Spirocycloalkyl compounds and pharmaceutical compositions that modulate IKZF2

Abstract

The present disclosure discloses compounds that bind to and modulate the activity of cerebron, and salts thereof. In some embodiments, binding and modulation of cerebron results in degradation of the IKAROS family zinc finger protein (e.g., IKZF2). The compounds have Formula I: Formula I:

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 478,449, filed on January 4, 2023, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure provides compounds and salts thereof that bind to cereblon to modulate cereblon activity. In some embodiments, certain compounds described herein bind to cereblon, resulting in a reduction in the level of cellular IKAROS family zinc finger (IKZF) proteins. In some embodiments, certain compounds described herein bind to cereblon but do not result in a reduction in cellular IKZF protein levels. In some embodiments, the compounds disclosed herein bind to cereblon to initiate degradation of IKZF proteins (e.g., IKZF2). Also disclosed are pharmaceutical compositions comprising the compounds or salts thereof (e.g., pharmaceutically acceptable salts), and methods for treating various IKZF2-mediated diseases or disorders using such compounds and / or their salts. Background Art

[0004] IKAROS family zinc finger 2 (IKZF2) (also known as Helios) is one of the 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 leads to enhanced anti-tumor immune responses (Kim et al., Science 350:334-339 (2015)). It is worth noting that Helios is highly expressed in regulatory T cells (Tregs) (T cell subsets that limit effector T cell activity) (Elkord et al., Expert Opin. Biol. Ther. 12:1423-1425 (2012)). Selective deletion of Helios in regulatory T cells results 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)). Therefore, Helios is a key factor in limiting T cell effector function in Tregs.

[0005] Helios expression has also been reported in "exhausted" T cells, in chronic viral infections (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 upregulated in dysfunctional chimeric antigen receptor (CAR) T cells (Long et al., Nat. Med. 21:581-590 (2015)). Overexpression or abnormal expression of Helios and various splice isoforms have been reported in several hematological malignancies, including T-cell leukemias and lymphomas (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, in a mixed lineage leukemia (MLL)-driven myeloid leukemia model, knockdown of Helios effectively inhibited 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)).

[0006] Currently, anti-CTLA4 antibodies are 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 therapeutic utility. Up to 75% of patients treated with a combination of anti-PD-1 and anti-CTLA4 have reported grade 3 or higher adverse events (National Cancer Institute, Division of Cancer Treatment and Diagnosis, Common Terminology of Adverse Events (CTCAE), https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm).

[0007] There is a need for therapies that can target Tregs in tumors without causing systemic activation of T effector cells. Therefore, IKZF2-specific modulators or degraders have the potential to focus enhanced immune responses to areas within or near tumors, providing potentially more tolerable and less toxic therapies for treating IKZF2-mediated diseases. Summary of the Invention

[0008] Disclosed are compounds that bind to cereblon and thereby modulate cereblon activity. In some embodiments, certain compounds described herein bind to cereblon, resulting in a reduction in cellular IKAROS family zinc finger (IKZF) protein levels. In some embodiments, certain compounds described herein bind to cereblon but do not result in a reduction in cellular IKZF protein levels. In some embodiments, certain compounds disclosed herein bind to cereblon, thereby initiating degradation of IKZF proteins (e.g., IKZF2). Also disclosed are pharmaceutical compositions comprising the compounds or salts thereof (e.g., pharmaceutically acceptable salts), as well as methods of using such compounds and / or their salts to treat various IKZF2-mediated diseases or conditions (including, for example, cancer).

[0009] In one embodiment, the disclosed compounds that bind to and modulate cereblon and, in some cases, degrade IKZF2 are represented by Formula I:

[0010]

[0011] 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, q, r, s, t and u are as defined in the detailed description and throughout the specification.

[0012] In one embodiment, the disclosed compounds that bind to and modulate cereblon and, in some cases, degrade IKZF2 are represented by Formula II:

[0013]

[0014] 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 in the detailed description and throughout the specification.

[0015] In one embodiment, the disclosed compounds that bind to and modulate cereblon and, in some cases, degrade IKZF2 are represented by Formula III:

[0016]

[0017] 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 in the detailed description and throughout the specification.

[0018] In one embodiment, the disclosed compounds that bind to and modulate cereblon and, in some cases, degrade IKZF2 are represented by Formula IV:

[0019]

[0020] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 3 、R 4 ,Y,Z,Z 1 As defined in the detailed description and throughout the specification.

[0021] In one embodiment, the disclosed compounds that bind to and modulate cereblon and, in some cases, degrade IKZF2 are represented by Formula V:

[0022]

[0023] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 4 、R 7 , Y, Z and Z 1 As defined in the detailed description and throughout the specification.

[0024] In one embodiment, the disclosed compounds that bind to and modulate cereblon and, in some cases, degrade IKZF2 are represented by Formula VI:

[0025]

[0026] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 4 、R 7 , Y, Z and Z 1 As defined in the detailed description and throughout the specification.

[0027] In one embodiment, a compound of Formula I or its subformulae is provided that selectively regulates IKZF (e.g., over translation termination factor GSPT1 (G1 to S phase transition 1 protein)). In one embodiment, a compound of Formula I or its subformulae is provided that selectively regulates IKZF2 over GSPT1.

[0028] In one embodiment, a composition is provided 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 subformulae" refers to compounds of Formula I, II, or its subformulae, III, IV, V, and VI as defined herein.

[0029] In one embodiment, the present disclosure provides a method for regulating cereblon, comprising contacting cereblon with an effective amount of a compound of Formula I, II, or subformulas thereof, III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions such that cereblon is regulated.

[0030] In one embodiment, the present disclosure provides a method for degrading IKZF2, comprising contacting IKZF2 with an effective amount of a compound of Formula I, II, or sub-formulas thereof, III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, under conditions where IKZF2 is degraded.

[0031] In one embodiment, a method for degrading IKZF2 in a subject is provided, 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 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.

[0032] Further provided is a method of treating cancer in a subject in need thereof, comprising: selecting a subject whose cancer is mediated at least in part by IKZF2, and administering to the subject an effective amount of a compound of Formula I, II, or subformulas thereof, 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 subformulas thereof, III, IV, V, and VI, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof. DETAILED DESCRIPTION

[0033] The present disclosure provides compounds, pharmaceutical compositions comprising 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, before providing a detailed description of the present disclosure, the following terms will first be defined. Unless otherwise defined, the terms used herein have their generally accepted scientific meanings.

[0034] definition

[0035] The terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the present disclosure. As used herein, unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" are intended to also include the plural forms.

[0036] A hyphen ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Connecting lines before or after a chemical group are for convenience; a chemical group may be used with or without one or more connecting lines without losing its general meaning. A wavy or dashed line drawn through a line in a structure indicates the specific point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0037] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0038] When used before a numerical value indicating, for example, temperature, time, amount, concentration, etc., including ranges, the term "about" indicates an approximate value that can vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. In one embodiment, when used in relation to a dosage, the term "about" means that the dosage can vary by + / - 10%.

[0039] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding other elements.

[0040] When used to define compositions and methods, "consisting essentially of shall be meant to exclude other elements having any significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0041] "Consisting of" shall mean excluding more than trace elements of other ingredients and substantial process steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0042] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has from 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, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is named by chemical name or represented by a molecular formula, all positional isomers having that number of carbon atoms are encompassed; 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).

[0043] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups (e.g., methylene, ethylene, and propylene), "arylene" or "arylenyl" groups (e.g., phenylene or naphthylene, or heteroarylene quinolinyl), respectively. Furthermore, unless otherwise expressly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atoms by which the moiety is connected to the rest of the molecule.

[0044] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 (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 (ie, C 2-4 Examples of alkenyl groups include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0045] "Alkynyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 12 (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 those groups having one triple bond and one double bond.

[0046] "Alkoxy" refers to an "alkyl-O-" group. 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.

[0047] “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.

[0048] "Acyl" refers to -C(O)R y Group, where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl and benzoyl.

[0049] "Acmido" refers to a "C-acmido" group (which refers to the group -C(O)NR y R z ) and "N-amido" groups (which refers to the group -NR y C(O)R z ) Both, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted, as defined herein, or R y and R z Together they form a cycloalkyl or heterocyclyl group; each of these groups may be unsubstituted or substituted as defined herein.

[0050] "Amino" refers to the group -NR y R z , where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein.

[0051] "(Alkyl)amino" refers to -NH(alkyl). For example, "(C1-C4 alkyl)amino" refers to an amine substituted with an alkyl group having 1-4 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 1-4 carbon atoms.

[0052] "Amidino" refers to -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 these groups may be unsubstituted or substituted as defined herein.

[0053] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) (including fused systems). As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12aryl) or 6 to 10 carbon ring atoms (i.e., C 6-10 Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group, regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is a heterocyclyl group, regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the point of attachment.

[0054] "Carbamoyl" refers to an "O-carbamoyl" group (which refers to the group -OC(O)NR y R z ) and "N-carbamoyl" (which refers to the group -NR y C(O)OR z ) Both, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein.

[0055] "Carboxylate" or "ester" refers to -OC(O)R x and -C(O)OR x Both, of which R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein.

[0056] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring 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 cycloalkenyl groups having at least one sp 3 As used herein, a cycloalkyl group has from 3 to 20 ring carbon atoms (i.e., C 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 3-6Cycloalkyl). 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, decahydrodecalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. In addition, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aromatic ring, regardless of its connection to the rest of the molecule. In addition, when two substitution positions are present on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", for example, spiro[2.5]octanyl, spiro[4.5]decyl or spiro[5.5]undecyl.

[0057] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0058] "Imino" refers to the group -C(NR y )R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein.

[0059] "Imido" refers to the group -C(O)NR y C(O)R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein.

[0060] "Guanidino" refers to the group -NHC(=NH)NH2.

[0061] "Halogen" or "halo" refers to an atom occupying Group VIIA of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, or iodine.

[0062] "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 by halogen. For example, when the residue is replaced by more than one halogen, it can be referred to by using a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to alkyl substituted by two (" two ") or three (" three ") halo groups (which can be, but need not necessarily be, the same halogen). The example of haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0063] "Haloalkoxy" refers to an alkoxy group as defined above wherein one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

[0064] "Hydroxyalkyl" refers to an alkyl group as defined above in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0065] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) (excluding any terminal carbon atoms) are each independently replaced by the same or different heteroatom groups, provided that the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of these groups can be unsubstituted or substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -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 y (i) alkyl, alkylene, 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.

[0066] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 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 carbon ring atoms (ie, C 3-8 In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, 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, benzothiophenyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, phenylthio (i.e., thiophenyl), imidazolyl, indazole

[0015] Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]phenylthio, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group may be attached via any ring of the fused system. Any aromatic ring, with single or multiple fused rings, containing at least one heteroatom is considered a heteroaryl group, regardless of how it is attached to the rest of the molecule (i.e., through any of the fused rings). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0067] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-."

[0068] "Heterocyclyl" - used interchangeably with "heterocycloalkyl" - refers to a saturated or partially unsaturated cyclic alkyl group in which one or more ring heteroatoms are 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 group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic, and can 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 a heterocyclyl, regardless of how it is attached (i.e., it can be attached through a carbon atom or a heteroatom). In addition, the term "heterocyclyl" is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of how it is attached to the rest of the molecule. As used herein, a heterocyclyl group has from 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 (ie, C 3-8 heterocyclyl) or 3 to 6 ring carbon atoms (ie, C 3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepanyl, benzodioxolyl, benzo[b][1,4]dioxolyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, dihydroindolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolinyl, octahydroisoindolinyl, 2-oxopiperazinyl, 2-oxopiperazinyl The term "heterocyclyl" also includes spiroheterocyclyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When two substitution positions are present on the same carbon atom, the term "heterocyclyl" also includes spiroheterocyclyl. The example of spiro heterocyclyl ring includes, for example, bicyclic and tricyclic systems, such as oxabicyclo [2.2.2] octyl, 2-oxa -7- azaspiro [3.5] nonyl, 2-oxa -6- azaspiro [3.4] octyl and 6-oxa -1- azaspiro [3.3] heptyl. The example of fused heterocyclyl ring includes, but is not limited to, 1,2,3,4- tetrahydroisoquinolinyl, 4,5,6,7- tetrahydrothieno [2,3-c] pyridinyl, indolinyl and isoindolinyl, wherein the heterocyclyl can be combined via any ring of the fused system. In some embodiments, heterocycloalkyl can be substituted on a heteroatom by an oxo group (e.g., S=O, S(=O) 2).

[0069] "Heterocycloalkyl" refers to the group "heterocyclo-alkyl-."

[0070] "Oxime" refers to the group -CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0071] "Oxo" refers to the moiety =0.

[0072] "Sulfonyl" refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0073] "Sulfinyl" refers to the group -S(O)R y , where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0074] "Sulfonamido" refers to the group -SO2NR y R z and -NR y SO2R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these groups may be unsubstituted or substituted as defined herein.

[0075] The term "optional" or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. In addition, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced with a moiety other than hydrogen.

[0076] As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond with a non-hydrogen atom, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, 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, thio, N-oxide, or -Si(R y )3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0077] In certain embodiments, "substituted" includes any of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by 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- 2OR g 、-NR g S(O) 1-2 NR g R h , =NSO2R g 、=NOR g 、-S(O) 1-2 NR g R h In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-CH2SO2R g or -CH2SO2NR g R h Replacement. In the above, R g and Rh 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" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond with amino, cyano, hydroxy, imino, nitro, oxo, thio, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl, or R g and R h The two of the radicals, taken together with the atoms to which they are attached, form a heterocyclyl ring which is unsubstituted or substituted with oxo, halo, or alkyl which is unsubstituted or substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0078] Polymers or similar indefinite structures obtained by defining substituents with unlimited additional further substituents (e.g., substituted aryl with substituted alkyl, which is itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substituents in the compounds described herein is three. For example, the 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 unallowed substitution patterns (e.g., a methyl group substituted by 5 fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unallowed 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.

[0079] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0080] Any compound or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures depicted 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, such as, respectively. 2 H. 3 H. 11 C. 13 C. 14C. 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, for example, incorporating radioactive isotopes such as 3 H and 14 Such isotopically labeled compounds can be used in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0081] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen atoms (such as hydrogen atoms on carbon atoms) are replaced by deuterium. Such compounds exhibit increased metabolic resistance 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 methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0082] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties, which relate to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements and / or an improvement in the therapeutic index. F 、 3 H or 11 C-labeled compounds can be used for PET, SPECT or other imaging studies. Isotopically labeled compounds and prodrugs thereof disclosed herein can generally be prepared by performing the procedures disclosed in the schemes or examples or the preparations described below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It should be understood that deuterium in this context is considered a substituent in the compounds described herein.

[0083] The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, 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 intended to represent deuterium.

[0084] 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.

[0085] Also provided are compounds described herein or pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs thereof. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0086] The term "solvate" may include, but is not limited to, solvates that retain one or more of the activities and / or properties of the compound and are not undesirable. Examples of solvates include, but are not limited to, compounds in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or a combination thereof.

[0087] 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. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing 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 prepared 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-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines such as 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)), dienylamines (i.e., HN(alkenyl)2), trialnylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkyl) , mono-, di- or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl), N(cycloalkyl), mono-, di- or tri-arylamines (i.e., NH2(aryl), HN(aryl), N(aryl), or mixed amines, and the like. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, triisopropylamine, tri-n-propylamine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0088] Some of the compounds can exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown and no matter how the nature of the equilibrium between the tautomers is, it is understood by those of ordinary skill in the art that compounds include both amide tautomers and imidic acid tautomers. Therefore, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0089] The compounds or their pharmaceutically acceptable salts include asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)- (or as (D)- or (L)- for amino acids). The present disclosure is intended to include all such possible isomers and 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, for example, chromatography and / or fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that the compounds include both E and Z geometric isomers.

[0090] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds but with different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers or mixtures thereof and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0091] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0092] Relative centers of compounds as depicted herein are represented graphically using a "fat bond" style (bold or parallel lines), and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0093] "Prodrug" means any compound according to the structure described herein that releases the active parent drug in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying the functional groups present in the compounds described herein in a manner such that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in these compounds in a manner such that the modifications are cleaved in conventional operations or in vivo to form the parent compound. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl or sulfhydryl groups in the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate free hydroxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives) of the hydroxyl functional groups in the compounds described herein, amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) and the like. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 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 hereby incorporated by reference in its entirety.

[0094] Compound

[0095] In some embodiments, provided herein is a compound that binds to and modulates cereblon and, in some cases, degrades IKZF2, having Formula I:

[0096]

[0097] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0098] in:

[0099] m and p are independently zero, one, two or three;

[0100] n is zero, one, or two;

[0101] q is one, two, or three;

[0102] r is zero, one, or two;

[0103] s is zero when r is non-zero and is one when r is zero;

[0104] t is zero or one;

[0105] u is one or two;

[0106] X is hydrogen, deuterium or fluorine;

[0107] Y is oxygen or NR, wherein R is hydrogen or C1-C4 alkyl;

[0108] Z and Z 1 Each independently CR 1 or N;

[0109] Each R 1 are independently selected from hydrogen, amino, unsubstituted or substituted by one to three R 5 (C1-C4 alkyl)amino substituted with substituents, unsubstituted or substituted with one to three R 5 Di-(C1-C4 alkyl)amino, cyano, halo, hydroxy, unsubstituted or substituted by one to three R 5 C1-C4 alkyl substituted with substituents and unsubstituted or substituted with one to three R 5 a C1-C4 alkoxy group substituted with a substituent; or

[0110] When Z 1 CR 1 When two adjacent R 1 Together with the carbon atoms to which they are attached, they form C3-C7 cycloalkyl, C6-C 10 aryl, 4- to 7-membered heterocycloalkyl having one to three heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having one to three heteroatoms selected from oxygen, nitrogen, and sulfur, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently replaced by one to three R 6 group substitution;

[0111] Each R 2 independently selected from cyano, halo, hydroxy, amino, unsubstituted or substituted by one to three R 5 C1-C4 alkylamino substituted with substituents, unsubstituted or substituted with one to three R 5 Di-(C1-C4 alkyl)amino substituted with a substituent, unsubstituted or substituted with one to three R 5 C1-C4 alkyl substituted with substituents and unsubstituted or substituted with one to three R 5 a C1-C4 alkoxy group substituted with a substituent;

[0112] Each R 3Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocycloalkyl group, each of which is surrounded by one to three R 7 Substituent substitution;

[0113] R 4 Selected from hydrogen and -CH2-OR 8 , where R 8 C(O)-R 9 OR-P(O)(OR 10 )2, where R 9 is a C1-C4 alkyl group or a C1-C4 alkoxy group, and each R 10 are independently H or C1-C4 alkyl;

[0114] Each R 5 are independently amino, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxy or C1-C4 alkoxy;

[0115] Each R 6 independently selected from amino, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxy and oxo;

[0116] Each R 7 independently selected from amino, C1-C4 alkyl which is unsubstituted or substituted by 1 to 3 halo, C1-C4 alkoxy which is unsubstituted or substituted by one to three halo, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxy, nitro, oxo, C5-C6 heteroaryl having one to three heteroatoms selected from O, NR and / or S, 4 to 7 membered heterocycloalkyl having one to three heteroatoms selected from oxygen, nitrogen and / or sulfur, and -C(O)CH3; and

[0117] R 11 is hydroxy, halo or cyano.

[0118] In some embodiments, the compound of Formula I that binds to cereblon and modulates and, in some cases, degrades IKZF2 has the structure of Formula II:

[0119]

[0120] 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.

[0121] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula II-1:

[0122]

[0123] 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.

[0124] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula II-2:

[0125]

[0126] 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.

[0127] In some embodiments, compounds of Formula I that bind to cereblon and modulate and, in some cases, degrade IKZF2 have the structure of Formula IIA:

[0128]

[0129] 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.

[0130] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIA-1:

[0131]

[0132] 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.

[0133] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIA-2:

[0134]

[0135] 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.

[0136] In some embodiments, compounds of Formula I that bind to cereblon and modulate and, in some cases, degrade IKZF2 have the structure of Formula IIB:

[0137]

[0138] 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.

[0139] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIB-1:

[0140]

[0141] 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.

[0142] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIB-2:

[0143]

[0144] 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.

[0145] In some embodiments, compounds of Formula I that bind to cereblon and modulate and, in some cases, degrade IKZF2 have the structure of Formula IIC:

[0146]

[0147] 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.

[0148] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIC-1:

[0149]

[0150] 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.

[0151] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIC-2:

[0152]

[0153] 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.

[0154] In some embodiments, compounds of Formula I that bind to cereblon and modulate and, in some cases, degrade IKZF2 have the structure of Formula IID:

[0155]

[0156] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 1 、R 3 and R 4 As defined herein.

[0157] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IID-1:

[0158]

[0159] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 1 、R 3 and R 4 As defined herein.

[0160] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IID-2:

[0161]

[0162] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 1 、R 3 and R 4 As defined herein.

[0163] In some embodiments, compounds of Formula I that bind to cereblon and modulate and, in some cases, degrade IKZF2 have the structure of Formula IIE:

[0164]

[0165] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 7 As defined herein.

[0166] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIE-1:

[0167]

[0168] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 7 As defined herein.

[0169] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IIE-2:

[0170]

[0171] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 7 As defined herein.

[0172] In some embodiments, in the compound of Formula I or II or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, X is hydrogen, deuterium or fluoro. In some embodiments, in the compound of Formula I or II or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, X is hydrogen. In some embodiments, in the compound of Formula I or II or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, X is deuterium. In some embodiments, in the compound of Formula I or II or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, X is fluoro.

[0173] In some embodiments, in the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, q is one, r is one, and s is zero. In some embodiments, in the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, q is one, r is zero, and s is one.

[0174] In some embodiments, in Formula I, Formula II or its subformulas, Formula III compounds or their pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, m is zero. In some embodiments, in Formula I, Formula II or its subformulas, Formula III compounds or their pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, m is one. In some embodiments, in Formula I, Formula II or its subformulas, Formula III compounds or their pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, m is two. In some embodiments, in Formula I, Formula II or its subformulas, Formula III compounds or their pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, m is three.

[0175] In some embodiments, in the compound of Formula I, II, or its subformulae, or Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, n is zero. In some embodiments, in the compound of Formula I, II, or its subformulae, or Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, n is one. In some embodiments, in the compound of Formula I, II, or its subformulae, or Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, n is two.

[0176] In some embodiments, in the compound of Formula I, II, or its subformulae, Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, u is one. In some embodiments, in the compound of Formula I, II, or its subformulae, Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, u is two.

[0177] In some embodiments, in the compound of Formula I, II, or its subformulae, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, p is zero. In some embodiments, in the compound of Formula I, II, or its subformulae, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, p is one. In some embodiments, in the compound of Formula I, II, or its subformulae, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, p is two. In some embodiments, in the compound of Formula I, II, or its subformulae, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, p is three.

[0178] In some embodiments, in the compound of Formula I, II, or its subformulae, Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, t is zero. In some embodiments, in the compound of Formula I, II, or its subformulae, Formula III, or its pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers, t is one.

[0179] In some embodiments, in the compound of Formula I, II or its subformulae, Formula III, IV, V, VI or its pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, R 4 In some embodiments, in the compounds of Formula I, II, or subformulae thereof, Formula III, IV, V, VI, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof, R 4 -CH2-OC(O)-R 9 or -CH2-OP(O)(OR 10 )2. In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV, V, VI or its pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer, R 4 In some embodiments, in the compound of Formula I, II or its subformulae, Formula III, IV, V, VI or its pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, R 4 It is -CH2-OP(O)(OCH3)2, -CH2-OP(O)(OCH2CH3)2, -CH2-OP(O)(OCH2CH2CH3)2 or -CH2-OP(O)(O(CH(CH3)2)2.

[0180] In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV, V, VI or its pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer, Z and Z 1 Each is CR 1 In some of such embodiments, Z and Z 1 In some embodiments, in the compounds of Formula I, II, or sub-formulas thereof, Formula III, IV, V, VI, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof, Z and Z 1 Each is CR 1 , one of the R 1 is halo, such as bromo, fluoro or chloro, and the other R1 In some embodiments, in the compounds of Formula I, II, or sub-formulas thereof, Formula III, IV, V, VI, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof, Z and Z 1 Each is N. In some embodiments, in the compound of Formula I, II or its sub-formula, Formula III, IV, V, VI or its pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer, Z or Z 1 One of them is CR 1 and Z or Z 1 The other of is N. In some of such embodiments, Z or Z 1 One of them is CH and Z or Z 1 The other of is N. In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV, V, VI or its pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer, R 1 is H. In some embodiments, in the compound of Formula I, II or its sub-formulas III, IV, V, VI or their pharmaceutically acceptable salts, solvates, stereoisomers and / or tautomers, one R 1 is H, and the other R 1 In some embodiments, in a compound of Formula I, II, or its sub-formula, 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 In some embodiments, Z and Z 1 Each is CH, and R 1 For hydrogen.

[0181] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula III:

[0182]

[0183] 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 Each is CH.

[0184] In some embodiments, compounds of Formula I that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula IV:

[0185]

[0186] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 3 、R 4 , Y, Z and Z 1 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 Each is CH.

[0187] In some embodiments, compounds of Formula IV that bind to and modulate cereblon and, in some cases, degrade IKZF2 have the structure of Formula V:

[0188]

[0189] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 4 、R 7 , Y, Z and Z 1 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 Each is CH.

[0190] In some embodiments, the compound of Formula IV that binds to and modulates cereblon and, in some cases, degrades IKZF2 has the structure of Formula VI:

[0191]

[0192] or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, wherein R 4 、R 7 , Y, Z and Z 1As 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 Z 1 Each is CH.

[0193] In some embodiments, in the compound of Formula I, II or its subformulae, Formula III, IV or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers, each R 3 joined to the carbon atom to which it is attached to form a 3-, 4-, 5-, or 6-membered cycloalkyl or heterocycloalkyl group, each of which is surrounded by one to three R 7 Substituent substitution.

[0194] In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 is joined to the carbon atom to which it is attached to form a 3-membered cycloalkyl group, which is surrounded by one to three R 7 In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 is joined to the carbon atom to which it is attached to form a 4-membered cycloalkyl group, which is surrounded by one to three R 7 In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 is joined to the carbon atom to which it is attached to form a 5-membered cycloalkyl group, which is surrounded by one to three R 7 In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 is joined to the carbon atom to which it is attached to form a 6-membered cycloalkyl group, which is surrounded by one to three R 7 Substituent substitution.

[0195] In some embodiments, in the compound of Formula I, II or its subformulae, Formula III, IV or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers, each R 3 and the carbon atom to which it is attached to form a 3-membered heterocycloalkyl group, which is surrounded by one to three R 7In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 and the carbon atom to which it is attached to form a 4-membered heterocycloalkyl group, which is surrounded by one to three R 7 In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 and the carbon atom to which it is attached to form a 5-membered heterocycloalkyl group, which is surrounded by one to three R 7 In some embodiments, in the compound of Formula I, II or its subformula, Formula III, IV or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, each R 3 and the carbon atom to which it is attached to form a 6-membered heterocycloalkyl group, which is surrounded by one to three R 7 Substituent substitution.

[0196] In some embodiments, in the compound of Formula I, II or its subformula, Formula III or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, Selected from

[0197] In some embodiments, provided herein are compounds selected from Table 1, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof.

[0198] Table 1

[0199]

[0200]

[0201]

[0202] In some embodiments, provided herein are cereblon-binding compounds selected from Table 1A, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof.

[0203] Table 1A

[0204]

[0205] 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.

[0206] Table 1B

[0207]

[0208]

[0209]

[0210] In some embodiments, provided herein are compounds selected from Table 2, or pharmaceutically acceptable salts, solvates, stereoisomers, and / or tautomers thereof.

[0211] Table 2

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219] General synthetic method

[0220] Formula I, II, III, IV, V and VI compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be appreciated that while typical process conditions (i.e., reaction temperature, time, reactant molar ratio, solvent, pressure, etc.) may be used, other process conditions may also be used unless otherwise specified. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0221] In addition, as will be apparent to those skilled in the art, conventional blocking groups may be necessary to prevent certain functional groups from experiencing undesirable reactions. It is well known in the art to specify suitable blocking groups for various functional groups and to protect specific functional groups and to deprotect suitable conditions for these groups. For example, many blocking groups are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999 and the references cited therein.

[0222] In addition, as will be apparent to those skilled in the art, intermediates and final compounds obtained as mixtures of enantiomers can be separated into their respective enantiomers by liquid chromatography using chiral stationary phases to achieve chiral selectivity. Suitable chiral stationary phases and suitable conditions for chiral separations are well known in the art. For example, many methods are described in F. Toda, Enantiomeric Separation: Fundamentals and Practical Methods, 1st edition, Springer, Dordrecht, 2004 and references cited therein.

[0223] The starting material for the following reaction is a commonly known compound or can be prepared by known procedures or its obvious modification. For example, many starting materials can be obtained from commercial suppliers (such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA)). Other starting materials can be prepared by being described in the procedures in the standard reference texts such as below or its obvious modification:Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 to 15 (John Wiley, and Sons, 2016), Rodd's Chemistry of Carbon Compounds, Volumes 1 to 5 and Supplement (ElsevierScience Publishers, 2001), Organic Reactions, Volumes 1 to 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).

[0224] Synthesis of representative compounds

[0225] The general synthesis of the compounds described herein is illustrated in the following reaction schemes. In the following schemes, 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.).

[0226]

[0227] For the reaction in Scheme 1, in the first step, at least a stoichiometric amount of the protected amino alcohol compound 1-2 is reacted with compound 1-1 (CAS# 64169-34-2 (wherein R 1 =H; Z and Z 1 Each is CH)) in an inert diluent such as THF, MeCN, toluene, etc., typically in the presence of a suitable catalyst such as Ir, Cu (OAc) 2, SmI 2, etc. The reaction is typically maintained at 20 ° C to 50 ° C until substantially complete. Conventional workup of the reaction solution can be followed by separation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compounds 1-3.

[0228] In the next step, at least a stoichiometric amount of thionyl chloride is combined with compound 1-3 in a diluent such as methanol, ethanol, etc. The reaction is typically maintained at 50° C. to 80° C. until substantially complete. Conventional workup of the reaction solution may be followed by separation and / or purification procedures such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 1-4.

[0229] In the next step, at least a stoichiometric amount of 3-aminopiperidine-2,6-dione hydrochloride (CAS# 24666-56-6 (where R 4 =H; X=H; q=1; r=0; s=1)) i.e., compound 1-5, is combined with compound 1-4 in an inert diluent (such as dichloromethane, tetrachloromethane, etc.) in the presence of a suitable base (such as triethylamine, diisopropylethylamine, pyridine, etc.). The reaction is typically maintained at 0°C to 30°C until substantially complete. Conventional workup of the reaction solution may be followed by isolation and / or purification procedures such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 1-6.

[0230] In the final step, the tert-butyloxycarbonyl (BOC) protecting group is removed by conventional conditions. The BOC group is exemplary only and other conventional amino blocking groups (such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc.) can be used. After the reaction is complete, the reaction solution can be subjected to conventional treatments and / or purification techniques such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc. to provide compound 1-7, which serves as an intermediate for the synthesis of the compound of formula IA.

[0231]

[0232] For the reaction in Scheme 2, the first step is a conventional alkylation reaction in which at least a stoichiometric amount of an alkylating agent 2-9 is combined with dimethyl malonate (compound 2-8) in an inert diluent (such as DMF, THF, MeCN, etc.) in the presence of a suitable base (such as sodium hydride, LDA, n-butyl lithium, cesium carbonate, etc.). Q is a leaving group (including but not limited to Br, Cl, I, triflate, etc.). The reaction is typically maintained at 0° C. to 70° C. until substantially complete. Conventional workup of the reaction solution may be followed by separation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc. to provide compound 2-10.

[0233] In the next step, at least a stoichiometric amount of compound 2-10 is reacted in an inert diluent (such as THF, MeCN, toluene, etc.) in the presence of a suitable reducing agent (such as lithium aluminum hydride, borane, etc.). The reaction is typically maintained at 0° C. to 30° C. until substantially complete. Conventional workup of the reaction solution may be followed by separation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc. to provide compound 2-11.

[0234] In the next step, the diol is converted into a suitable leaving group and at least a stoichiometric amount of p-toluenesulfonyl chloride is added to compound 2-11 in an inert diluent (such as THF, MeCN, toluene, etc.) in the presence of a suitable base (such as triethylamine, diisopropylethylamine, pyridine, etc.). The reaction is typically maintained at 0° C. to 30° C. until substantially complete. The Ts group is merely exemplary and other conventional leaving groups such as iodine, bromine, triflate, mesylate, etc. can be used. Conventional workup of the reaction solution can be followed by separation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc. to provide compound 2-12.

[0235] 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, toluene, etc.) in the presence of a suitable base (such as triethylamine, diisopropylethylamine, pyridine, etc.). The reaction is typically maintained at 80° C. to 120° C. until substantially complete. Conventional workup of the reaction solution may be followed by separation and / or purification procedures such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of formula IA.

[0236]

[0237] In some embodiments, compounds of Formula I and its subformulae are prepared as shown in Scheme 3. In Scheme 3, the first step is a conventional esterification and chlorination reaction, wherein at least a stoichiometric amount of thionyl chloride is reacted with 5-bromoisobenzo-1(3H)-one (CAS# 64169-34-2 (where R1 =H; Z and Z 1 The reaction mixture is then stirred for 1 h. The mixture is stirred for 1 h. The mixture is stirred for 2 h. The mixture is stirred for 3 ...2 h. The mixture is stirred for 3 h. The mixture is stirred for 3 h. The mixture is stirred for 1 h. The mixture is stirred for 2 h. The mixture is stirred for 3 h. The mixture is stirred for 1 h.

[0238] In the next step, at least a stoichiometric amount of 3-aminopiperidine-2,6-dione hydrochloride (CAS# 24666-56-6 (where R 4 =H; X = H; q = 1; r = 0; s = 1)) Compound 1-5 is combined 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 can be followed by isolation and / or purification procedures such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc. to provide Compound 3-16.

[0239] In the next step, at least a stoichiometric amount of compound 3-17 is combined with compound 3-16 in an inert diluent (such as THF, MeCN, toluene, etc.) in the presence of a suitable catalyst (such as Ir, Cu (OAc) 2, SmI 2, etc.). The reaction is typically maintained at 60 ° C to 80 ° C until substantially complete. Conventional workup of the reaction solution can be followed by separation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc. to provide compound 3-18.

[0240] In the next step, at least a stoichiometric amount of an oxidizing agent is combined with compound 3-18 under conventional oxidation reaction conditions well known in the art, including the use of Jones reagent, meta-chloroperbenzoic acid (mCPBA), Dess-Martin periodinane, and the like. The reaction is typically carried out in an inert solvent such as MeCN, THF, dichloromethane, toluene, and the like. The reaction is typically carried out at about 0° C. to about 30° C. for a period of time to substantially complete the reaction, as evidenced by, for example, thin layer chromatography. After the reaction is complete, conventional workup of the reaction solution may be followed by separation and / or purification processes, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like, to provide compound 3-19.

[0241] In the final step, at least a stoichiometric amount of a suitable amine, i.e., 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 , etc. The reaction is typically carried out in an inert solvent such as MeCN, MeOH, THF, etc. The reaction is typically carried out at about 0° C. to about 30° C. for a period of time to substantially complete the reaction, as demonstrated by, for example, thin layer chromatography. After completion of the reaction, the conventional treatment of the reaction solution can be followed by separation and / or purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., optionally using such processes to provide a compound of Formula I.

[0242] Other starting materials used herein are well known in the art, commercially available, or can be prepared by conventional synthetic methods.

[0243] method

[0244] In one embodiment, the compounds of Formulas I, II, III, IV, V, and VI and compositions described herein can be used in a method for modulating cereblon activity. The method comprises 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 the compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0245] In one embodiment, the compounds of Formulas I, II, III, IV, V, and VI and compositions described herein can be used in a method for treating an IKZF2-dependent disease or condition, or a disease or condition mediated at least in part by IKZF2. The method comprises administering to a subject suffering from an IKZF2-dependent disease or condition an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof.

[0246] In one embodiment, the compounds and compositions of Formulas I, II, III, IV, V, and VI described herein selectively modulate IKZF (e.g., over the translation termination factor GSPT1). In some embodiments, the compounds and compositions of Formulas I, II, III, IV, V, and VI described herein selectively modulate IKZF2 over GSPT1.

[0247] In one embodiment, provided is a compound as described herein or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, for use in treating an IKZF2-dependent disease or disorder.

[0248] In one embodiment, the method relates to a compound as described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, for use in the manufacture of a medicament for reducing the level of IKZF2 protein, wherein reducing the level of such protein treats or ameliorates a disease or condition.

[0249] In one embodiment, the methods described herein comprise the use of prodrugs of the compounds described herein.

[0250] 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 the compound or a pharmaceutically acceptable salt, solvate, stereoisomer and / or tautomer thereof, for use as described herein, wherein cereblon targeting is involved in the dose-response IC 50 The desired compound concentration is in the range of about 0.003 μM to about 0.06 μM. Cereblon targets the dose response IC 50 Measured by the assay 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.

[0251] 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 the compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for a use as described herein, wherein IKZF2 degradation of the compound described herein at a concentration of 1 μM is in the range of about 25%-99%. IKZF2 degradation is measured by an assay described in the Biological Examples. In some embodiments, IKZF2 degradation 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, IKZF2 degradation 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, IKZF2 degradation is greater than 60%. In some embodiments, IKZF2 is degraded by more than 70%. In some embodiments, IKZF2 is degraded by more than 80%. In some embodiments, IKZF2 is degraded by more than 90%.

[0252] Non-limiting examples of IKZF2-dependent diseases or disorders include proliferative diseases or disorders, which can be non-cancerous or cancerous.

[0253] Examples of non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative disorders; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic lung 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 injury; nerve damage; Alzheimer's disease; Zymheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Rett's syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; herniated, ruptured, or prolapsed disc syndrome; osteolithiasis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases such as osteoporosis; graft-versus-host disease; multiple sclerosis; lupus; fibromyalgia; HIV and other viral diseases such as herpes zoster, herpes simplex type I or II, influenza virus, and cytomegalovirus; and diabetes mellitus.

[0254] In certain embodiments, the compounds or compositions described herein can be used to treat cancer and other proliferative disorders, including but not limited to breast cancer, cervical cancer, colon cancer and rectal 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.

[0255] In certain embodiments, the compounds or compositions described herein can be used to treat cancer (including but not limited to glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal 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 cancer, liver cancer, or esophageal cancer).

[0256] In some embodiments, examples of cancer include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma and brain astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroblastoma, Transected epithelial tumors, optic pathway and hypothalamic gliomas, breast cancer, bronchial adenoma / carcinoid, carcinoid tumors, gastrointestinal tract, nervous system cancer, nervous system lymphoma, central nervous system cancer, 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, lymphomas, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retina Blastoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor (GIST), Germ Cell Tumor and Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor Glioma, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Eye Cancer, Islet Cell Tumor (Endocrine Pancreas), Kaposi's Sarcoma, Kidney Cancer, Kidney Cancer, Laryngeal Cancer, Acute Lymphocytic Leukemia, Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Hairy Cell Leukemia, Lip and Oral Cancer, Liver Cancer, Lung Cancer, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Non-Hodgkin's Lymphoma Lymphoma, primary central nervous system lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycoidosis, myelodysplastic syndrome, myelodysplastic / myeloproliferative disease, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disease, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oral cavity cancercancer), oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pinealoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer Adenocarcinoma, Ewing sarcoma family of tumors, soft tissue sarcomas, uterine cancer, uterine sarcoma, skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue tumors, squamous cell carcinoma, supratentorial primitive neuroectodermal tumors, testicular cancer, pharyngeal cancer, thymoma, thymomas and thymomas, thyroid cancer, transitional cell carcinoma of the renal pelvis and bladder and other urinary organs, gestational trophoblastic tumors, urethral cancer, endometrial cancer, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0257] In certain embodiments, the compounds described herein can be used to treat cancer (including but not limited to glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal 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 cancer, liver cancer or esophageal cancer) and / or other cancers described herein.

[0258] In certain embodiments, the compounds described herein are useful in the treatment of cancer and other proliferative disorders, including but not limited to breast cancer, cervical cancer, colon cancer and rectal 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.

[0259] In certain embodiments, the compounds and compositions described herein can be used to treat an IKZF2-dependent disease or condition, such as liposarcoma, glioblastoma, bladder cancer, adrenocortical carcinoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical, oropharyngeal, penile, anal, thyroid, or vaginal cancer, or Epstein-Barr virus-associated nasopharyngeal, gastric, rectal, thyroid, Hodgkin lymphoma, or diffuse large B-cell lymphoma. The cancer can be selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumors, 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 condition 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 condition is a disease or condition selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC) and microsatellite stable colorectal cancer (mssCRC).

[0260] The compounds of the present disclosure may be administered in an amount effective to treat or prevent a disorder in a subject and / or prevent its progression.

[0261] Generally speaking, the methods of using the compounds of the present application comprise administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0262] In certain embodiments, the compounds described herein can be used to treat proliferative diseases (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, the level of target cell proteins (e.g., pathogenic proteins and oncogenic proteins) is regulated or their growth is inhibited or the protein is degraded by contacting the cells with the compounds or compositions described herein. In other embodiments, the compounds can be used to treat cancer.

[0263] Therefore, in another aspect of the present application, a method for treating cancer is provided, comprising administering a therapeutically effective amount of a compound or composition described herein to a subject in need thereof. In certain embodiments, a method for treating cancer is provided, comprising administering a therapeutically effective amount of a compound or a pharmaceutical composition comprising a compound described herein to a subject in need thereof, the amount and time of which are based on achieving 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 refers to an amount that effectively kills or inhibits the growth of tumor cells. According to the methods of the present application, the compounds and compositions can be administered using any dose and any route of administration that effectively kills or inhibits the growth of tumor cells. Therefore, as used herein, the expression "an amount that effectively kills or inhibits the growth of tumor cells" refers to a sufficient dose of a drug for killing or inhibiting the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age and overall condition of the subject, the severity of the disease, the specific anticancer 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 refers to an amount that effectively reduces the level of a target protein. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition refers to an amount effective to kill or inhibit the growth of skin cells.

[0264] In certain embodiments, the method involves administering to a subject (including but not limited to a human or other mammal in need thereof) a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof.

[0265] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or any of them in combination with one or more additional therapeutic agents.

[0266] Another aspect of the present application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferative disorder in a patient, comprising the step of administering to the patient a compound of Formula I, II, III, IV, V and VI or a composition comprising the same.

[0267] It should be understood that the compounds and compositions according to the methods of the present application can be administered using any amount and any route of administration that is effective for treating cancer and / or a disorder associated with excessive cell proliferation. For example, when using a compound to treat cancer, as used herein, the expression "effective amount" refers to a sufficient amount of the drug to inhibit cell proliferation or to a sufficient amount to reduce the effects of the cancer. The exact amount required will vary from subject to subject, depending on the species, age, and overall condition of the subject, the severity of the disease, the specific anticancer agent, its mode of administration, and the like.

[0268] The present application provides a method for treating a proliferative disease in a subject in need thereof, namely, 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 a subject in need thereof. The proliferative disease can be cancer or a precancerous condition. The present application further provides the use of a compound of the present application or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof for the preparation of a medicament for treating a proliferative disease.

[0269] The present application also provides a method for protecting a subject in need thereof from a proliferative disorder, i.e., administering a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, and / or tautomer thereof to a subject in need of such treatment. The proliferative disorder 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 preparation of a medicament for preventing a proliferative disorder.

[0270] As used herein, the term "proliferative disorder" refers to a disorder in which cell growth is dysregulated or abnormal or both may result in an undesirable disorder or disease (which may or may not be cancerous). The exemplary proliferative disorders of the present application encompass various disorders in which cell division is dysregulated. Exemplary proliferative diseases include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous conditions, tumors in situ, cystic tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, blood tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell whose division rate exceeds or is higher than the expected or observed rate of adjacent or parallel cells in the same tissue. Proliferative disorders include precancerous conditions or precancerous conditions. Proliferative diseases include cancer. In certain embodiments, the methods provided herein are used to treat or alleviate cancer symptoms. The term "cancer" includes solid tumors and hematological tumors and / or malignant tumors. "Precancerous cells" or "precancerous cells" are cells that exhibit proliferative disorders (i.e., precancerous conditions or precancerous conditions). "Cancer cells" or "cancerous cells" are cells that exhibit a proliferative disorder (i.e., cancer). Any reproducible measurement method can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified by using appropriate molecular markers.

[0271] "Hematologic proliferative disorders" are proliferative disorders involving hematologic cells. Proliferative diseases of the hematologic system may include lymphoma, leukemia, myeloid neoplasms, mast cell tumors, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granuloma, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown cause, and essential thrombocythemia. Proliferative disorders of the hematologic system may include hyperplasia, dysplasia, and metaplasia of hematologic cells. In certain embodiments, the compositions of the present application may be used to treat a cancer selected from the group consisting of a hematologic cancer of the present application or a hematologic proliferative disorder of the present application. The hematological cancers of the present application may include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphoma of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, and mast cell leukemia), myeloid tumors, and mast cell tumors.

[0272] "Lung proliferative disorder" is a proliferative disorder involving lung cells. Lung proliferative disorder can include all forms of proliferative disorders that affect lung cells. Lung proliferative disorder can include lung cancer, precancerous or precancerous conditions of the lung, benign growths or lesions of the lung and malignant growths or lesions of the lung, and metastatic lesions of body tissues and organs other than the lung. In some embodiments, the compositions of the present application can be used to treat lung cancer or lung proliferative disorder. Lung cancer can include all forms of lung cancer. Lung cancer can include malignant lung tumors, carcinoma in situ, typical carcinoids, and atypical carcinoids. 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 cell carcinoma, and mesothelioma. Lung cancer can include "scar cancer", bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung tumors with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0273] Pulmonary proliferative disease can include all forms of proliferative disease that affect lung cells. Pulmonary proliferative disease can include lung cancer and pre-lung cancer conditions. Pulmonary proliferative disease includes hyperplasia, metaplasia and dysplasia of the lung. Pulmonary proliferative disease includes asbestos-induced hyperplasia, squamous metaplasia and benign reactive mesothelial metaplasia. Pulmonary proliferative disease can include that columnar epithelium is replaced by stratified squamous epithelium and mucosal dysplasia. The risk of individual development of pulmonary proliferative disease disease exposed to inhalation of harmful environmental factors (such as cigarette smoke and asbestos) may increase. Past lung diseases that may make individuals prone to developing into pulmonary proliferative disease can include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granuloma, asbestosis, fibrosing alveolitis and Hodgkin's disease.

[0274] "Proliferative disorders of the colon" are proliferative disorders involving colon cells. In some embodiments, the proliferative disorders of the colon are colon cancer. In some embodiments, the compositions of the present application can be used to treat colon cancer or proliferative disorders of the colon. Colon cancer can include all forms of colon cancer. Colon cancer can include sporadic and hereditary colon cancer. Colon cancer can include malignant colon tumors, carcinoma in situ, typical carcinoids, and atypical carcinoids. Colon cancer can include adenocarcinomas, squamous cell carcinomas, and adenosquamous cell carcinomas. Colon cancer may be associated with a hereditary syndrome selected from the group consisting of: hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Colon cancer may be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis.

[0275] Colon proliferative disorders can include all forms of proliferative disorders that affect colon cells. Colon proliferative disorders can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colon proliferative disorders can include adenomas. Colon proliferative disorders can be characterized by colon hyperplasia, metaplasia, and dysplasia. Previous colon disease that may predispose an individual to the development of colon proliferative disorders can include previous colon cancer. Current diseases that may predispose an individual to the development of colon proliferative disorders include Crohn's disease and ulcerative colitis. Colon proliferative disorders may be associated with mutations in genes selected from the group consisting of p53, ras, FAP, and DCC. Due to the presence of mutations in genes selected from the group consisting of p53, ras, FAP, and DCC, the risk of an individual developing colon proliferative disorders may increase.

[0276] " pancreatic proliferative disorder " is the proliferative disorder related to pancreatic cells. Pancreatic proliferative disorder can include all forms of proliferative disorders affecting pancreatic cells. Pancreatic proliferative disorder includes pancreatic cancer, pancreatic precancerous disease or precancerous condition, pancreatic hyperplasia, pancreatic dysplasia, benign growth of pancreas or lesions and pancreatic malignant growth or lesions and metastatic lesions of tissues and organs beyond pancreatic cancer. Pancreatic cancer includes all forms of pancreatic cancer. Pancreatic cancer includes 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 histology and ultrastructural heterogeneity (e.g., mixed cell types).

[0277] A "proliferative disorder of the prostate" is a proliferative disorder involving prostate cells. Proliferative disorders of the prostate can include all forms of proliferative disorders affecting prostate cells. Proliferative disorders of the prostate can include prostate cancer, precancerous or precancerous conditions of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, as well as metastatic lesions of tissues and organs other than the prostate. Proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.

[0278] A "proliferative disorder of the skin" is a proliferative disorder involving skin cells. Proliferative disorders of the skin can include all forms of proliferative disorders affecting skin cells. Proliferative disorders of the skin include precancerous or precancerous conditions of the skin, benign hyperplasias or lesions of the skin, melanomas, malignant melanomas, and other malignant growths or lesions of the skin, as well as metastatic lesions to tissues and organs other than the skin. Proliferative disorders of the skin include hyperplasia, metaplasia, and dysplasia of the skin.

[0279] "Proliferative disorders of the ovary" are proliferative disorders involving ovarian cells. Proliferative disorders of the ovary can include all forms of proliferative disorders affecting ovarian cells. Proliferative disorders of the ovary can include precancerous or precancerous conditions of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions to body tissues and organs other than the ovary. Proliferative disorders of the skin include hyperplasia, metaplasia, and dysplasia of ovarian cells.

[0280] "Proliferative disorders of the breast" are proliferative disorders involving breast cells. Proliferative disorders of the breast include all forms of proliferative disorders affecting breast cells. Proliferative disorders of the breast include breast cancer, precancerous or precancerous conditions of the breast, benign growths or lesions of the breast, malignant growths or lesions of the breast, and metastatic lesions to tissues and organs other than the breast. Proliferative disorders of the breast include hyperplasia, metaplasia, and dysplasia of the breast.

[0281] The cancer to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, wherein the tumor (T) has been designated as TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c or T4d stage; and wherein the regional lymph nodes (N) have been designated as NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b or N3c stage; and wherein distant metastasis (M) can be designated as MX, M0 or M1 stage. The cancer to be treated can be staged as I stage, IIA stage, IIB stage, IIIA stage, IIIB stage, IIIC stage or IV stage according to the American Joint Committee on Cancer (AJCC) classification. The cancer to be treated can be designated as GX grade (e.g., grade that cannot be assessed), grade 1, grade 2, grade 3 or grade 4 according to the AJCC classification. Cancers treated can be staged according to the AJCC pathological classification (pN), i.e., pNX, pN0, PN0(I-), PN0(I+), PN0(mol-), PN0(mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0282] Cancer to be treated may include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter. Cancer to be treated may include a tumor that has been determined to be about 2 centimeters to about 5 centimeters in diameter. Cancer to be treated may include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter. Cancer to be treated may include a tumor that has been determined to be greater than 5 centimeters in diameter. Cancer to be treated may be classified as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated by microscopic appearance. Cancer to be treated may be classified by microscopic appearance regarding mitotic count (e.g., amount of cell division) or nuclear pleomorphism (e.g., changes in cells). Cancer to be treated may be classified by microscopic appearance as cancer associated with necrotic areas (e.g., areas of dead or degenerated cells). Cancer to be treated may be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes with abnormal appearance. Cancer to be treated may be classified as aneuploid, triploid, tetraploid, or having altered ploidy. Cancer to be treated may be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a regional deletion, duplication, or amplification of a portion of a chromosome.

[0283] The cancer to be treated can be assessed by DNA cell counting, flow cytometry, or image cytometry. The cancer to be treated can be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis phase of cell division (e.g., in the S phase of cell division). The cancer to be treated can be classified as having a low S phase fraction or a high S phase fraction.

[0284] As used herein, a "normal cell" is a cell that cannot be classified as part of a "proliferative disorder." A normal cell lacks dysregulation or abnormal growth, or both, that may lead to the development of an undesirable condition or disease. In some embodiments, a normal cell has normally functioning cell cycle checkpoint control mechanisms.

[0285] Those skilled in the art can refer to general reference texts for detailed descriptions of known techniques or equivalent techniques discussed herein. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), 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 ed. (1990). Of course, these texts can also be consulted when forming or using aspects of the present application.

[0286] In certain embodiments, the compounds of the present application can be used to treat proliferative diseases (e.g., cancer, benign tumors, inflammatory diseases and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, the level of target cell proteins (e.g., pathogenic proteins and oncoproteins) is regulated or their growth is inhibited by contacting the cells with compounds or compositions described herein. In other embodiments, compounds can be used to treat cancer.

[0287] In certain embodiments, the method involves administering to a subject (including but not limited to a human or animal) in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof.

[0288] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or any of them in combination with one or more additional therapeutic agents.

[0289] For example, other therapies or anticancer agents that can be used in combination with the compounds disclosed herein include surgery, radiation therapy, endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents to mitigate any side effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including but not limited to alkylating drugs (nitrogen mustard, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists, and Antigens and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), spindle toxins (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (adriamycin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase) and hormones (tamoxifen, leuprorelin, flutamide and megestrol acetate), just to name a few. For a more comprehensive discussion of cancer treatment overview, see The Merck Manual, 20th edition, 2020, the entire contents of which are hereby incorporated by reference. See also the National Cancer Institute (NCI) website (www.nci.nih.gov) and the U.S. Food and Drug Administration (FDA) website for FDA-approved tumor drug list (www.fda.gov / cder / cancer / druglistframe).

[0290] In certain embodiments, the pharmaceutical composition comprising the compound disclosed herein further comprises one or more additional therapeutically active ingredients (e.g., chemotherapy and / or palliative care). For the purposes of this application, the term "palliative care" refers to a treatment that focuses on alleviating the symptoms of the disease and / or the side effects of the treatment regimen rather than curative treatment. For example, palliative care encompasses analgesics, antiemetics, and anti-nausea drugs. In addition, chemotherapy, radiotherapy, and surgery can all be used for palliative care (i.e., to alleviate symptoms rather than cure; for example, to shrink a tumor and reduce pressure, bleeding, pain, and other cancer symptoms).

[0291] Administration, pharmaceutical composition

[0292] Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration of the therapeutic agent, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0293] Depending on the intended mode of administration, the disclosed compositions can be in solid, semisolid or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit dosage form, and consistent with conventional pharmaceutical practice. Likewise, they can also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously or intramuscularly, all of which use forms well known to those skilled in the pharmaceutical arts.

[0294] 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, for example, purified water, a triglyceride oil (such as a 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 its esters or triglycerides or a mixture thereof, omega-3 fatty acids or derivatives thereof, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, hard c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), waxes and / or polyvinylpyrrolidone (if desired); d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt or an effervescent mixture; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, such as 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 promote absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0295] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compounds are dissolved in or mixed with 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, frozen microparticles, or serum proteins) can be used to dissolve the disclosed compounds.

[0296] The disclosed compounds may also be formulated as suppositories, which may be prepared from fatty emulsions or suspensions; using polyalkylene glycols, such as propylene glycol, as carriers.

[0297] The disclosed compounds can also 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 phosphatidylcholine.

[0298] In some embodiments, the lipid component film is hydrated with an aqueous solution of the drug to form a lipid layer that encapsulates the drug, as described in US Pat. No. 5,262,564, which is hereby incorporated by reference in its entirety.

[0299] The disclosed compounds can also be delivered by using monoclonal antibodies as a separate carrier coupled to the disclosed compounds. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the disclosed compounds can be coupled with a class of biodegradable polymers for realizing controlled drug release, such as crosslinking or amphiphilic block copolymers of polylactic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels. In one embodiment, the disclosed compounds are not covalently bound to polymers, such as polycarboxylic acid polymers or polyacrylates.

[0300] Parenteral injectable administration is generally for subcutaneous, intramuscular or intravenous injection and infusion. Injections can be prepared in conventional forms as liquid solutions or suspensions or solid forms suitable for dissolution in liquid prior to injection.

[0301] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula I, II, III, IV, V or VI and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent or a surfactant.

[0302] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compound by weight or volume.

[0303] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit comprises a device for separately storing the compositions, such as a container, a divided bottle, or a divided aluminum foil package. An example of such a kit is a blister pack, such as is commonly used for packaging tablets, capsules, and the like.

[0304] The kits of the present disclosure can be used for administering different dosage forms, e.g., oral and parenteral, for administering separate compositions at different dosing intervals, or for titrating separate compositions against each other. To aid compliance, the kits of the present disclosure typically include instructions for administration.

[0305] Pharmaceutical dosage forms of the compounds of the present disclosure can be manufactured by any method well known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee preparation, tableting, suspending, extruding, spray drying, grinding, emulsifying, (nano / micro) encapsulation, embedding or lyophilization processes. As described above, the compositions of the present disclosure may include one or more physiologically acceptable inactive ingredients that assist in processing the active molecule into a product for pharmaceutical use.

[0306] As described above, compositions are typically composed of a compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic effects of the claimed compound. Such excipients can be any solid, liquid, semisolid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[0307] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skimmed milk powder, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal, vegetable or synthetic oils, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, especially liquid carriers for injectable solutions, include water, saline, aqueous dextrose and ethylene glycol.

[0308] The compounds of the present disclosure can be dispersed in aerosol form using compressed gases. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like. Other suitable pharmaceutical excipients and formulations thereof are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 18th edition, 1990).

[0309] If desired, the compositions of the present disclosure may be presented in a package or dispenser device containing one or more unit dosage forms containing the active ingredient. Such packaging or devices may, for example, comprise metal or plastic foil, such as blister packs, or glass and rubber stoppers, such as vials. The package or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the present disclosure formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0310] The amount of compound in the formulation can vary within the range employed by those skilled in the art. Typically, the formulation will contain from about 0.01 wt% to 99.99 wt% of the disclosed compound (in weight percent (wt%)), 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 from about 1 wt% to 80 wt%. Representative pharmaceutical formulations are described below.

[0311] Formulation Examples

[0312] The following are representative pharmaceutical formulations containing compounds of the present disclosure.

[0313] Formulation Example 1 - Tablet Formulation

[0314] The following ingredients are mixed thoroughly and compressed into single scored tablets.

[0315]

[0316] Formulation Example 2 - Capsule Formulation

[0317] Mix the following ingredients thoroughly and fill into hard shell gelatin capsules

[0318]

[0319] Formulation Example 3 - Suspension Formulation

[0320] The following ingredients are mixed to form a suspension for oral administration.

[0321]

[0322] Formulation Example 4 - Injection Formulation

[0323] The following ingredients are mixed to form an injectable formulation.

[0324]

[0325] Formulation Example 5 - Suppository Formulation

[0326] The total weight of the suppository is 2.5 g by mixing the compound of the present disclosure with H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York) was mixed and had the following composition:

[0327]

[0328] Drug administration

[0329] The dosage regimen using the disclosed compounds is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound employed. 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.

[0330] When used for the indicated effects, the effective dose of the disclosed compounds ranges from about 0.5 mg to about 5000 mg of the disclosed compounds required to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compounds, or within the range of one amount to another in the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored.

[0331] The following synthetic and biological examples are intended to illustrate the present disclosure but should not be construed in any way as limiting the scope of the present disclosure.Unless otherwise indicated, all temperatures are in degrees Celsius.

[0332] Examples

[0333] The present disclosure may be further understood by reference to the following examples, which are intended to be purely illustrative of the present disclosure. The scope of the present disclosure is not limited by the exemplary embodiments, which are intended to illustrate only a single aspect of the present disclosure. Any functionally equivalent methods are within the scope of the present disclosure. In addition to the modifications described herein, various modifications of the present disclosure will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications fall within the scope of the appended claims.

[0334] In this specification and the following examples, all temperatures are in degrees Celsius. In addition, the following abbreviations have the following meanings. If not defined, these abbreviations have their generally accepted meanings in the art.

[0335] Abbreviation meaning

[0336] δ chemical shift (ppm)

[0337] ACN or MeCN Acetonitrile

[0338] Boc tert-butyloxycarbonyl

[0339] BRET Bioluminescence Resonance Energy Transfer

[0340] Cbz benzyloxycarbonyl

[0341] DC 50 Concentration that results in 50% degradation of target protein

[0342] DCM dichloromethane

[0343] DHA Docosahexaenoic acid

[0344] DIEA Diisopropylethylamine

[0345] DMAP 4-dimethylaminopyridine

[0346] DMF N,N-dimethylformamide

[0347] DMP Dess-Martin Oxidant

[0348] DMSO dimethyl sulfoxide

[0349] Chloroform-d deuterated chloroform

[0350] d6-DMSO deuterated dimethyl sulfoxide

[0351] d4-methanol deuterated methanol

[0352] EPA Eicosapentaenoic acid

[0353] eq. equivalent

[0354] ESI electrospray ionization

[0355] EtOAc

[0356] FBS fetal bovine serum

[0357] FITC fluorescein isothiocyanate

[0358] Fmoc fluorenylmethoxycarbonyl

[0359] g grams

[0360] 1 H NMR proton nuclear magnetic resonance spectroscopy

[0361] h hour

[0362] HPLC high-performance liquid chromatography

[0363] L liter

[0364] LAH lithium aluminum hydride

[0365] LC liquid chromatography

[0366] LC-MS liquid chromatography-mass spectrometry

[0367] M Moore

[0368] mCPBA m-Chloroperbenzoic acid

[0369] MeOH methanol

[0370] mg milligrams

[0371] mmol millimole

[0372] mL milliliters

[0373] μL microliter

[0374] umol or μmol micromole

[0375] μM micromolar

[0376] μm micrometer

[0377] m / z mass to charge ratio

[0378] min

[0379] N Normal

[0380] nm nanometer

[0381] PBS Phosphate-buffered saline

[0382] PE petroleum ether

[0383] pM picomolar

[0384] Appropriate amount

[0385] Rf retention factor

[0386] rt room temperature

[0387] Rt retention time

[0388] t-Bu tert-butyl

[0389] TEA triethylamine

[0390] TFA trifluoroacetic acid

[0391] THF Tetrahydrofuran

[0392] TPP or PPh3 triphenyl phosphite

[0393] TRITC Tetramethylrhodamine

[0394] TsCl 4-Toluenesulfonyl chloride

[0395] UV

[0396] v / v volume / volume ratio

[0397] wt% weight percentage

[0398] NMR abbreviation br = broad

[0399] d = doublet

[0400] dd = doublet

[0401] m = multiplet

[0402] q = quartet

[0403] s = single peak

[0404] t = triplet

[0405] LC-MS method (general method)

[0406] LC / MS method: Gradient: 5% B over 0.40 min, 5% to 95% B over 0.40-3.00 min, 95% B held for 1.00 min, then 95% to 5% B over 0.01 min; flow rate: 1.0 mL / min. Mobile phase A: 0.04% trifluoroacetic acid in water, mobile phase B: 0.02% trifluoroacetic acid in acetonitrile. Column: Luna C18 50 x 2.0 mm (5 μm particles). Detection: diode array (DAD) and evaporative light scattering (ELSD) with positive electrospray ionization. MS range: 100-1000 Da.

[0407] Example 1

[0408] Preparation of 3-(5-(((1S,2S)-2-(5-azaspiro[2.3]hexane-5-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 12)

[0409]

[0410] 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 (400MHz, d6-DMSO) δ10.95 (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).

[0411] Example 2

[0412] Preparation of 3-(5-(((1S,2S)-2-(6-hydroxy-2-azaspiro[3.3]heptane-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]heptane-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 8)

[0413]

[0414] Step 1:

[0415] To 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) were added (1S,2S)-cyclohexane-1,2-diol (461.15 mg, 3.97 mmol, 1.2 eq), Ir[(dF(CF3)ppy)] To the mixture was added 2-dtbbpy]PF6 (37.12 mg, 33.08 μmol, 0.01 eq) and dtbbpy (44.40 mg, 165.42 μmol, 0.05 eq), NiCl2. Glyme (36.35 mg, 165.42 μmol, 0.05 eq), TMP (560.76 mg, 3.97 mmol, 673.99 μL, 1.2 eq). The mixture was stirred at 25 ° C for 4 hours. The reaction mixture was filtered and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0% to 50% v / v petroleum ether / ethyl acetate) to obtain 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) δ7.65-7.57(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,1H),1.37-1.27(m,3H),1.13(br d,J=7.9Hz,1H),0.90-0.78(m,2H),-0.02(s,9H).

[0416]

[0417] Step 2:

[0418] 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 hours. The reaction mixture was filtered and the filtrate was neutralized with saturated NaHCO. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over NaSO, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0% to 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)δ7.59(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).

[0419]

[0420] Step 3:

[0421] 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 hours. 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 hours. 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) δ10.96(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).

[0422]

[0423] Step 4:

[0424] 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 hours. NaBHCN (23.80 mg, 378.81 μmol, 3 eq) was added to the reaction mixture and stirred at 20° C. for 3 hours. 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)δ10.97(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 = 15.6 Hz, 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. 1HNMR(400MHz,d6-DMSO)δ10.97(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).

[0425] Example 3

[0426] Preparation of 3-(5-(((1S,2S)-2-(6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-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]heptane-2-yl)cyclohexyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 2)

[0427]

[0428] Step 1:

[0429] 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 N2. The mixture was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with water (100 mL) at 0 ° C and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, 0% to 50% v / v petroleum ether in ethyl acetate) to obtain tert-butyl 6-hydroxy-6-methyl-2-azaspiro[3.3]heptane-2-carboxylate. 1H NMR (400MHz, d6-DMSO) δ4.85(s,1H),3.82-3.68(m,4H),2.09(s,4H),1.32(s,9H),1.09(s,3H).

[0430]

[0431] Step 2:

[0432] 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]heptane-6-ol. 1 H NMR(400MHz,d6-DMSO)δ8.86(br s,1H),4.02-3.83(m,4H),2.22-2.14(m,4H),1.13(s,3H).

[0433]

[0434] Step 3:

[0435] 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. 1H NMR (400MHz, d6-DMSO) δ10.97(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(brd,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 = 4.0 Hz, 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. 1 H NMR(400MHz,d6-DMSO)δ10.97(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),3.22(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).

[0436] Additional compounds listed in Table 3 were prepared according to the procedures outlined in the general scheme above, except that the amine in the above examples was replaced with the amine depicted in the final product.

[0437] Table 3

[0438]

[0439]

[0440]

[0441]

[0442]

[0443] Biological example: Cereblon (CRBN) targeted engagement

[0444] HEK-293T cells at approximately 75% confluence were harvested by trypsinization and plated (500,000 cells / well) in 2 mL of Dulbecco's Modified Eagle Medium (DMEM) + 10% fetal bovine serum (FBS) in 6-well tissue culture plates and incubated overnight at 37°C.

[0445] 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 of Nluc-CRBN and 990 ng of the DDB1 expression vector (Promega) was added to 125 μL of Opti-Minimum Essential Medium (Opti-MEM) in a 1.5 mL Eppendorf tube along with 2 μL of P3000 reagent (Thermo Fisher). TM ; Thermo Fisher). This solution was added to the Lipofectamine 3000 transfection reagent (5 μL; Thermo Fisher) in Opti-MEM (125 μL), mixed, and incubated at room temperature for 15 minutes. The transfection mixture was added dropwise to the cells and incubated overnight at 37°C, 5% CO2. After transfection, the cells were washed once with PBS, and trypsin (250 μL) was added and incubated for 30-45 seconds to detach the cells. Complete medium (2 mL) was added to resuspend the cells, thereby forming a single cell suspension. At room temperature, the cells were centrifuged at a speed of 320 x g for 5 min, the supernatant was removed, and the cell pellet was resuspended in Opti-MEM (3 mL; repeated washing steps x2). After final resuspension in 5 mL Opti-MEM, the cells were counted and resuspended in Opti-MEM at a density of 200,000 cells / mL.

[0446] Cereblon targeting engagement was monitored in transfected HEK-293T cells by bioluminescence resonance energy transfer (BRET) using the NanoBRET TE intracellular E3 ligase assay (Promega). Briefly, transfected HEK-293T cells (38 μL / well) were seeded in 384-well plates (white opaque plates, Corning 3574, low binding surface). 2 μL of 10 μM CRBN tracer (diluted 1:5 in tracer dilution buffer) was added to each well. Centrifugation was performed at 320 x g for 1 min at room temperature. Test compounds were added in an 11-point dilution series (typically 10 μM to 100 pM) using a TECAN D300e 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 min at room temperature and then incubated at 37 ° C for 2 hours.

[0447] After incubation, allow the plate to cool to room temperature for 15 minutes. Add 20 μL of 3X complete NanoBRET to each well. TM Substrate plus inhibitor solution (Promega, 1:166 substrate and 1:500 extracellular The plate was covered with foil and incubated at room temperature with shaking for 3 minutes. The plate was read in a CLARIOstar microplate reader (BMG LabTech) at 450 nm (donor emission) and 610 nm (acceptor emission). IC was determined by regression using GraphPad Prism. 50 Values ​​were best fitted to a four-parameter logistic curve.

[0448] IKZF2 degradation assay

[0449] Generation of stable cell lines

[0450] A polycistronic plasmid was constructed for mammalian expression of fluorescent reporter gene fusions of the human transcription factors IKZF1 (Ikaros), IKZF2 (Helios), and IKZF3 (Aiolos). The C-termini of the corresponding protein sequences were linked to three repeats of a GGGGS linker, followed by mNeonGreen, a P2A sequence, and then mScarlet. The DNA sequence of the open reading frame is as follows:

[0451] IKZF1-mNeonGreen-P2A-mScarlet coding sequence (SEQ ID NO. 1):

[0452]

[0453] IKZF2-mNeonGreen-P2A-mScarlet coding sequence (SEQ ID NO 2):

[0454]

[0455] IKZF3-mNeonGreen-P2A-mScarlet coding sequence (SEQ ID NO 3):

[0456]

[0457] IKZF1, IKZF2, and IKZF3 constructs were cloned into the UCOE hygromycin expression vector (Millipore Sigma). Reporter gene 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 by limiting dilution or fluorescence-activated cell sorting.

[0458] The cloned stable cell lines were kept under a constant 200 μg / mL hygromycin B selection and passaged simultaneously for degradation assays. Flow cytometry analysis performed on a BD Accuri C6 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. HEK 293T EF1a-IKZF2 clone 9 had an average FITC MFI of 150,000 and a PE MFI of 26,000. HEK 293T EF1a-IKZF3 clone 9 had an average FITC MFI of 400,000 and a PE MFI of 60,000. The fluorescence intensity of the IKZF1 / 2 / 3-mNeonGreen (FITC channel) and mScarlet (PE channel) reporter genes was regularly analyzed by flow cytometry to confirm consistent expression levels between experiments.

[0459] IKZF1 / 2 / 3 reporter gene degradation assay

[0460] IKZF1 / IKZF2 / IKZF3 degradation assays were performed by harvesting HEK 293T reporter cell lines and resuspending the cells in culture medium formulated for reduced background fluorescence (FluoroBrite; Thermo Fisher). The respective cell lines were seeded at a density of 4,000 cells / well into black-walled, 384-well, optical-grade assay tissue culture plates. The cells were incubated overnight at 37°C to allow attachment to the assay plates. Compound dilutions were prepared in DMSO from 10 mM compound stocks. The assay plates were treated with the appropriate compound concentrations by dispensing the DMSO dilutions into quadruplicate wells at a maximum of 0.5% final DMSO.

[0461] After incubation for 24 hours with the compound, the assay plate was imaged on an ImageXpress Pico microscope system (cells were maintained at 37°C during imaging) to obtain fluorescence readings. The assay plate was imaged in FITC and tetramethylrhodamine (TRITC) channels to obtain mNeonGreen fluorescence intensity (reporter gene degradation data) and mScarlet fluorescence intensity (for cell segmentation). 293T-IKZF1 and 293T-IKZF3 reporter gene cell lines were imaged with 500 milliseconds (ms) exposure for both FITC and TRITC channels, while 293T-IKZF2 reporter cell lines were imaged with 1000 milliseconds exposure for FITC and 1250 milliseconds exposure for TRITC. Using a 2-channel cell scoring analysis with a "positive percentage" reading, the resulting data were analyzed using CellReporter Xpress software. The TRITC channel was selected for "nucleus" segmentation with a threshold of 20, while the FITC channel was selected for "marker 1" segmentation with a threshold of 100 for the IKZF1 and IKZF3 reporter lines. The IKZF2 reporter line had a threshold setting of 120 for the FITC channel and a threshold setting of 20 for TRITC. For each cell line, the minimum segmentation width was set to 6 μm and the maximum segmentation width was set to 15 μm. DC was determined by regression using GraphPad Prism. 50 Calculations were performed to best fit a four-parameter logistic curve.

[0462] Table 4 shows the results from the above assays.

[0463] Table 4

[0464]

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, in: m and p are independently zero, one, two or three; n is zero, one, or two; q is one, two, or three; r is zero, one, or two; s is zero when r is non-zero and is one when r is zero; t is zero or one; u is one or two; X is hydrogen, deuterium or fluorine; Y is oxygen or NR, wherein R is hydrogen or C1-C4 alkyl; Z and Z 1 Each independently CR 1 or N; Each R 1 are independently selected from hydrogen, amino, unsubstituted or substituted by one to three R 5 (C1-C4 alkyl)amino substituted with substituents, unsubstituted or substituted with one to three R 5 Di-(C1-C4 alkyl)amino, cyano, halo, hydroxy, unsubstituted or substituted by one to three R 5 C1-C4 alkyl substituted with substituents and unsubstituted or substituted with one to three R 5 a C1-C4 alkoxy group substituted with a substituent; or When Z 1 CR 1 When two adjacent R 1 Together with the carbon atoms to which they are attached, they form C3-C7 cycloalkyl, C6-C 10 aryl, 4- to 7-membered heterocycloalkyl having one to three heteroatoms selected from oxygen, nitrogen, or sulfur, or 5- to 6-membered heteroaryl having one to three heteroatoms selected from oxygen, nitrogen, and sulfur, wherein each of the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently replaced by one to three R 6 group substitution; Each R 2 independently selected from cyano, halo, hydroxy, amino, unsubstituted or substituted by one to three R 5 C1-C4 alkylamino substituted with substituents, unsubstituted or substituted with one to three R 5 Di-(C1-C4 alkyl)amino substituted with a substituent, unsubstituted or substituted with one to three R 5 C1-C4 alkyl substituted with substituents and unsubstituted or substituted with one to three R 5 a C1-C4 alkoxy group substituted with a substituent; Each R 3 joined together with the carbon atoms to which they are attached to form a 3, 4, 5 or 6 membered cycloalkyl or heterocycloalkyl group, each of which is surrounded by one to three R 7 Substituent substitution; R 4 Selected from hydrogen and -CH2-OR 8 , where R 8 C(O)-R 9 OR-P(O)(OR 10 )2, where R 9 is a C1-C4 alkyl group or a C1-C4 alkoxy group, 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, hydroxy or C1-C4 alkoxy; Each R 6 independently selected from amino, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxy and oxo; Each R 7 independently selected from amino, C1-C4 alkyl which is unsubstituted or substituted by one to three halo, C1-C4 alkoxy which is unsubstituted or substituted by one to three halo, (C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, cyano, halo, hydroxy, nitro, oxo, C5-C6 heteroaryl having one to three heteroatoms selected from O, NR and / or S, 4 to 7 membered heterocycloalkyl having one to three heteroatoms selected from oxygen, nitrogen and / or sulfur, and -C(O)CH3; and R 11 is hydroxy, halo or cyano.

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

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein p is two.

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

5. The compound according to any one of claims 1 to 4, which has the structure of formula III: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

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

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

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z and Z 1 Each is CR 1 .

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

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein m is zero. 11 . The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Y is O.

12. The compound according to any one of claims 1 to 11, which has the structure of formula IV: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

13. The compound according to claim 12, which has the structure of formula V: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

14. The compound according to claim 12, which has the structure of Formula VI: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

15. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Selected from 16. A compound or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof selected from Table 1, Table 1A or Table 1B.

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

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

19. A method for modulating cereblon activity, the method comprising: The cereblon is contacted 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 wherein the cereblon is modulated.

20. A method for degrading IKZF2, comprising: IKZF2 is contacted 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 wherein IKZF2 is degraded.

21. A method of degrading IKZF2 in a subject, the method comprising: 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, is administered to the subject.

22. A method of treating cancer in a subject in need thereof, the method comprising: A subject whose cancer is mediated at least in part by IKZF2 is selected, and 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, is administered to the subject.

23. A method of treating cancer in a subject in need thereof, the method comprising: A subject whose cancer is mediated at least in part by IKZF2 is selected, and an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and 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, is administered to the subject.

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