-mediated diseases. Summary of the Invention

[0007] Compounds that bind to cereblon and thereby modulate its activity are disclosed. In some embodiments, certain compounds described herein bind to cereblon, thereby reducing cellular IKAROS family zinc finger (IKZF) protein levels. In some embodiments, certain compounds described herein bind to cereblon but do not thereby reduce cellular IKZF protein levels. In some embodiments, certain compounds disclosed herein bind to cereblon, thereby initiating the degradation of IKZF proteins (e.g., IKZF2). Also disclosed are pharmaceutical compositions comprising the above-described compounds, or salts thereof (e.g., pharmaceutically acceptable salts thereof), and methods of using the compounds and / or salts thereof to treat various diseases or disorders mediated by IKZF2, including, for example, cancer.

[0008] In one embodiment, the disclosed compounds that bind to and regulate cereblon and optionally degrade IKZF2 are compounds of Formula I: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, and R of formula I 1 , R 2 , R 3 , R 4 , R 11 , X, Y, Z, Z 1 , m, n, p, q, r, s, t, and u are as defined in the detailed description and throughout this specification.

[0009] In one embodiment, the disclosed compound that binds to and regulates cereblon and optionally degrades IKZF2 is a compound represented by Formula II: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, and R of Formula II 1 , R 2 , R 3 , R 4 , R 11 , X, Y, Z, Z 1 , m, n, p, s, t, and u are as defined in the detailed description and throughout this specification.

[0010] In one embodiment, the disclosed compound that binds to and regulates cereblon and optionally degrades IKZF2 is a compound represented by formula III: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, and R of formula III 1 , R 2 , R 3 , R 4 , R 11 , Y, Z, Z 1, m, n, t, and u are as defined in the detailed description and throughout this specification.

[0011] In one embodiment, the disclosed compound that binds to and regulates cereblon and optionally degrades IKZF2 is a compound represented by formula IV: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 3 , R 4 , Y, Z, Z 1 is as defined in the detailed description and throughout this specification.

[0012] In one embodiment, the disclosed compound that binds to and regulates cereblon and optionally degrades IKZF2 is a compound represented by Formula V: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R of formula V 4 , R 7 , Y, Z, and Z 1 is as defined in the detailed description and throughout this specification.

[0013] In one embodiment, the disclosed compound that binds to and regulates cereblon and optionally degrades IKZF2 is a compound represented by formula VI: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R of formula VI 4 , R 7 , Y, Z, and Z 1 is as defined in the detailed description and throughout this specification.

[0014] In one embodiment, there is provided a compound of Formula I or a subformula thereof that selectively modulates IKZF (e.g., over translation termination factor GSPT1 (G1 to S phase transition 1 protein)). In one embodiment, there is provided a compound of Formula I or a subformula thereof that selectively modulates IKZF2 over GSPT1.

[0015] In one embodiment, there is provided a composition comprising a compound of Formula I or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer of a compound of Formula I or any subformula thereof. "Compounds of Formula I and its subformulas" refers to compounds of Formula I, II or subformulas III, IV, V, and VI as defined herein.

[0016] In one embodiment, the disclosure provides a method of modulating cereblon, the method comprising contacting cereblon with an effective amount of a compound of Formula I, II or subformulas III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions such that cereblon is modulated.

[0017] In one embodiment, the present disclosure provides a method for degrading IKZF2, the method comprising contacting IKZF2 with an effective amount of a compound of Formula I, II or its subformulas III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions in which IKZF2 is degraded.

[0018] In one embodiment, a method for degrading IKZF2 in a subject is provided, the method comprising administering to the subject an effective amount of a compound of Formula I, II or its subformulas III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or administering to the subject a pharmaceutical composition comprising an effective amount of a compound of Formula I, II or its subformulas III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable excipient.

[0019] Further provided is a method for treating cancer in a subject in need thereof, the method comprising selecting a subject whose cancer is at least partially mediated by IKZF2, and administering to the subject an effective amount of a compound of Formula I, II, or its subformulas III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I, II, or its subformulas III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure provides compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions mediated, at least in part, by the IKZF2 transcription factor. However, prior to describing the disclosure in detail, the following terms are first defined. Unless defined, terms used herein have their generally accepted scientific meaning.

[0021] definition The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0022] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. The use of dashes at the beginning or end of a chemical group is a matter of convenience, and a chemical group may be represented using one or more dashes without loss of ordinary meaning. A wavy or dashed line drawn across a line in a structure indicates a particular point of attachment of the group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are written or designated.

[0023] "C u-v " prefix indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0024] The term "about," when used before a numerical designation including a range, such as temperature, time, amount, concentration, etc., indicates an approximation that may vary by (±) 10%, 5%, 1%, or any subrange or subvalue therebetween. In one embodiment, the term "about" used in reference to a dosage means that the dosage may vary by ±10%.

[0025] By "comprising" or "comprises," it is intended that the compositions and methods include the recited elements, but do not exclude other elements.

[0026] When used to define compositions and methods, "consisting essentially of" shall mean excluding other elements of any essential importance to the recited combination. Thus, a composition consisting essentially of elements as defined herein will not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.

[0027] "Consisting of" shall mean excluding more than trace amounts of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0028] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbon atoms may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0029] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups may also be referred to as "alkylene" or "alkylenyl" groups (e.g., methylenyl, ethylenyl, propylenyl), "arylene" or "arylenyl" groups (e.g., phenylenyl or naphthylenyl, or, in the case of heteroarylene, quinolinyl), respectively. Also, unless otherwise noted, when a combination of groups is referred to herein as a single moiety (e.g., arylalkyl or aralkyl), the last-mentioned group includes the atom through which the moiety is attached to the remainder of the molecule.

[0030] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0031] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0032] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0033] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0034] "Acyl" is -C(O)R y R refers to the group y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl. Each may be unsubstituted or substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0035] "Amide" is -C(O)NR y R z "C-amido" group, which refers to the group -NR y C(O)R z The "N-amido" group refers to both the y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein, or R y and R z together form a cycloalkyl or heterocyclyl, each of which may be unsubstituted or substituted as defined herein.

[0036] "Amino" is -NR y Rz R refers to the group y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0037] "(Alkyl)amino" refers to -NH(alkyl). For example, "(C1-C4 alkyl)amino" refers to an amine substituted with an alkyl group having from 1 to 4 carbon atoms. "Di-(alkyl)amino" refers to -N(alkyl). For example, "di-(C1-C4 alkyl)amino" refers to an amine substituted with two alkyl groups having from 1 to 4 carbon atoms.

[0038] "Amidino" is -C(NR y )(NR z 2), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0039] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused rings. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 ring carbon atoms (i.e., C 6-12 aryl), or 6 to 10 ring carbon atoms (i.e., C 6-10aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, anthryl, etc. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl regardless of the point of attachment. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl regardless of the point of attachment. When one or more aryl groups are fused to a cycloalkyl, the resulting ring system is a cycloalkyl regardless of the point of attachment.

[0040] "Carbamoyl" is -OC(O)NR y R z "O-carbamoyl" refers to the -NR group y C(O)OR z The term "N-carbamoyl" refers to both the N- and N-carbamoyl groups, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0041] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x Here, R refers to both x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0042] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cyclic groups having at least one sp 3As used herein, "cycloalkyl" refers to a fused carbocyclic ring system having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decanyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aryl ring, with or without attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0043] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0044] "Imino" is -C(NR y )R z R refers to the group y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0045] "Imide" is -C(O)NR y C(O)R z R refers to the group y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0046] "Guanidino" refers to the group -NHC(=NH)NH2.

[0047] "Halogen" or "halo" refers to an atom in Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0048] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced with halogen. For example, if a residue is substituted with multiple halogens, it can be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, where the halo groups are not necessarily the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0049] "Haloalkoxy" refers to an alkoxy group as defined above in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced with halogen.

[0050] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms have been replaced by hydroxy groups.

[0051] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and associated hydrogen atoms), excluding the terminal carbon atom(s), are each independently replaced with the same or different heteroatom groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced with the same or different heteroatom groups. Heteroatom groups include -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl. Each can be unsubstituted or substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., --CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc.), where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein. As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0052] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple condensed rings, where one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 ring carbon atoms (i.e., C 3-8Heteroaryl) and contains 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In some cases, heteroaryl includes 5- to 10-membered, 5- to 7-membered, or 5- to 6-membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothianiyl, isothiazolyl, thiophenyl (i.e., thienyl), imidazolyl, indazolyl, indolyl, Includes indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl can be attached via any ring of the fused system. Aromatic rings containing at least one heteroatom and having single or multiple fused rings are considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., via any of the fused rings).Heteroaryl does not encompass or overlap with aryl, as defined above.

[0053] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0054] "Heterocyclyl" (used interchangeably with "heterocycloalkyl") refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl may be monocyclic or multicyclic, and the multicyclic rings may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - ) moiety. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of attachment (i.e., it can be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass non-aromatic rings containing at least one heteroatom, which ring can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclyl) has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindoline, and the like.

[0033] The term "heterocyclyl" includes "spiroheterocyclyl" when there are two substitution positions on the same carbon atom. Examples of spiroheterocycles include bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, and the heterocyclyl can be attached via either ring of the fused system. In some embodiments, heterocycloalkyls can be substituted with oxo group(s) on the heteroatom (e.g., S=O, S(=O)).

[0055] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0056] "Oxime" is -CR y (=NOH) group, R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0057] "Oxo" refers to the moiety =O.

[0058] "Sulfonyl" is -S(O)R y R refers to the group y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl. Each may be unsubstituted or substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0059] "Sulfinyl" is -S(O)R y R refers to the group y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl. Each may be unsubstituted or substituted as defined herein. Examples of sulfinyl include methylsulfinyl, ethylsulfinyl, phenylsulfinyl, toluenesulfinyl, and the like.

[0060] "Sulfonamide" is -SO2NR y R z and -NR y SO2R z R refers to the group y and R zare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0061] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and include cases where the event or circumstance occurs and cases where the event or circumstance does not occur. Also, the term "optionally substituted" refers to any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group that may or may not be replaced with a non-hydrogen moiety.

[0062] As used herein, the term "substituted" means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl), at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced with a bond to a non-hydrogen atom, and the non-hydrogen atom can be, for example, an alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, or the like. , azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y)3, each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0063] In certain embodiments, "substituted" includes any combination of substituted or unsubstituted groups, in which one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O) 1-2 R h , -C(O)R g , -C(O)OR g , -OC(O)OR g , -OC(O)R g , -C(O)NR g R h , -OC(O)NR g R h , -OR g , -SR g , -S(O)R g , -S(O)2R g , -OS(O) 1-2 R g , -S(O) 1-2 OR g , -NR g S(O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(O) 1-2 NR g R h, -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" refers to one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms being replaced with -C(O)R. g , -C(O)OR g , -C(O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" refers to any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced with a bond to amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h taken together with the atom to which they are attached form a heterocyclyl ring that is unsubstituted or substituted with oxo, halo, or alkyl, or form a heterocyclyl ring that is unsubstituted or substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0064] Polymers or similar undefined structures obtained by defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to [(substituted aryl)substituted aryl]substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorine atoms or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein.

[0065] In certain embodiments, the phrase "one or more," as used herein, refers to 1 to 5. In certain embodiments, the phrase "one or more," as used herein, refers to 1 to 3.

[0066] Any compound or structure provided herein is also intended to represent unlabeled and isotopically labeled forms of the compound. These forms of compounds are also referred to as "isotopically enriched analogs." Isotopically labeled compounds have the structure shown herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P,32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, and 14 and those into which a radioactive isotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques including metabolism studies, reaction kinetic studies, drug or substrate tissue distribution assays, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in radiotherapy of patients.

[0067] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens (e.g., hydrogens on carbon atoms) are replaced with deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0068] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, or 11C-labeled compounds can be useful for PET, SPECT, or other imaging studies. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents with non-isotopically labeled reagents, and carrying out the procedures disclosed in the schemes or in the examples and preparations described below. It is understood that deuterium in this context is considered a substituent in the compounds provided in the present disclosure.

[0069] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0070] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0071] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0072] The term "solvate" can include, but is not limited to, solvates that retain one or more activity and / or properties of a compound and are not undesirable. Examples of solvates include, but are not limited to, a compound in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or a combination thereof.

[0073] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkylamines Suitable amines include, but are not limited to, salts of primary, secondary, and tertiary amines such as alkenylamines (i.e., NH(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)), mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or tri-arylamines (i.e., NH(aryl), HN(aryl), N(aryl)), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0074] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, one skilled in the art will understand that the compound includes both the amide and imidic acid tautomers. Thus, an amide-containing compound is understood to include its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to include its amide tautomer.

[0075] The compounds, or pharmaceutically acceptable salts thereof, may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)- (or, in the case of amino acids, (D)- or (L)-). The present disclosure is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and / or fractional crystallization. Prior techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0076] "Stereoisomer" refers to a compound consisting of the same atoms connected by the same bonds, but having different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0077] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0078] Relative centers of compounds depicted herein are depicted using a "bold bond" style (bold or parallel lines) and absolute stereochemistry is represented using a wedge bond (bold or parallel lines).

[0079] "Prodrug" refers to any compound that, upon administration to a mammalian subject, releases an active parent drug in vivo according to the structure described herein. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein so that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds described herein in such a way that the modifications are cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like, of the hydroxy functional groups of the compounds described herein. The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series; "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0080] compound In some embodiments, compounds of Formula I bind to and regulate cereblon and optionally degrade IKZF2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; During the ceremony, m and p are each 0, 1, 2, or 3; n is 0, 1, or 2; q is 1, 2, or 3; r is 0, 1, or 2; s is 0 if r is not 0, and 1 if r is 0; t is 0 or 1, u is 1 or 2, X is hydrogen, deuterium, or fluoro; Y is oxygen or NR, R is hydrogen or C1-C4 alkyl, Z and Z 1 are each independently CR 1 or N, Each R 1 is hydrogen, amino, unsubstituted, or 1 to 3 R 5 (C1-C4 alkyl)amino substituted with a substituent, unsubstituted, or 1 to 3 R in each alkyl group 5 Substituted di-(C1-C4 alkyl)amino, cyano, halo, hydroxyl, unsubstituted or 1-3 R 5 C1-C4 alkyl substituted with a substituent, and unsubstituted or 1 to 3 R 5 C1-C4 alkoxy substituted with a substituent; or Z 1 is CR 1 If two adjacent R 1 together with the carbon atoms to which they are attached, form C3-C7 cycloalkyl, C6-C 10forming a 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from aryl, oxygen, nitrogen, or sulfur, or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from 1 to 3 R 6 independently substituted with groups, Each R 2 is cyano, halo, hydroxyl, amino, unsubstituted or 1-3 R 5 C1-C4 alkylamino substituted with a substituent, unsubstituted or 1 to 3 R on each alkyl group 5 Di-(C1-C4 alkyl)amino substituted with a substituent, unsubstituted or 1 to 3 R 5 C1-C4 alkyl substituted with a substituent, and unsubstituted or 1 to 3 R 5 C1-C4 alkoxy substituted by a substituent; Each R 3 Each of these, together with the carbon atoms attached to it, is made up of 1 to 3 R 7 forming a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocycloalkyl substituted by a substituent, R 4 is hydrogen and -CH2-OR 8 Selected from R 8 is C(O)-R 9 or -P(O)(OR 10 )2 and R 9 is C1-C4 alkyl, or C1-C4 alkoxy, and each R 10 are independently H or C1-C4 alkyl. Each R 5 are independently amino, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxyl, or C1-C4 alkoxy; Each R 6 is independently selected from amino, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxyl, and oxo; Each R7 are independently selected from amino, C1-C4 alkyl unsubstituted or substituted with 1-3 halo, C1-C4 alkoxy unsubstituted or substituted with 1-3 halo, (C1-C4 alkyl)amino, di-C1-C4 alkyl)amino, cyano, halo, hydroxyl, nitro, oxo, C5-C6 heteroaryl having 1-3 heteroatoms selected from O, NR, and / or S, 4- to 7-membered heterocycloalkyl having 1-3 heteroatoms selected from oxygen, nitrogen, and / or sulfur, and —C(O)CH3; and R 11 is hydroxyl, halo, or cyano.

[0081] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula II: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , X, Y, Z, Z 1 , m, n, p, s, t, and u are as defined herein.

[0082] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula II-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , X, Y, Z, Z 1, m, n, p, s, t, and u are as defined herein.

[0083] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula II-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , X, Y, Z, Z 1 , m, n, p, s, t, and u are as defined herein.

[0084] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIA: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , m, n, p, t, and u are as defined herein.

[0085] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIA-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R11 , m, n, p, t, and u are as defined herein.

[0086] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIA-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , m, n, p, t, and u are as defined herein.

[0087] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIB: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , m, n, t, and u are as defined herein.

[0088] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIB-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11, m, n, t, and u are as defined herein.

[0089] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIB-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , m, n, t, and u are as defined herein.

[0090] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIC: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , m, and t are as defined herein.

[0091] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIC-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11, m, and t are as defined herein.

[0092] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIC-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , m, and t are as defined herein.

[0093] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IID: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 3 , and R 4 is as defined herein.

[0094] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IID-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 3 , and R 4 is as defined herein.

[0095] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IID-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 3 , and R 4 is as defined herein.

[0096] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIE: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 7 is as defined herein.

[0097] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIE-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 7 is as defined herein.

[0098] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IIE-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 7is as defined herein.

[0099] In some embodiments, in the compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, X is hydrogen, deuterium, or fluoro. In some embodiments, in the compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, X is hydrogen. In some embodiments, in the compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, X is deuterium. In some embodiments, in the compound of Formula I or II, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, X is fluoro.

[0100] In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, q is 1, r is 1, and s is 0. In some embodiments, in a compound of formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, q is 1, r is 0, and s is 1.

[0101] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, m is 0. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, m is 1. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, m is 2. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, m is 3.

[0102] In some embodiments, in the compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, n is 0. In some embodiments, in the compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, n is 1. In some embodiments, in the compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, n is 2.

[0103] In some embodiments, in the compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, u is 1. In some embodiments, in the compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, u is 2.

[0104] In some embodiments, in a compound of Formula I, II, or a subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, p is 0. In some embodiments, in a compound of Formula I, II, or a subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, p is 1. In some embodiments, in a compound of Formula I, II, or a subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, p is 2. In some embodiments, in a compound of Formula I, II, or a subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, p is 3.

[0105] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, t is 0. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, t is 1.

[0106] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, R 4 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, R 4 -CH2-OC(O)-R 9 or -CH2-OP(O)(OR 10 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, R 4 is -CH2-OC(O)-CH3, -CH2-OC(O)-CH2CH3, -CH2-OC(O)-CH2CH2CH3, or -CH2-OC(O)-CH(CH3). In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, R 4 is -CH2-OP(O)(OCH3)2, -CH2-OP(O)(OCH2CH3)2, -CH2-OP(O)(OCH2CH2CH3)2, or CH2OP(O)(O(CH(CH3)2)2).

[0107] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, Z and Z 1 are CR 1 In some such embodiments, Z and Z 1 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Z and Z are each CH. In some embodiments, in a compound of Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, Z and Z are each CH. 1 are CR 1 and one R 1 is halo, such as bromo, fluoro, or chloro, and the other R 1 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, Z and Z 1 and each is N. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, Z or Z 1 One of them is CR 1 and Z or Z 1 and the other is N. In some such embodiments, Z or Z 1 One of the groups is CH and the other is Z or Z 1 and the other is N. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, R 1 is H. In some embodiments, in Formula I, II, or subformulas thereof, Formula III, IV, V, VI, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof, one R 1 is H, and the other R 1is F. In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, V, VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, one R 1 is H, and the other R 1 is Cl. In some embodiments, Z and Z 1 are CH and R 1 is hydrogen.

[0108] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula III: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 11 , Y, Z, Z 1 , m, n, t, and u are as defined herein. In some embodiments of Formula III, Y is O. In some embodiments of Formula III, Y is NR. In some embodiments, R is hydrogen. In some embodiments, R is C1-C4 alkyl. In some embodiments of Formula III, Z and Z 1 are CH respectively.

[0109] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula IV: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 3 , R 4 , Y, Z, and Z 1is as defined herein. In some embodiments of Formula IV, Y is O. In some embodiments of Formula IV, Y is NR. In some embodiments, R is hydrogen. In some embodiments, R is C1-C4 alkyl. In some embodiments of Formula IV, Z and Z 1 are CH respectively.

[0110] In some embodiments, the compound of Formula I that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula V: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 4 , R 7 , Y, Z, and Z 1 is as defined herein. In some embodiments of Formula V, Y is O. In some embodiments of Formula V, Y is NR. In some embodiments, R is hydrogen. In some embodiments, R is C1-C4 alkyl. In some embodiments of Formula V, Z and Z 1 are CH respectively.

[0111] In some embodiments, the compound of Formula IV that binds to and regulates cereblon and optionally degrades IKZF2 is a compound having the structure of Formula VI: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, wherein R 4 , R 7 , Y, Z, and Z 1 is as defined herein. In some embodiments of Formula VI, Y is O. In some embodiments of Formula VI, Y is NR. In some embodiments, R is hydrogen. In some embodiments, R is C1-C4 alkyl. In some embodiments of Formula VI, Z and Z1 are CH respectively.

[0112] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 Each of these, together with the carbon atoms attached to it, is made up of 1 to 3 R 7 It forms a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocycloalkyl substituted with substituents.

[0113] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 Form a 6-membered cycloalkyl substituted with a substituent.

[0114] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, IV, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, each R 3 together with the carbon atom attached to it, form one to three R 7 Form a 6-membered heterocycloalkyl substituted with a substituent.

[0115] In some embodiments, in a compound of Formula I, II, or a subformula thereof, Formula III, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, [ka] is selected from.

[0116] In some embodiments, provided herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof. TIFF2026502995000032.tif194170TIFF2026502995000033.tif223170TIFF2026502995000034.tif167170

[0117] In some embodiments, provided herein is a compound that binds to cereblon selected from Table 1A, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof. TIFF2026502995000035.tif60170TIFF2026502995000036.tif95170

[0118] In some embodiments, provided herein is a compound that degrades IKZF2 selected from Table 1B, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof. TIFF2026502995000037.tif139170TIFF2026502995000038.tif250170TIFF2026502995000039.tif45170

[0119] In some embodiments, provided herein is a compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof. TIFF2026502995000040.tif54170TIFF2026502995000041.tif203170TIFF2026502995000042.tif220170TIFF20265029950 00043.tif213170TIFF2026502995000044.tif214170TIFF2026502995000045.tif230170TIFF2026502995000046.tif217170

[0120] General synthesis method The compounds of Formulas I, II, III, IV, V, and VI described herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, although such conditions can be determined by one skilled in the art by routine optimization procedures.

[0121] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in TW Greene and PG M Buts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and the references cited therein.

[0122] Furthermore, as will be apparent to those skilled in the art, intermediates and final compounds obtained as enantiomeric mixtures can be separated into their respective enantiomers by liquid chromatography using a chiral stationary phase to provide chiral selectivity. Suitable chiral stationary phases and suitable conditions for chiral separation are well known in the art. Numerous methods are described, for example, in F. Toda, Enantiomeric Separation: Fundamentals and Practical Methods, 1st Edition, Springer, Dordrecht, 2004, and the references cited therein.

[0123] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), and Emka-Chemce (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in standard references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 2016), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 2001), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 2019), March's Advanced Organic Chemistry (John Wiley and Sons, 8th Edition, 2019), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0124] Synthesis of representative compounds The general synthesis of the compounds described herein is shown in the following reaction schemes. In the schemes below, the substituent R 1 , R 2 , R 3 , R 4 , X, Y, Z, Z 1 , m, n, p, q, r, s, t, and u are as defined throughout the specification. Q is a leaving group (including but not limited to Br, Cl, I, triflate, etc.). [ka]

[0125] For the reaction of Scheme 1, in the first step, at least a stoichiometric amount of a protected amino alcohol, compound 1-2, is reacted with compound 1-1, CAS#64169-34-2 (where R 1 =H; Z and Z 1 (where each is CH) and mixed in an inert diluent such as THF, MeCN, or toluene, typically in the presence of a suitable catalyst such as Ir, Cu(OAc)2, or SmI2. The reaction is typically maintained at 20°C to 50°C until substantially complete. Conventional workup of the reaction solution, followed by isolation and / or purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide compounds 1-3.

[0126] In the next step, at least a stoichiometric equivalent of thionyl chloride is mixed with compound 1-3 in a diluent such as methanol or ethanol. The reaction is typically maintained at 50°C to 80°C until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide compound 1-4.

[0127] In the next step, at least a stoichiometric amount of 3-aminopiperidine-2,6-dione hydrochloride, CAS# 24666-56-6 (R 4 =H; X=H; q=1; r=0; s=1), compound 1-5 is mixed with compound 1-4 in an inert diluent such as dichloromethane or tetrachloromethane in the presence of a suitable base such as triethylamine, diisopropylethylamine, or pyridine. The reaction is typically maintained at 0°C to 30°C until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be performed to provide compound 1-6.

[0128] In the final step, the t-butoxycarbonyl (BOC) protecting group is removed using conventional conditions. The BOC group is merely exemplary; other conventional amino-protecting groups, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be used. Upon completion of the reaction, conventional workup of the reaction solution followed by isolation and / or purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., can be carried out to obtain compounds 1-7, which serve as intermediates for the synthesis of compounds of formula IA. [ka]

[0129] Regarding the reaction of Scheme 2, the first step is a conventional alkylation reaction in which at least a stoichiometric equivalent of alkylating reagent 2-9 is combined with dimethyl malonate, compound 2-8, in an inert diluent such as DMF, THF, or MeCN in the presence of a suitable base such as sodium hydride, LDA, n-BuLi, or cesium carbonate. Q is a leaving group (including, but not limited to, Br, Cl, I, triflate, and the like). The reaction is typically maintained at 0°C to 70°C until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide compound 2-10.

[0130] In the next step, at least a stoichiometric amount of compound 2-10 is reacted in an inert diluent, such as THF, MeCN, or toluene, in the presence of a suitable reducing agent, such as lithium aluminum hydride or borane. The reaction is typically maintained at 0°C to 30°C until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide compound 2-11.

[0131] In the next step, the diol is converted to a suitable leaving group, and at least a stoichiometric amount of tosyl chloride is added to compound 2-11 in an inert diluent, such as THF, MeCN, or toluene, in the presence of a suitable base, such as triethylamine, diisopropylethylamine, or pyridine. The reaction is typically maintained at 0°C to 30°C until substantially complete. The Ts group is illustrative only; other conventional leaving groups, such as iodo, bromo, triflate, or mesylate, can also be used. Conventional workup of the reaction solution, followed by isolation and / or purification processes, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can provide compound 2-12.

[0132] In the final step, at least a stoichiometric amount of compound 2-12 is added to compound 1-7 in an inert diluent, such as THF, MeCN, or toluene, in the presence of a suitable base, such as triethylamine, diisopropylethylamine, or pyridine. The reaction is typically maintained at 80° C. to 120° C. until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide the compound of Formula IA. [ka]

[0133] In some embodiments, compounds of Formula I and its subformulas are prepared as shown in Scheme 3. In Scheme 3, the first step is a conventional esterification and chlorination reaction in which at least a stoichiometric equivalent of thionyl chloride is reacted with 5-bromoisobenzo-1(3H)-one, CAS#64169-34-2 (where R 1 =H; Z and Z 1(wherein each is CH) is mixed with compound 3-14 in a diluent such as methanol or ethanol. The reaction is typically maintained at 50°C to 80°C until substantially complete. Conventional workup of the reaction solution followed by isolation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., can be carried out to provide compound 3-15.

[0134] In the next step, at least a stoichiometric amount of 3-aminopiperidine-2,6-dione hydrochloride, CAS# 24666-56-6 (R 4 =H; X=H; q=1; r=0; s=1), compound 1-5 is mixed with compound 3-15 in an inert diluent such as THF, DMF, MeCN, toluene, etc., typically in the presence of a suitable base such as triethylamine, diisopropylamine, DIEA, pyridine, etc. The reaction is typically maintained at 80°C to 100°C until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., can be carried out to provide compound 3-16.

[0135] In the next step, at least a stoichiometric amount of compound 3-17 is mixed with compound 3-16 in an inert diluent such as THF, MeCN, or toluene, typically in the presence of a suitable catalyst such as Ir, Cu(OAc)2, or SmI2. The reaction is typically maintained at 60°C to 80°C until substantially complete. Conventional workup of the reaction solution, followed by an isolation and / or purification process such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide compound 3-18.

[0136] In the next step, at least a stoichiometric amount of an oxidation reagent is combined with compound 3-18 under conventional oxidation reaction conditions known in the art, including the use of Jones reagent, metachloroperoxybenzoic acid (mCPBA), Dess-Martin periodinane, and the like. The reaction is typically carried out in an inert solvent, such as MeCN, THF, methylene chloride, or toluene. The reaction is typically carried out at about 0°C to about 30°C for a time sufficient for the reaction to be substantially complete, as assessed, for example, by thin layer chromatography. Upon completion of the reaction, conventional workup of the reaction solution, followed by an isolation and / or purification process, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), can be carried out to provide compound 3-19.

[0137] In the final step, at least a stoichiometric amount of the appropriate amine, compound 3-20, is combined with compound 3-19 under conventional reductive amination reaction conditions well known in the art, including the use of NaCNBH, NaBH(OAc), NaBH, and the like. The reaction is typically carried out in an inert solvent, such as MeCN, MeOH, or THF. The reaction is typically carried out at about 0° C. to about 30° C. for a time sufficient for the reaction to be substantially complete, as assessed, for example, by thin layer chromatography. Upon completion of the reaction, conventional workup of the reaction solution, followed optionally by isolation and / or purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), and the like, provides the compound of Formula I.

[0138] Other starting materials used herein are well known in the art, are commercially available, or can be prepared by conventional synthetic methods.

[0139] method In one embodiment, the compounds of Formulas I, II, III, IV, V, and VI and compositions described herein are useful in methods for modulating cereblon activity. These methods include administering to a subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0140] In one embodiment, the compounds of Formula I, II, III, IV, V, and VI, and compositions described herein, are useful in methods for treating an IKZF2-dependent disease or disorder, or a disease or disorder mediated at least in part by IKZF2. These methods comprise administering to a subject suffering from an IKZF2-dependent disease or disorder an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0141] In one embodiment, the compounds of Formula I, II, III, IV, V, and VI, and compositions described herein, selectively modulate IKZF (e.g., over the translation termination factor GSPT1). In some embodiments, the compounds of Formula I, II, III, IV, V, and VI, and compositions described herein, selectively modulate IKZF2 over GSPT1.

[0142] In one embodiment, there is provided a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for use in treating an IKZF2-dependent disease or disorder.

[0143] In one embodiment, the method relates to the use of a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for the manufacture of a medicament for reducing IKZF2 protein levels, whereby a reduction in such protein levels treats or ameliorates a disease or disorder.

[0144] In one embodiment, the methods described herein include the use of a prodrug of a compound described herein.

[0145] In one embodiment, the method relates to a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for use as described herein, to enhance cereblon target engagement dose-response IC 50 The concentration of compound required for cereblon target engagement ranges from about 0.003 μM to about 0.06 μM. Dose-response IC 50 is measured by the assays described in the Biological Examples. In some embodiments, the cereblon binding concentration is about 0.003 μM to about 0.006 μM, about 0.005 μM to about 0.008 μM, about 0.007 μM to about 0.01 μM, about 0.009 μM to about 0.012 μM, about 0.012 μM to about 0.015 μM, about 0.015 μM to about 0.018 μM, about 0.018 μM to about 0.021 μM, about 0.021 μM to about 0.024 μM, about 0.024 μM to about 0.027 μM, or about 0.027 μM to about 0.030 μM. In some embodiments, the cereblon binding concentration is less than 0.015 μM. In some embodiments, the cereblon binding concentration is less than 0.010 μM. In some embodiments, the cereblon binding concentration is less than 0.005 μM.

[0146] In one embodiment, the method relates to a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for use as described herein, wherein the compound described herein exhibits IKZF2 degradation in the range of about 25% to about 99% at a concentration of 1 μM. The degradation of IKZF2 is measured by the assay described in the Biological Examples. In some embodiments, the degradation of IKZF2 is about 25% to about 50%, about 45% to about 70%, about 65% to about 90%, or about 75% to about 99%. In some embodiments, degradation of IKZF2 is about 25% to about 35%, about 35% to about 45%, about 45% to about 55%, about 55% to about 65%, about 65% to about 75%, about 75% to about 85%, or about 85% to about 99%. In some embodiments, degradation of IKZF2 is greater than 60%. In some embodiments, degradation of IKZF2 is greater than 70%. In some embodiments, degradation of IKZF2 is greater than 80%. In some embodiments, degradation of IKZF2 is greater than 90%.

[0147] Non-limiting examples of IKZF2-dependent diseases or disorders include non-cancerous or cancerous proliferative diseases or disorders.

[0148] Examples of non-cancerous conditions or disorders include rheumatoid arthritis, inflammation, autoimmune diseases, lymphoproliferative disorders, acromegaly, ankylosing spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammation, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, pancreatic fibrosis, liver fibrosis, acute and chronic kidney disease, irritable bowel syndrome, fever, restenosis, cerebral malaria, stroke and ischemic disorders, neurotrauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute and chronic pain, and These conditions include, but are not limited to, pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis, herniated, ruptured, or prolapsed disc syndrome, osteopetrosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, graft versus host reaction, multiple sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as shingles, herpes simplex type I or II, influenza virus, cytomegalovirus, and diabetes.

[0149] In certain embodiments, the compounds or compositions described herein are useful for treating cancer and other proliferative diseases, including, but not limited to, breast cancer, cervical cancer, colorectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the compounds or compositions described herein are active against solid tumors.

[0150] In certain embodiments, the compounds or compositions described herein are useful for treating cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colorectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain tumor, liver cancer, or esophageal cancer).

[0151] In some embodiments, exemplary cancers include adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anal canal and rectal cancer, anal canal cancer, appendix cancer, pediatric cerebellar astrocytoma, pediatric brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, bone and joint cancer, osteosarcoma and osteosarcoma, malignant fibroblastoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, brain astrocytoma / malignant glioma, ventricular tubuloblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial gland cancer, bronchial adenocarcinoma, bronchial duct cancer, thoracic sarcoidosis ... tumor / carcinoid, carcinoid tumor, gastrointestinal cancer, nervous system cancer, nervous system lymphoma, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous t-cell lymphoma, lymphoid tumors, mycosis fungoides, Sézari syndrome, endometrial cancer, esophageal cancer, retroperitoneal primary, extracranial germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal cancer, gastrointestinal stromal tumor (GIST), germ cell tumors, ovarian germ cell tumors, gestational glioma, head and neck cancer, liver Cell (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (pancreatic endocrine), Kaposi's sarcoma, kidney cancer, kidney cancer, pharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the neck, oral cancer , tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myeloproliferative dyscrasias syndrome, myeloproliferative dyscrasias / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cavity cancer, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary gland tumor, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter,These include, but are not limited to, transitional cell tumor, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma family tumors, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, supra-curative primitive neuroectodermal tumor, testicular cancer, laryngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblast tumor, urethral cancer, endometrial cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0152] In certain embodiments, the compounds described herein are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colorectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain tumor, liver cancer, or esophageal cancer) and / or any other cancer described herein.

[0153] In certain embodiments, the compounds described herein are useful for the treatment of cancer and other proliferative diseases, including, but not limited to, breast cancer, cervical cancer, colorectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the compounds are active against solid tumors.

[0154] In certain embodiments, the compounds and compositions described herein are useful for treating IKZF2-dependent diseases or disorders, such as liposarcoma, glioblastoma, bladder cancer, adrenocortical carcinoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile cancer, anal cancer, thyroid cancer, or vaginal cancer, or Epstein-Barr virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, or diffuse large B-cell lymphoma. The cancer may be selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colorectal cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, bile duct cancer, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancer, immune response-deficient cancer, immunogenic cancer, and Ewing's sarcoma. In one embodiment, the IKZF2-dependent disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the IKZF2-dependent disease or disorder is a disease or disorder selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite-stable colorectal cancer (mssCRC).

[0155] The compounds of the present disclosure can be administered in an amount effective to treat or prevent a disorder in a subject and / or prevent its onset.

[0156] In general, the methods of use of the compounds of the present application involve administering a therapeutically effective amount of a compound described herein to a subject in need thereof.

[0157] In certain embodiments, the compounds described herein are useful for treating proliferative diseases (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In certain embodiments, the therapeutic methods of the present application involve contacting cells with a compound or composition described herein to modulate the level of a cellular protein of interest, such as a pathogenic or oncogenic protein, or inhibit its proliferation, or degrade the protein. In other embodiments, the compounds are useful for treating cancer.

[0158] Accordingly, in another aspect of the present application, there is provided a method for treating cancer, comprising administering a therapeutically effective amount of a compound or composition described herein to a subject in need thereof. In certain embodiments, there is provided a method for treating cancer, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutical composition containing a compound, to a subject in need thereof, in an amount and for a period of time necessary to achieve the desired result. In some embodiments, the compounds of the present application are administered orally or intravenously. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition is an amount effective to kill or inhibit the growth of tumor cells. According to the methods of the present application, compounds and compositions may be administered in any amount and by any route of administration effective to kill or inhibit the growth of tumor cells. Thus, as used herein, the phrase "an amount effective to kill or inhibit the growth of tumor cells" refers to an amount of agent sufficient to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the subject's species, age, and general health, the severity of the disease, the particular anti-cancer agent, its mode of administration, etc. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition described herein is an amount effective to reduce the level of a target protein. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition is an amount effective to kill skin cells or inhibit the growth of tumor cells.

[0159] In certain embodiments, the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to, a human or other mammal in need thereof).

[0160] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds and methods of treating subjects using these compounds, pharmaceutical compositions thereof, or any of these in combination with one or more additional therapeutic agents.

[0161] Another aspect of the present application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferation disorder in a patient, said method comprising administering to said patient a compound of Formula I, II, III, IV, V, and VI, or a composition comprising said compound.

[0162] It will be understood that, according to the methods of the present application, the compounds and compositions can be administered in any amount and by any route of administration effective for treating cancer and / or diseases associated with cell hyperproliferation. For example, when using a compound to treat cancer, the term "effective amount" as used herein refers to an amount of drug sufficient to inhibit cell proliferation or an amount sufficient to reduce the effects of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general health of the subject, the severity of the disease, the specific drug, its mode of administration, etc.

[0163] The present application provides a method of treating a proliferative disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof. The proliferative disease may be cancer or a precancerous condition. The present application further provides use of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for preparing a medicament useful for treating a proliferative disease.

[0164] The present application also provides a method for preventing a proliferative disease in a subject in need thereof by administering a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, to the subject in need of such treatment. The proliferative disease may be cancer or a precancerous condition. The present application also provides the use of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for the manufacture of a medicament useful for preventing a proliferative disease.

[0165] As used herein, the term "proliferative disorder" refers to a condition in which unregulated cell growth, abnormal proliferation, or both can lead to the development of an undesirable condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the present application encompass a variety of conditions in which cell division becomes unregulated. Examples of proliferative disorders include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous conditions, intraepithelial neoplasia, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancer, carcinoma, leukemia, lymphoma, sarcoma, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell that divides at a rate that exceeds or is faster than the rate expected or observed between adjacent or juxtaposed cells within the same tissue. Proliferative disorders include precancers or precancerous conditions. Proliferative disorders include cancer. In some embodiments, the methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes not only solid tumors but also hematological tumors and malignant tumors. A "precancerous cell" or "precancerous cell" is a cell that exhibits a proliferative disorder that is a precancer or precancerous condition. A "cancer cell" or "cancerous cell" is a cell that exhibits a proliferative disorder that is a cancer. Any reproducible means of measurement can be used to identify cancerous or precancerous cells. Cancerous or precancerous cells can be identified by histological classification or grading of tissue specimens (e.g., biopsy specimens). Cancerous or precancerous cells can be identified by using appropriate molecular markers.

[0166] A "blood proliferative disorder" is a proliferative disorder involving cells of the blood system. Blood proliferative disorders may include lymphoma, leukemia, myeloid tumors, mast cell tumors, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown etiology, and essential thrombocythemia. Blood proliferative disorders may include hyperplasia, dysplasia, and metaplasia of blood cells. In some embodiments, the compositions of the present application may be used to treat a cancer selected from the group consisting of a blood cancer of the present application or a blood proliferative disorder of the present application. Hematological cancers in this application may include multiple myeloma, lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphomas of lymphoid and cutaneous origin), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid tumors, and mast cell tumors.

[0167] A "pulmonary proliferative disorder" is a proliferative disorder involving lung cells. Pulmonary proliferative disorders can include any form of proliferative disorder affecting lung cells. Pulmonary proliferative disorders can include lung cancer, precancer or precancerous conditions of the lung, benign lung tumors or lesions, malignant lung tumors or lesions, and metastatic lesions in tissues and organs of the body other than the lung. In some embodiments, the compositions of the present application can be used to treat lung cancer or a pulmonary proliferative disorder. Lung cancer can include any type of lung cancer. Lung cancer can include malignant lung tumors, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous carcinoma, and mesothelioma. Lung cancer can include "scar carcinoma," bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung tumors with histologic and ultrastructural heterogeneity (eg, mixed cell types).

[0168] Pulmonary proliferative disorders may include any form of proliferative disorder affecting lung cells. Pulmonary proliferative disorders may include lung cancer, precancerous lung conditions, etc. Pulmonary proliferative disorders may include pulmonary hyperplasia, metaplasia, and dysplasia. Pulmonary proliferative disorders may include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Pulmonary proliferative disorders may include replacement of columnar epithelium with stratified squamous epithelium and mucosal dysplasia. Individuals exposed to harmful environmental factors, such as tobacco smoke and asbestos, may be at increased risk for developing pulmonary proliferative disorders. Previous lung diseases that may predispose to the development of pulmonary proliferative disorders include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granulomas, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

[0169] A "colorectal proliferative disorder" is a proliferative disorder involving cells of the colorectal. In some embodiments, the colorectal proliferative disorder is colorectal cancer. In some embodiments, the compositions of the present application can be used to treat colorectal cancer or colorectal proliferative disorders. Colorectal cancer can include all types of colorectal cancer. Colorectal cancer can include sporadic and hereditary colorectal cancer. Colorectal cancer can include malignant colorectal neoplasia, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colorectal cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous carcinoma. Colorectal cancer can be associated with a genetic syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis. Colorectal cancer can be caused by a genetic syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis.

[0170] Colonic proliferative disorders can include any form of proliferative disorder affecting colon cells. Colonic proliferative disorders can include colon cancer, precancerous colon conditions, colonic adenomatous polyps, and metachronous colonic lesions. Colonic proliferative disorders can include adenomas. Colonic proliferative disorders are characterized by colonic hyperplasia, metaplasia, and dysplasia. Previous colonic disorders that may lead to the development of colonic proliferative disorders can include previous colon cancer. Current disorders that may increase an individual's risk of developing colonic proliferative disorders can include Crohn's disease and ulcerative colitis. Colonic proliferative disorders can be associated with mutations in genes selected from the group consisting of p53, ras, FAP, and DCC. Individuals can be at increased risk for developing colonic proliferative disorders due to the presence of mutations in genes selected from the group consisting of p53, ras, FAP, and DCC.

[0171] A "pancreatic proliferative disorder" is a proliferative disorder involving cells of the pancreas. Pancreatic proliferative disorders can include any form of proliferative disorder affecting pancreatic cells. Pancreatic proliferative disorders can include pancreatic cancer, precancer or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign pancreatic growths or lesions, malignant pancreatic tumors or lesions, and metastatic disease to tissues or organs outside the pancreas. Pancreatic cancer includes all forms of pancreatic cancer. Pancreatic cancer can include pancreatic ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary tumor, mucinous cystadenoma, papillary cystic tumor, and serous cystadenoma. Pancreatic cancer can also include pancreatic tumors with histologic and ultrastructural heterogeneity (eg, mixed cell types).

[0172] A "proliferative disorder of the prostate" is a proliferative disorder involving cells of the prostate gland. Proliferative disorders of the prostate gland can include any form of proliferative disorder affecting prostate cells. Proliferative disorders of the prostate gland can include prostate cancer, precancer or precancerous conditions of the prostate gland, benign growths or lesions of the prostate gland, malignant growths or lesions of the prostate gland, and metastatic disease to tissues or organs outside the prostate gland. Proliferative disorders of the prostate gland can include hyperplasia, metaplasia, and dysplasia of the prostate gland.

[0173] A "cutaneous proliferative disorder" is a proliferative disorder involving skin cells. A cutaneous proliferative disorder can include any form of proliferative disorder affecting skin cells. A cutaneous proliferative disorder can include precancerous or precancerous conditions of the skin, benign skin growths or lesions, melanoma, malignant melanoma, other malignant skin growths or lesions, and metastatic lesions to other body tissues or organs. A cutaneous proliferative disorder can include cutaneous hyperplasia, metaplasia, or dysplasia.

[0174] An "ovarian proliferative disorder" is a proliferative disorder involving ovarian cells. Ovarian proliferative disorders can include all forms of proliferative disorders affecting ovarian cells. Ovarian proliferative disorders can include precancer or precancerous conditions of the ovary, benign ovarian growths or lesions, ovarian cancer, malignant ovarian growths or lesions, and metastatic lesions of body tissues and organs other than the ovaries. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of ovarian cells.

[0175] A "proliferative disorder of the breast" is a proliferative disorder involving cells of the breast. Proliferative disorders of the breast can include any form of proliferative disorder affecting breast cells. Proliferative disorders of the breast can include breast cancer, precancer or precancerous conditions of the breast, benign growths or lesions of the breast, malignant growths or lesions of the breast, and metastatic disease to tissues or organs in the body other than the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0176] Cancers to be treated may be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system. Tumors (T) may be staged as TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; regional lymph nodes (N) may be staged as NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and distant metastases (M) may be staged as MX, M0, or M1. Cancers to be treated may be staged according to the American Joint Committee on Cancer (AJCC) classification as stage I, stage IIA, stage IIB, stage IIIA, stage IIIB, stage IIIC, or stage IV. Cancers to be treated can be graded according to the AJCC classification as grade GX (e.g., grade cannot be assessed), grade 1, grade 2, grade 3, or grade 4. Cancers to be treated can be staged according to the AJCC pathological classification (pN) as pNX, pN0, PN0(I-), PN0(I+), PN0(mol-), PN0(mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0177] Cancers to be treated may include tumors measured approximately 2 centimeters or less in diameter. Cancers to be treated may include tumors measured approximately 2 centimeters to approximately 5 centimeters in diameter. Cancers to be treated may include tumors measured approximately 3 centimeters or more in diameter. Cancers to be treated may include tumors measured greater than 5 centimeters in diameter. Cancers to be treated may be classified by microscopic appearance as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. Cancers to be treated may be classified by microscopic appearance in terms of mitotic rate (e.g., amount of cell division) or nuclear pleomorphism (e.g., cellular changes). Cancers to be treated may be classified by microscopic appearance as associated with areas of necrosis (e.g., areas of dead or degenerating cells). Cancers to be treated may be classified as having karyotypic abnormalities, chromosomal numerical abnormalities, or one or more abnormally appearing chromosomes. Cancers to be treated may be classified as having aneuploidy, triploidy, tetraploidy, or ploidy abnormalities. Cancers that are amenable to treatment can be classified as having chromosomal translocations, deletions or duplications of entire chromosomes, or partial deletions, duplications, or amplifications of chromosomes.

[0178] The cancer to be treated can be assessed by DNA cytometry, flow cytometry, or image cytometry. The cancer to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthetic stage of cell division (e.g., S phase of cell division). The cancer to be treated can be typed as having a low or high S phase fraction.

[0179] As used herein, a "normal cell" is a cell that cannot be classified as part of a "proliferative disorder." Normal cells lack unregulated or abnormal growth, or both, that can lead to the development of an undesirable condition or disease. In some embodiments, normal cells have normally functioning cell cycle checkpoint control mechanisms.

[0180] Those skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These documents include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). Of course, these documents may also be referenced in the making or use of this application.

[0181] In certain embodiments, the compounds of the present application are useful for treating proliferative diseases (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In certain embodiments, the therapeutic methods of the present application involve contacting the cells with a compound or composition described herein to modulate the level or inhibit the proliferation of a cellular protein of interest, such as, for example, a pathogenic protein or an oncogenic protein. In other embodiments, the compounds are useful for treating cancer.

[0182] In certain embodiments, the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative to a subject (including, but not limited to, a human or animal) in need thereof.

[0183] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds and methods of treating subjects using these compounds, pharmaceutical compositions thereof, or any of these in combination with one or more additional therapeutic agents.

[0184] For example, other therapies or anti-cancer agents that may be used in combination with the compounds disclosed herein include surgery, radiation therapy, endocrine therapy, biological response modifiers (such as interferons, interleukins, and tumor necrosis factors (TNF)), hyperthermia and cryotherapy, drugs that reduce side effects (such as antiemetics), and alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, benzodiazepine, benzocaine ... These include: spindle poisons (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan), antiretrovirals (topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, megestrol). For a more comprehensive discussion of cancer treatment overview, see The See the Merck Manual, Twentieth Ed. 2020, the entire contents of which are incorporated herein by reference. For lists of FDA-approved oncology drugs, see also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website (www.fda.gov / cder / cancer / druglistframe).

[0185] In certain embodiments, pharmaceutical compositions comprising the compounds disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic and / or palliative agents). For purposes of this application, the term "palliative" refers to treatment focused on reducing the symptoms of a disease and / or the side effects of a treatment regimen, and is not intended to be curative. For example, palliative treatments include painkillers, anti-nausea and vomiting medications, etc. Additionally, chemotherapy, radiation therapy, and surgery can all be used for palliative purposes (i.e., to reduce symptoms without curative intent, e.g., shrink tumors, reduce pressure, bleeding, pain, and other symptoms of cancer).

[0186] Administration of the Pharmaceutical Composition Administration of the disclosed compounds and pharmaceutical compositions can be achieved by any method of administering a therapeutic agent, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration methods.

[0187] Depending on the intended method of administration, the disclosed compositions can be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and the like, sometimes in unit doses, consistent with conventional pharmaceutical practice. Similarly, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, all of which can be administered using forms well known to those skilled in the pharmaceutical arts.

[0188] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, triglyceride oil, such as hydrogenated or partially hydrogenated vegetable oil, or a mixture thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or an ester or triglyceride thereof, or a mixture thereof, omega-3 fatty acid or a derivative thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, a magnesium salt or a calcium salt thereof, sodium oleate, sodium stearate, stearyl alcohol, PEG-100, PEG-100 stearate ... magnesium aluminate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol, as well as for tablets; c) binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or β-lactose, corn-based sweeteners, natural and synthetic gums such as gum acacia, gum tragacanth, sodium alginate, waxes, and / or polyvinylpyrrolidone (if required); d) disintegrants, e.g. starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colourings, flavourings, sweeteners; f) emulsifiers or dispersing agents (Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifiers, and / or g) agents that enhance absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0189] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds can be dissolved or mixed in a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0190] The disclosed compounds can also be formulated as suppositories which can be prepared from fatty emulsions or suspensions, using polyalkylene glycols such as propylene glycol as the carrier.

[0191] The compounds of the present disclosure can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids containing cholesterol, stearylamine, or phosphatidylcholines.

[0192] In some embodiments, a film of lipid components is hydrated with an aqueous solution of the drug to form a lipid layer that encapsulates the drug, a method described in U.S. Pat. No. 5,262,564, which is incorporated herein by reference in its entirety.

[0193] The disclosed compounds can also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are bound. The disclosed compounds can also be conjugated with soluble polymers as targetable drug carriers. Such polymers include palmitoyl-substituted polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparamidephenol, or polyethyleneoxide polylysine. Furthermore, the disclosed compounds can be conjugated to biodegradable polymer classes useful for achieving controlled drug release, such as polylactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked hydrogels or amphiphilic block copolymers. In one embodiment, the disclosed compounds are not covalently conjugated to polymers such as polycarboxylic acid polymers or polyacrylates.

[0194] Parenteral injection administration is generally used for subcutaneous, intramuscular or intravenous injection and infusion. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0195] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V, or VI and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0196] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compounds by weight or volume.

[0197] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present disclosure.In one embodiment, the kit comprises a means for separately retaining the compositions, such as a container, a divided bottle, or a divided foil packet.An example of such a kit includes a blister pack, typically used to package tablets, capsules, etc.

[0198] The kits of the present disclosure can be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions against one another. To aid in compliance, the kits of the present disclosure typically include directions for administration.

[0199] Pharmaceutical dosage forms of the compounds of the present disclosure can be prepared by any method known in the art, such as, for example, conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, shaping, emulsifying, (nano / micro)encapsulating, entrapping, or lyophilizing processes. As mentioned above, the compositions of the present disclosure can contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into preparations for pharmaceutical use.

[0200] As mentioned above, composition generally consists of the compound of the present disclosure and at least one pharmaceutically acceptable excipient combination.Acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic effect of claimed compound.Such excipient can be solid, liquid, semi-solid, or gaseous excipient in the case of aerosol composition, that can be commonly available to those skilled in the art.

[0201] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk powder, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0202] Compressed gases can be used to disperse the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0203] The compositions of the present disclosure may be provided in a pack or dispenser device, if desired, containing one or more unit dosage forms containing the active ingredient.Such a pack or device may be, for example, made of metal or plastic foil, such as a blister pack, or glass and rubber stopper, such as a vial.The pack or dispenser device may be accompanied by instructions for administration.Also, a composition containing the compound of the present disclosure formulated in a suitable pharmaceutical carrier may be prepared, placed in an appropriate container, and labeled for the treatment of the indicated condition.

[0204] The amount of compound in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain about 0.01 to 99.99% by weight of the compound of the present disclosure, based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80% by weight. Representative pharmaceutical formulations are described below.

[0205] Formulation Examples The following are representative pharmaceutical formulations containing compounds of the present disclosure.

[0206] Formulation Example 1 - Tablet Formulation The following ingredients are thoroughly mixed and compressed into scored tablets. TIFF2026502995000050.tif58170

[0207] Formulation Example 2 - Capsule Formulation The following ingredients are thoroughly mixed and loaded into hard-shell gelatin capsules: TIFF2026502995000051.tif43170

[0208] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration: TIFF2026502995000052.tif94170

[0209] Formulation Example 4 - Injection The following ingredients are mixed to prepare an injection: TIFF2026502995000053.tif43170

[0210] Formulation Example 5 - Suppository Formulation Suppositories weighing 2.5 g are prepared by mixing a compound of the present disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids, Riches-Nelson, Inc., New York) and have the following composition: TIFF2026502995000054.tif23170

[0211] Administration Dosage regimens utilizing the disclosed compounds are selected depending on a variety of factors, including the type, species, age, weight, sex, and health of the patient, the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the particular disclosed compound being used. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0212] Effective dosages of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5,000 mg of the disclosed compounds required to treat a medical condition. Compositions for in vivo or ex vivo use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or any range from one amount to another listed in the dosage amounts. In one embodiment, the composition is in the form of a tablet that can be scored.

[0213] The following synthetic and biological examples are offered to illustrate the present disclosure and are not to be construed in any way as limiting the scope of the disclosure. Unless otherwise noted, all temperatures are in degrees Celsius. [Example]

[0214] The present disclosure will be further understood by reference to the following examples, which are intended to be purely exemplary of the present disclosure. The present disclosure is not limited in scope by the exemplified embodiments, which are intended merely as illustrations of single aspects of the disclosure. All functionally equivalent methods are within the scope of the present disclosure. Various modifications of the present disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be encompassed within the scope of the appended claims.

[0215] In this specification and in the examples that follow, all temperatures are expressed in degrees Celsius. Additionally, the following abbreviations have the following meanings: If not defined, these abbreviations have their art-recognized meanings. TIFF2026502995000055.tif122170TIFF2026502995000056.tif248170TIFF2026502995000057.tif181170

[0216] LC-MS method (general method) LC / MS method: Gradient: 5% B until 0.40 min, 5-95% B from 0.40-3.00 min, held at 95% B for 1.00 min, then 95-5% B at 0.01 min. Flow rate: 1.0 mL / min. Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna C18 50x2.0 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, and electrospray positive ionization. MS range was 100-1000 Daltons.

[0217] Example 1 Preparation of 3-(5-(((1S,2S)-2-(5-azaspiro[2.3]hexan-5-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 12) [ka] To a solution of 1,1-bis(bromomethyl)cyclopropane (0.1 g, 438.74 μmol, 3 eq) and 3-(5-(((1S,2S)-2-aminocyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (52.27 mg, 146.25 μmol, 1 eq) in MeCN (1 mL) was added DIEA (94.51 mg, 731.24 μmol, 127.37 μL, 5 eq) at 20° C. The reaction mixture was stirred at 120° C. for 12 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give 3-(5-(((1S,2S)-2-(5-azaspiro[2.3]hexan-5-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 1 H NMR(400 MHz,d6-DMSO) δ 10.95(s,1H),8.21-8.13(m,1H),7.60(d,J=8.4Hz,1H),7.21-6.97(m,2H),5.06(dd,J=5.0,13.3Hz,1H),4.38-4.24(m,2H),3.35(br s,2H),3.26(br d,J=6.8Hz,2H),2.97-2.80(m,2H),2.71-2.53(m,2H),2.41-2.30(m,2H),2.03-1.92(m,2H),1.86-1.75(m,1H),1.64(br s,2H),1.41-1.09(m,4H),0.43(s,4H).

[0218] Example 2 Preparation of 3-(5-(((1S,2S)-2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 7) and 3-(5-(((1S,2R)-2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 8) [ka] Step 1: A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1.5 g, 3.31 mmol, 1 eq) in MeCN (20 mL) was prepared using (1S,2S)-cyclohexane-1,2-diol (461.15 mg, 3.97 mmol, 1.2 eq), Ir[(dF(CF [3)ppy]2dtbbpy]PF6 (37.12 mg, 33.08 μmol, 0.01 eq), dtbbpy (44.40 mg, 165.42 μmol, 0.05 eq), NiCl2.glyme (36.35 mg, 165.42 μmol, 0.05 eq), and TMP (560.76 mg, 3.97 mmol, 673.99 μL, 1.2 eq) were added. The mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0–50% v / v petroleum ether in ethyl acetate) to give 3-(5-(((1S,2S)-2-hydroxycyclohexyl)oxy)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione. 1 H NMR(400MHz,d6-DMSO) δ 7.65-7.57(m,1H),7.19(s,1H),7.07(dd,J=2.1,8.4Hz,1H),5.18(dd,J=5.0,13.4Hz,1H),5.05(q,J=9.7Hz,2H),4.94(dd,J=1.2, 4.7Hz,1H),4.47(d,J=3.6Hz,1H),4.40(dd,J=4.9,17.1Hz,1H),4.26-4.12(m,2H),3.61-3.46(m,3H),3.14-2.99(m,2H),2.78(br dd,J=2.1,15.6Hz,1H),2.43-2.28(m,1H),2.07-2.01(m,2H),1.94-1.82(m,1H),1.79-1.69(m,1H),1.63(br d,J=9.6Hz,2H),1.58-1.53(m,H), 1.37-1.27(m,3H),1.13(br d,J=7.9Hz,1H),0.90-0.78(m,2H),-0.02(s,9H). [ka]

[0219] Step 2: To a solution of 3-(5-(((1S,2S)-2-hydroxycyclohexyl)oxy)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (2.4 g, 4.91 mmol, 1 eq) in DCM (20 mL) was added DMP (6.25 g, 14.73 mmol, 4.56 mL, 3 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0–50% v / v petroleum ether in ethyl acetate) to give 3-(1-oxo-5-(((S)-2-oxocyclohexyl)oxy)isoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione. 1 H NMR(400MHz,d6-DMSO) δ 7.59(d,J=8.5Hz,1H),7.07(s,1H),7.00(br d,J=8.5Hz,1H),5.24-5.13(m,2H),5.04(q,J=9.8Hz,2H),4.38(dd,J=4.8,17.1Hz ,1H),4.26-4.16(m,1H),3.57-3.46(m,2H),3.13-2.97(m,1H),2.84-2.72(m,1H), 2.65(dt,J=6.1,13.3Hz,1H),2.44-2.28(m,3H),2.02(ddd,J=3.0,5.7,10.0Hz,2H ),1.93-1.74(m,3H),1.67-1.49(m,1H),0.88-0.80(m,2H),-0.02(d,J=1.3Hz,9H). [ka]

[0220] Step 3: To a solution of 3-(1-oxo-5-(((S)-2-oxocyclohexyl)oxy)isoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (500 mg, 1.03 mmol, 1 eq) in DCM (5 mL) was added MsOH (394.98 mg, 4.11 mmol, 292.58 μL, 4 eq). The mixture was stirred at 25° C. for 3 h. Triethylamine (831.75 mg, 8.22 mmol, 1.14 mL, 8 eq)) and N,N′-dimethylethane-1,2-diamine (108.69 mg, 1.23 mmol, 132.71 μL, 1.2 eq) were added at 0° C. The mixture was warmed to 25° C. and stirred for 12 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC to give 3-(1-oxo-5-(((S)-2-oxocyclohexyl)oxy)isoindolin-2-yl)piperidine-2,6-dione. 1 H NMR(400MHz,d6-DMSO) δ 10.96(s,1H),7.58(d,J=8.4Hz,1H),7.07(br s,1H),6.99(br d,J=8.4Hz,1H),5.18(br s,1H),5.06(br dd,J=4.4,12.7Hz,1H),4.42-4.30(m,1H),4.28-4.17(m,1H),2.98-2.80(m,1H),2.72-2.54(m,2H),2.44-2.26(m,3H),2.00(br s,2H),1.93-1.70(m,3H),1.58(br d,J=11.8Hz,1H). [ka]

[0221] Step 4: To a solution of 3-(1-oxo-5-(((S)-2-oxocyclohexyl)oxy)isoindolin-2-yl)piperidine-2,6-dione (45 mg, 126.27 μmol, 1 eq) in DMA (1 mL) and MeOH (1 mL) was added 2-azaspiro[3.3]heptan-6-ol hydrochloride (18.89 mg, 126.27 μmol, 1 eq) and ZnCl (51.63 mg, 378.81 μmol, 17.74 μL, 3 eq). The mixture was stirred at 20 °C for 12 h. NaBHCN (23.80 mg, 378.81 μmol, 3 eq) was added to the reaction mixture and stirred at 20 °C for 3 h. The mixture was filtered and purified by preparative HPLC to give 3-(5-(((1S,2R)-2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 1 H NMR(400MHz,d6-DMSO) δ 10.97(s,1H),8.21(s,1H),7.61(d,J=8.4Hz,1H),7.16(s,1H),7.09-6.98(m,1H),5.07(dd,J=5.1,13. 4Hz,1H),4.90(dt,J=1.8,3.6Hz,1H),4.61-4.50(m,1H),4.43-4.33(m,1H),4.32-4.18(m,1H),3.90(br t,J=7.3Hz,1H),3.08(br d,J=15.6Hz,7H),2.98-2.82(m,3H),2.72-2.57(m,2H),2.46-2.18(m,7H),2.04-1.91(m,3H),1.87-1.76(m,2H),1.64-1.16(m,9H)and 3-(5-(((1S,2S)-2-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 1H NMR(400MHz,d6-DMSO) δ 10.97(br s,1H),8.18(s,1H),7.62(d,J=8.4Hz,1H),7.16(s,1H),7.02(dd,J=1.6,8.5Hz,1H),5.07(dd,J=4.9,13.1Hz,1H),4.89(br s,1H),4.45-4.33(m,1H),4.31-4.20(m,2H),3.92-3.86(m,1H),3.24-3.05(m,12H),2.96-2.8 6(m,2H),2.70-2.55(m,2H),2.44-2.14(m,6H),2.02-1.94(m,2H),1.85-1.74(m,3H),1.62(br s,2H),1.38-1.28(m,2H),1.23-0.99(m,3H).

[0222] Example 3 Preparation of 3-(5-(((1S,2S)-2-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 1) and 3-(5-(((1S,2R)-2-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 2) [ka] Step 1: To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 23.67 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3.0 M in THF, 31.56 mL, 4 eq) at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (100 mL) at 0 °C and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, 0–50% v / v petroleum ether in ethyl acetate) to give tert-butyl 6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxylate. 1 H NMR(400MHz,d6-DMSO) δ 4.85(s,1H),3.82-3.68(m,4H),2.09(s,4H),1.32(s,9H),1.09(s,3H). [ka]

[0223] Step 2: To a solution of tert-butyl 6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 879.90 μmol, 1 eq) in DCM (1 mL) was added DCM (1 mL) and TFA (0.2 mL) at 0° C. The mixture was stirred at 20° C. for 4 hours. The reaction was concentrated under reduced pressure to give 6-methyl-2-azaspiro[3.3]heptan-6-ol. 1 H NMR(400MHz,6-DMSO) δ 8.86(br s,1H),4.02-.83(m,4H),2.22-2.14(m,4H),1.13(s,3H). [ka]

[0224] Step 3: To a solution of 3-(1-oxo-5-(((S)-2-oxocyclohexyl)oxy)isoindolin-2-yl)piperidine-2,6-dione (0.02 g, 157.25 μmol, 1 eq) in DMA (1 mL) and MeOH (1 mL) was added 6-methyl-2-azaspiro[3.3]heptan-6-ol (67.25 mg, 188.70 μmol, 1.2 eq) and ZnCl (64.30 mg, 471.76 μmol, 22.10 μL, 3 eq). The mixture was stirred at 20 °C for 2 h. NaBHCN (20.59 mg, 327.61 μmol, 1 eq) was added and stirred at 20 °C for 12 h. The mixture was filtered to give the crude product. The crude product was purified by preparative HPLC to give 3-(5-(((1S,2R)-2-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 1 H NMR(400MHz,d6-DMSO) δ 10.97(s,1H),7.60(d,J=8.4Hz,1H),7.16(s,1H),7.06-6.99(m,1H),5.07(dd,J=5.1,13.3Hz,1H),4.75(s,1H),4.55(br d,J=7.8Hz,1H),4.43-4.34(m,1H),4.29-4.21(m,1H),3.10(s,2H),3.06-2.99(m,2H),2.96-2.82(m,2H),2.43-2.38(m,2H),2.36(br d,J=4.0Hz,1H),2.07-1.91(m,6H),1.61-1.47(m,4H),1.24(br s,2H),1.12(s,3H)and 3-(5-(((1S,2S)-2-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 1H NMR(400MHz,d6-DMSO) δ 10.97(br s,1H),7.61(d,J=8.5Hz,1H),7.15(s,1H),7.01(br d,J=8.6Hz,1H),5.07(dd,J=4.3,13.1Hz,1H),4.74(s,1H),4.43-4.35(m,1H),4.30-4.19(m,2H),.22 (br d,J=6.6Hz,2H),3.16(br d,J=7.3Hz,1H),3.10(br d,J=6.3Hz,1H),3.05(br d,J=7.1Hz,1H),2.97-2.85(m,1H),2.42-2.38(m,1H),2.29-2.21(m,1H),2.06-1.92(m,7H),1.79-1.70(m,1H),1.62(br d,J=4.4Hz,2H),1.33(br s,2H),1.25-1.19(m,1H),1.12-1.08(m,3H).

[0225] The additional compounds shown in Table 3 were prepared following the procedures shown in the general scheme above, except that the amine in the above example was replaced with the amine shown in the final product. TIFF2026502995000066.tif239170TIFF2026502995000067.tif243170TIFF2026502995000068.tif242170TIFF2026502995000069.tif24117 0TIFF2026502995000070.tif243170TIFF2026502995000071.tif242170TIFF2026502995000072.tif239170TIFF2026502995000073.tif95170

[0226] Biological Examples Cereblon (CRBN) Targeted Engagement HEK-293T cells were harvested with trypsin at approximately 75% confluence and seeded (500,000 cells / well) into 6-well tissue culture plates with 2 mL of Dulbecco's modified Eagle's medium (DMEM) plus 10% fetal bovine serum (FBS) and incubated overnight at 37°C.

[0227] The NanoLuc-CRBN fusion vector (Nluc-CRBN, Promega) contains the coding region for the human E3 ligase component cereblon (CRBN) fused to the C-terminus of the NanoLuc luciferase coding region. A mixture of 10 ng Nluc-CRBN and 990 ng DDB1 Expression Vector (Promega) was added to 125 μL of Opti-Minimum Essential Medium (Opti-MEM™; Thermo Fisher Scientific) along with 2 μL of P3000 reagent in a 1.5 mL Eppendorf tube. This solution was added to Lipofectamine 3000 transfection reagent (5 μL; Thermo Fisher Scientific) in Opti-MEM (125 μL), mixed well, and incubated at room temperature for 15 minutes. The transfection mixture was added dropwise to the cells and incubated overnight at 37°C and 5% CO2. After transfection, cells were washed once with PBS, and trypsin (250 μL) was added and incubated for 30–45 seconds to remove the cells. Complete medium (2 mL) was added to resuspend the cells to form a single cell suspension. The cells were centrifuged at 320 x g for 5 minutes at room temperature, the supernatant was removed, and the cell pellet was resuspended in Opti-MEM (3 mL; the washing step was repeated twice). After a final resuspension in 5 mL of Opti-MEM, the cells were counted and resuspended at 200,000 cells / mL in Opti-MEM.

[0228] Cereblon target engagement was monitored by bioluminescence resonance energy transfer (BRET) in transfected HEK-293T cells using the NanoBRETTE Intracellular E3 Ligase Assay (Promega). Briefly, transfected HEK-293T cells (38 μL / well) were seeded into a 384-well plate (white opaque plate, Corning 3574, low-binding surface). 2 μL of 10 μM CRBN tracer (diluted 1:5 in tracer dilution buffer) was added to each well. The plate was centrifuged at 320 x g for 1 minute at room temperature. Test compounds were added in an 11-step dilution series (typically 10 μM to 100 pM) using a TECAND 300e digital dispenser. The plate was shaken for 2 minutes on a microplate shaker to mix the compounds. The plate was centrifuged at 320 x g for 1 minute at room temperature and then incubated at 37 °C for 2 hours.

[0229] After incubation, the plate was allowed to cool at room temperature for 15 minutes. 20 μL of 3X Complete NanoBRET™ Nano-Glo® substrate and inhibitor solution (Promega, substrate 1:166, extracellular NanoLuc® inhibitor diluted 1:500 in Opti-MEM) was added to each well. The plate was covered with aluminum foil and incubated at room temperature with shaking for 3 minutes. The plate was measured at 450 nm (donor emission) and 610 nm (acceptor emission) on a CLARIOstar microplate reader (BMG LabTech). IC 50 Values ​​were determined by regression analysis using Graph Pad Prism to best fit a four-parameter logistic curve.

[0230] IKZF2 degradation assay Generation of stable cell lines A polycistronic plasmid was constructed to express fluorescent reporter fusion proteins of the human transcription factors IKZF1 (Ikaros), IKZF2 (Helios), and IKZF3 (Aiolos) in mammalian cells. Each protein sequence contains three repeats of the GGGGS linker at the C-terminus, followed by mNeonGreen, P2A, and mScarlet. The DNA sequences of the open reading frames are as follows:

[0231] IKZF1-mNeonGreen-P2A-mScarlet coding sequence (SEQ ID NO. 1):

[0232] Coding sequence of IKZF2-mNeonGreen-P2A-mScarlet (SEQ ID NO. 2):

[0233] Coding sequence of IKZF3-mNeonGreen-P2A-mScarlet (SEQ ID NO. 3):

[0234] IKZF1, IKZF2, and IKZF3 constructs were cloned into the UCOE-hygromycin expression vector (Millipore Sigma). The reporter constructs were transfected into adherent HEK 293T cells using a cationic lipid reagent, and stable integrants were selected by treatment with 200 μg / mL hygromycin B. Clonal populations were obtained from the stable integrant population using limiting dilution or fluorescence-activated cell sorting.

[0235] The cloned stable cell lines were selectively maintained in a constant concentration of 200 μg / mL hygromycin B while being subcultured for use in degradation assays. Flow cytometry analysis using a BD Accuri C6 tube showed that the HEK 293T CMV-IKZF1 clone 7 cell line had an average fluorescein isothiocyanate mean fluorescence intensity (FITC MFI) of 230,000 and a phycoerythrin mean fluorescence intensity (PE MFI) of 33,000. The HEK 293T EF1a-IKZF2 clone 9 had an average FITC MFI of 150,000 and a PE MFI of 26,000. The HEK 293T EF1a-IKZF3 clone 9 had an average FITC MFI of 400,000 and a PE MFI of 60,000. The fluorescence intensities of the IKZF1 / 2 / 3-mNeonGreen (FITC channel) and mScarlet (PE channel) reporters were analyzed periodically by flow cytometry to confirm consistent expression levels between experiments.

[0236] IKZF1 / 2 / 3 reporter degradation assay The IKZF1 / IKZF2 / IKZF3 degradation assay was performed by harvesting the HEK 293T reporter cell line and resuspending the cells in medium (FluoroBrite, Thermo Fisher Scientific) formulated to reduce background fluorescence. Each cell line was seeded at a density of 4000 cells / well in a black-walled, 384-well optical-grade assay tissue culture plate. Cells were incubated overnight at 37°C to allow attachment to the assay plate. Compound dilutions were prepared in DMSO from 10 mM compound stocks. The DMSO dilutions were dispensed into quadruplicate wells of the assay plate, with the appropriate compound concentrations applied, resulting in a final DMSO concentration of up to 0.5%.

[0237] After 24 hours of incubation with compounds, the assay plates were imaged using an ImageXpress Pico microscope system (cells were maintained at 37°C during imaging) to obtain fluorescence readings. The assay plates were imaged in the FITC and tetramethylrhodamine (TRITC) channels to obtain mNeonGreen fluorescence intensity (reporter degradation data) and mScarlet fluorescence intensity (for cell segmentation). The 293T-IKZF1 and 293T-IKZF3 reporter cell lines were imaged using 500 millisecond (ms) exposure times in both the FITC and TRITC channels, while the 293T-IKZF2 reporter cell line was imaged using 1000 ms exposure times in the FITC channel and 1250 ms exposure times in the TRITC channel. The resulting data were analyzed using Cell Reporter Xpress software using a two-channel cell scoring analysis with a "positive rate" readout. The TRITC channel was selected for "nuclei" segmentation, and the threshold was set at 20. Meanwhile, the FITC channel was selected for "Marker 1" segmentation, and the threshold for the IKZF1 and IKZF3 reporter lines was set to 100. For the IKZF2 reporter line, the threshold for the FITC channel was set to 120, and the threshold for the TRITC channel was set to 20. For all cell lines, the minimum segmentation width was set to 6 micrometers, and the maximum segmentation width was set to 15 micrometers. 50 Calculations of were performed by regression analysis using GraphPad Prism to best fit a four-parameter logistic curve.

[0238] Table 4 shows the results of the above assays. TIFF2026502995000074.tif119170

Claims

1. A compound of formula I, 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, During the ceremony, m and p are independently 0, 1, 2, or 3; n is 0, 1, or 2; q is 1, 2, or 3; r is 0, 1, or 2; s is 0 if r is not 0, and is 1 if r is 0; t is 0 or 1; u is 1 or 2; X is hydrogen, deuterium, or fluoro; Y is oxygen or NR, and R is hydrogen or C １ -C ４ is alkyl, Z and Z １ are each independently CR １ or N, Each R １ are independently hydrogen, amino, unsubstituted, or 1 to 3 R ５ Substituted with a substituent (C １ -C ４ alkyl)amino, unsubstituted or 1 to 3 R in each alkyl group ５ Di-(C １ -C ４ alkyl)amino, cyano, halo, hydroxyl, unsubstituted or 1 to 3 R ５ C substituted with a substituent １ -C ４ alkyl, and unsubstituted or 1 to 3 R ５ C substituted with a substituent １ -C ４ alkoxy, or Z １ is CR １ If two adjacent R １ together with the carbon atoms to which they are attached, form C ３ -C ７ Cycloalkyl, C ６ -C １０ forming a 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from aryl, oxygen, nitrogen, or sulfur, or a 5- to 6-membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is selected from 1 to 3 R ６ independently substituted with groups, Each R ２ is cyano, halo, hydroxyl, amino, unsubstituted, or 1 to 3 R ５ C substituted with a substituent １ -C ４ alkylamino, unsubstituted or 1 to 3 R in each alkyl group ５ Di-(C １ -C ４ alkyl)amino, unsubstituted or 1 to 3 R ５ C substituted with a substituent １ -C ４ alkyl, and unsubstituted or 1 to 3 R ５ C substituted with a substituent １ -C ４ independently selected from alkoxy; Each R ３ together with the carbon atom attached thereto, form 1 to 3 R ７ forming a 3-, 4-, 5- or 6-membered cycloalkyl or heterocycloalkyl substituted by a substituent; R ４ is hydrogen and -CH ２ -OR ８ and R ８ is C(O)-R ９ or -P(O)(OR １０ ) ２ and R ９ is C １ -C ４ Alkyl, or C １ -C ４ alkoxy, and each R １０ are independently H or C １ -C ４ is alkyl, Each R ５ are independently amino, (C １ -C ４ alkyl)amino, di-(C １ -C ４ alkyl)amino, cyano, halo, hydroxyl, or C １ -C ４ is an alkoxy; Each R ６ are independently amino, (C １ -C ４ alkyl)amino, di-(C １ -C ４ alkyl)amino, cyano, halo, hydroxyl, and oxo; Each R ７ is amino, unsubstituted or substituted with 1 to 3 halo, １ -C ４ Alkyl, unsubstituted or substituted with 1 to 3 halo C １ -C ４ Alkoxy, (C １ -C ４ alkyl)amino, di-(C １ -C ４ C having 1 to 3 heteroatoms selected from alkyl)amino, cyano, halo, hydroxyl, nitro, oxo, O, NR, and / or S ５ -C ６ heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and / or sulfur, and —C(O)CH ３ are independently selected from, and R １１ is hydroxyl, halo, or cyano, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein X is hydrogen.

3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein p is 2.

4. 4. The compound of any one of claims 1 to 3, wherein q is 1 and r is 0, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

5. The compound of any one of claims 1 to 4, having the structure of Formula III: 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

6. 6. The compound of any one of claims 1 to 5, wherein n is 0 and u is 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

7. R ４ The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein is hydrogen.

8. Z and Z １ are C-R respectively １ 8. The compound of any one of claims 1 to 7, wherein:

9. R １ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein

10. 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m is 0.

11. 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein Y is O.

12. The compound of any one of claims 1 to 11 having the structure of Formula IV 【Transformation 3】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

13. 13. The compound of any one of claims 12 having the structure of Formula V 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

14. 13. The compound of any one of claims 12 having the structure of Formula VI: 【Transformation 5】 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. 【Request Item 15】 【Chemistry 6】 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, selected from:

16. A compound selected from Table 1, Table 1A, or Table 1B, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

17. A compound selected from Table 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, an effective amount of a compound according to any one of claims 1 to 17, and a pharmaceutically acceptable excipient.

19. 20. A method for modulating the activity of cereblon, comprising contacting cereblon with an effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions such that cereblon is modulated.

20. A method for degrading IKZF2, comprising contacting IKZF2 with an effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions in which IKZF2 is degraded.

21. 20. A method for degrading IKZF2 in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

22. 20. A method for treating cancer in a subject in need thereof, comprising selecting a subject whose cancer is at least partially mediated by IKZF2, and administering to said subject an effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

23. 20. A method for treating cancer in a subject in need thereof, comprising selecting a subject whose cancer is at least partially mediated by IKZF2, and administering to the subject an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

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