Quinoxaline dione and pyrido [2, 3-b] pyrazine-2, 3-dione B cell lymphoma 6 (BCL6) degradation agent and application thereof

Abstract

Compounds, compositions, and methods for treating cancers characterized by aberrant B cell lymphoma 6 (BCL6) activity are described.

Description

[0001] Related Applications

[0002] This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application Serial No. 63 / 390,482, filed on July 19, 2022, which is incorporated herein by reference in its entirety.

[0003] background

[0004] BCL6 is a promising drug target for non-Hodgkin lymphomas such as diffuse large B-cell lymphoma (DLBCL) (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)) and follicular lymphoma (Bosga-Bouwer et al., Genes Chromosomes Cancer 44:301-304 (2005)). Pathologically increased BCL6 expression due to somatic BCL6 translocation, exon mutation, promoter mutation or regulatory pathway mutation is a common driver of B cell malignancies (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). In genetically engineered mice, overexpression of BCL6 drives lymphoma development (Cattoretti et al., Cancer Cell 7:445-455 (2005)). As a master transcriptional repressor, BCL6 allows rapid expression of germinal center (GC) B cells and tolerates genomic instability caused by immunoglobulin gene hypermutation and class switching recombination (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). BCL6 inhibits a series of genes related to DNA damage response (Ranuncolo et al., Blood Cells Mol. Dis. 41:95-99 (2008)), cell cycle checkpoints (Tunyaplin et al., J. Immunol. 173:1158-1165 (2004)) and differentiation (Phan et al., Nat. Immunol. 6:1054-1060 (2005)).

[0005] Knockout of BCL6 in lymphoma cells leads to tumor stasis (Schlager et al., Oncotarget 11: 875-890 (2020)). Several peptide and small molecule inhibitors targeting BCL6 have shown efficacy in vivo, but only at high concentrations, which limits their translation into clinical therapeutics (Cerchietti et al., Cancer Cell 17: 400-411 (2010); Cardenas et al., J. Clin. Invest. 126: 3351-3362 (2016)).

[0006] Overview

[0007] A first aspect of the present disclosure relates to a compound having a structure represented by Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0010] is phenyl or pyridyl;

[0011] yes

[0012] X is a bond, (C3-C6)carbocyclyl, (C3-C6)carbocyclyl(C=O) or SO2;

[0013] X0 is N or CCN,

[0014] X1 is CH2, S, CHF, CHCl, CHOH or CF2;

[0015] R1 is (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, (C3-C6) carbocyclyl, 4- to 6-membered heterocyclyl, (C1-C6) alkyl-(C3-C6) carbocyclyl or (C1-C6) alkyl-4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 1a Group substitution, where R 1a is deuterium, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl;

[0016] R2 and R 2’are each independently H, (C1-C3)alkyl, (C1-C3)hydroxyalkyl or (C1-C3)aminoalkyl,

[0017] or R2 and R 2' , together with the same carbon atom to which they are attached, form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 2a Group substitution, where R 2a is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl;

[0018] R3 and R 3’ are each independently H, (C1-C3)alkyl, (C1-C3)hydroxyalkyl or (C1-C3)aminoalkyl, or

[0019] R3 and R 3' , together with the same carbon atom to which they are attached, form C=O, (C3-C6) carbocyclyl, 4-membered to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 3a group substituted, where each R 3a are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl, or two of them 3a The groups, together with the same carbon atom to which they are attached, form C=O,

[0020] or R2 or R 2' and R3 or R 3' , together with the same carbon atom to which they are attached, form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 2a Group substitution;

[0021] R4 is H, OH, NH-(C1-C6) alkyl, NH-(C1-C6) hydroxyalkyl, NH-(C1-C6) aminoalkyl, NH-(C3-C6) carbocyclyl, NH-4- to 6-membered heterocyclyl, NH-(C1-C6) alkyl-(C3-C6) carbocyclyl, NH-(C1-C6) alkyl-4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 4a group substituted, where each R 4a is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl;

[0022] R5 is halogen or (C 1- C3) alkoxy;

[0023] R6 and R 6' are each independently H or halogen;

[0024] R7 is H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, CN, NO2, OH, (C2-C4)alkenyl, (C2-C4)alkynyl, or -R 7a -R 7b , where R 7a Not present or O, N(R 7a1 )(CR 7a1 R 7a2 ) q ,S,SO,SO2,C(O),C(O)O,OC(O),C(O)N(R 7a1 )、N(R 7a1 )C(O), N(R 7a1 )C(O)N(R 7a2 )、N(R 7a1 )C(O)O、OC(O)N(R 7a1 )、S(O)2N(R 7a1 )、N(R 7a1 )SO2, where R 7a1 and R 7a2 are each independently H or (C1-C4) alkyl, and q is 0, 1, 2, and R 7b is H, (C1-C6) alkyl, (C6-C 10)aryl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C1-C4)alkynyl, (C3-C6)cycloalkenyl, wherein the alkyl, aryl, cycloalkyl, alkenyl, alkynyl or cycloalkenyl is further optionally substituted with one or more substituents independently selected from the group consisting of oxo, (C1-C4)alkyl, (C1-C4)cycloalkyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, amino, CN, OH, amido, carboxyl, carbamoyl, sulfamoyl, thiol, C(O)NR 7b1 R 7b2 , R 7b1 R 7b2 OR 7b1 Substituents, where R 7b1 and R 7b2 Each is independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, wherein the oxo, alkyl, cycloalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, amino, CN, OH, amide, carboxyl, carbamoyl, sulfamoyl or thiol is optionally further substituted by R 7b3 -R 7b4 Substitution, where R 7b3 is absent or is (C1-C5)alkylene which is optionally substituted by one or more substituents selected from (C1-C2)alkyl or oxo, and R 7b4 Yes (C6-C 10 )aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, (C3-C6)carbocyclyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, CN, OH, (C1-C4)alkoxy, C(O)R 7b4a 、COOR 7b4b 、C(O)NR 7b4a R 7b4b or NR 7b4a R 7b4b , where: R 7b4a and R 7b4b each independently selected from H or (C1-C4) alkyl; the aryl, heteroaryl, heterocyclic or carbocyclic radical is optionally further substituted by one or more substituents independently selected from (C1-C4) alkyl, halogen, (C1-C4) haloalkyl, amino, CN or OH; and the heterocyclic or heteroaryl radical contains at least one nitrogen atom and is connected via nitrogen, wherein the heterocyclic radical is optionally and independently substituted by one or more identical or different groups independently selected from R9, and the heteroaryl radical is optionally and independently substituted by one or more independently selected from R 10 The same or different groups are substituted;

[0025] R8 is halogen or CN;

[0026] R9 is =O, CN, C≡CH, OH, COOH, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, 5-membered or 6-membered heteroaryl, phenyl, N(R 11 R 12 )、C(O)-R 13 、C(O)N(R 14 R 15 ) or a 5- to 8-membered heterocyclyl, wherein the (C1-C6)alkyl is optionally substituted by COOH, OH, COO-(C1-C6)alkyl, -CON(C1-C6)alkyl, (C1-C6)alkoxy, N((C1-C3)alkyl), phenyl or a 5- or 6-membered heterocyclyl, and the heteroaryl, phenyl or heterocyclyl is optionally substituted by a group selected from (C1-C6)alkyl;

[0027] R 10 COOH, (C1-C6) alkyl, C(O)-R 16 or C(O)N(R 17 )(R 18 );

[0028] R 11 is H or (C 1- C4) alkyl;

[0029] R 12 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 6-membered heterocyclyl or 6-membered heteroaryl;

[0030] R 13 is (C1-C3)alkyl-N(C1-C3)alkyl)2 or 5-membered or 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by (C1-C3)alkyl;

[0031] R 14 is hydrogen or (C 1- C3) alkyl;

[0032] R 15 is (C1-C6)alkyl optionally substituted by NH2, (C1-C6)alkoxy, O-(C1-C6)alkyl-NH2 or O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, or R 15 is a 6-membered heterocyclic group optionally substituted by a (C1-C3)alkyl group;

[0033] R 16 is a 6-membered heterocyclic group optionally substituted by a (C1-C3)alkyl group;

[0034] R 17 and R 18Each is independently H or (C1-C3) alkyl;

[0035] R 19 is H, =O, -CN, –C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, acylamino, carboxyl, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclic group, –NR 20 R 21 , –C(O)R 22 , –C(O)NR 23 R 24 or L1Y1, wherein the alkyl, phenyl or heterocyclyl is optionally substituted with one or more groups selected from halo, –COOH, –OH, –NH2, (C1-C6)alkyl, –C(O)O–(C1-C6)alkyl, –C(O)N(C1-C6alkyl)2, –O–(C1-C6)alkyl, –N(C1-C3alkyl)2, phenyl and 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more groups selected from halo and (C1-C6)alkyl;

[0036] L1 is absent, (C1-C6) alkylene or (C3-C7) carbocyclyl; wherein the alkylene or carbocyclyl is further optionally replaced by one or more identical or different R 25 or L1 is the same as R 26 (C2-C4)alkylene group combined to form a 4- to 6-membered heterocyclic group; and

[0037] Y1 is –CN, –OH, halo, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, 4- to 7-membered heterocyclyl, (C3-C6)carbocyclyl, –NR 26 R 27 , –C(O)R 22 , –C(O)NR 23 R 24 ; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C4)alkyl, halo, (C1-C4)haloalkyl, –CN, –OH and –NH2;

[0038] R 19 'Not present, H, -CN, -C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, amide, carboxyl, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclic group, -NR 20 R21 、-C(O)R 22 or -C(O)NR 23 R 24 wherein the alkyl, phenyl or heterocyclic group is further optionally replaced by one or more identical or different R 25 Group substitution, or

[0039] R 19 ' and L1 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclic group or a 4- to 7-membered heterocyclic group; wherein the carbocyclic group or heterocyclic group is further optionally replaced by one or more identical or different R 25 Group substitution;

[0040] R 20 is hydrogen, (C1-C4)alkyl or (C3-C6)cycloalkyl;

[0041] R 21 is hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl or 6-membered heterocyclyl;

[0042] R 22 is -(C1-C3)alkyl-N(C1-C3alkyl)2, (C3-C6)cycloalkyl or 5- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with (C1-C3)alkyl;

[0043] R 23 is hydrogen, (C1-C3)alkyl or (C3-C6)cycloalkyl;

[0044] R 24 is (C3-C6)cycloalkyl or (C1-C6)alkyl, which is optionally substituted with –NH2, –O-(C1-C6)alkyl, –O-(C1-C6)alkyl-NH2 or –O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2;

[0045] Each R 25and alkyl. In some embodiments, alkyl is an alkyl radical, and alkyl is an alkyl radical. In some embodiments, alkyl is an alkyl radical, and alkyl is an alkyl radical. In some embodiments, alkyl is an alkyl radical, and alkyl is an alkyl radical. acyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido or phosphinyl;

[0046] R 26 and R 27 are independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl or monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein the alkyl, carbocyclic, heterocyclic, aryl or heteroaryl is further optionally replaced by one or more identical or different R 25 Group substitution, or

[0047] R 26 and R 27 Together with the nitrogen atom to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the heterocyclic group is further optionally substituted by one or more identical or different R 25 Group substitution;

[0048] m is 0, 1, or 2;

[0049] n is 0, 1, 2 or 3; and

[0050] o is either 0 or 1.

[0051] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0052] Another aspect of the present disclosure relates to a method of treating a cancer characterized by or mediated by aberrant B-cell lymphoma 6 (BCL6) activity, which involves administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0053] In some embodiments, the cancer is a lymphoid malignancy. In some embodiments, the malignant lymphoma is peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia / lymphoma (ALL), cutaneous T-cell lymphoma, chronic myeloid leukemia, or B-cell non-Hodgkin's lymphoma.

[0054] Details

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter belongs. As used in the specification and appended claims, unless otherwise indicated, the following terms have the indicated meanings for ease of understanding the present disclosure.

[0056] As used in this description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and so forth.

[0057] Unless otherwise indicated, the term "about" means within 10% (eg, within 5%, 2%, or 1%) of the particular value modified by the term "about."

[0058] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude other unrecited elements or method steps. In contrast, the transitional phrase "consisting of excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps of the invention "and those that do not materially affect the basic and novel characteristics."

[0059] With respect to the compounds of the present disclosure, and to the extent that the following terminology is used to further describe them herein, the following definitions apply.

[0060] As used herein, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group. In some embodiments, and in the range not specified for any one or more groups in the compound of formula (I), the alkyl group is a C1-C4 group. In other embodiments, the alkyl group is a C0-C4, C0-C3, C1-C4, C1-C3 or C1-C2 group (wherein the C0 alkyl refers to a bond). Representative examples of alkyl include methyl, ethyl, 1-propyl, 2-propyl, isopropyl, 1-butyl, 2-methyl-1-propyl, 2-butyl and 2-methyl-2-propyl. In some embodiments, the alkyl is a C1-C3 alkyl. In some embodiments, the alkyl is a C3-C5 branched alkyl.

[0061] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group, which consists only of carbon and hydrogen. The alkylene chain can be connected to the rest of the molecule by a bond and to the group by a bond. In some embodiments, and in the range not specified for any one or more groups in the compound of formula (I), the alkylene includes 1 to 4 carbon atoms (C1-C4 alkylene (e.g., methylene, ethylene, propylene, butylene)). In other embodiments, the alkylene contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene contains 1 carbon atom (C1 alkylene).

[0062] As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical with at least one carbon-carbon double bond.Alkenyl includes free radicals with "cis" and "trans" directions, or alternatively "E" and "Z" directions. In some embodiments, and in the range of any one or more groups not specified separately for the compound of formula (I), alkenyl is a C2-C6 group. In other embodiments, alkenyl is a C2-C6 or C2-C3 group. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-diene, hexadecane-1-enyl, hexadecane-2-enyl, hexadecane-3-enyl, hexadecane-4-enyl and hexa-1,3-dienyl.

[0063] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as described above to which an oxygen group is attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbon groups covalently linked by oxygen. Thus, the substituent of the alkyl group that makes the alkyl group an ether is or is similar to an alkoxy group, for example, it can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0064] As used herein, the term "alkyleneoxy" refers to a group of the general formula (-OC n H 2n -) saturated monovalent aliphatic group, wherein n represents an integer (e.g., 1, 2, 3, 4, 5, 6 or 7), and includes straight and branched groups. The alkyleneoxy chain can be connected to the rest of the molecule by a bond and to the group by a bond. In some embodiments, and in the range not specified for any one or more groups in the compound of formula (I), the alkyleneoxy group contains 1 to 3 carbon atoms (-O-C1-C3 alkyleneoxy). In other embodiments, the alkyleneoxy group contains 1 to 5 carbon atoms (-O-C1-C5 alkoxy alkene).

[0065] As used herein, the term "cyclic group" broadly refers to any group containing a saturated, partially saturated or aromatic ring system, used alone or as part of a larger moiety (e.g., carbocyclyl (cycloalkyl, cycloalkenyl), heterocyclyl (heterocyclylalkyl, heterocyclyl), aryl and heteroaryl). A cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, to the extent not otherwise specified for any one or more groups in the compounds of formula (I), a cyclic group may contain one or more (e.g., 1, 2 or 3) carbocyclyl, heterocyclyl, aryl or heteroaryl.

[0066] As used herein, the term "carbocycle" (also referred to as "carbocyclyl") refers to a group containing a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms, either alone or as part of a larger portion, either alone or as part of a larger portion (e.g., an alkcarbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spirocyclic systems and combinations thereof. In the absence of any one or more groups in the compounds of formula (I) that are otherwise specified, in one embodiment, the carbocyclyl includes 3 to 15 carbon atoms (C3-C 15 In one embodiment, the carbocyclyl group comprises 3 to 12 carbon atoms (C3-C 12 In another embodiment, carbocyclyl includes C3-C8, C3-C 10 or C5-C 10In another embodiment, the carbocyclyl as a monocyclic ring includes C3-C8, C3-C6 or C5-C6. In some embodiments, the carbocyclyl as a bicyclic ring includes C7-C 12 In some embodiments, the carbocyclic group as a spirocyclic system includes C5-C 12 Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, deuterated cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spiro carbocyclyl include spiro [2.2] pentane, spiro [2.3] hexane, spiro [2.4] heptane, spiro [2.5] octane and spiro [4.5] decane. The term carbocyclyl includes an aromatic ring system as described herein. The term carbocyclyl also includes a cycloalkyl ring (e.g., a saturated or partially unsaturated monocarbocyclyl, a dicarbocyclyl or a spiro carbocyclyl). The term carbocyclic group also includes a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different ring groups (e.g., aromatic rings or heterocycles), wherein the connecting base or point of attachment is on the carbocyclic ring.

[0067] As used herein, the term "heterocyclyl" refers to a "carbocyclyl" containing a saturated, partially unsaturated or aromatic ring system, used alone or as part of a larger portion, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N, N(O), S, S(O) or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spirocyclic systems and combinations thereof. In some embodiments, within the scope of any one or more groups not otherwise specified for the compounds of formula (I), heterocyclyl refers to a 3- to 15-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaromatic ring system, such as a 5- to 14-membered heteroaromatic ring system. The term heterocyclyl also includes C3-C8 heterocycloalkyl, which is a saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring system containing 3 to 8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

[0068] In some embodiments, the heterocyclic group includes 3 to 12 ring atoms, and includes monocyclic, bicyclic, tricyclic and spirocyclic systems, wherein the ring atoms are carbon, and 1 to 5 ring atoms are heteroatoms, such as nitrogen, sulfur or oxygen. In some embodiments, within the scope not otherwise specified, the heterocyclic group includes 3 to 7-membered monocycles with one or more heteroatoms selected from nitrogen, sulfur or oxygen. In some embodiments, the heterocyclic group includes 4 to 6-membered monocycles with one or more heteroatoms selected from nitrogen, sulfur or oxygen. In some embodiments, the heterocyclic group includes 3-membered monocycles. In some embodiments, the heterocyclic group includes 4-membered monocycles. In some embodiments, the heterocyclic group includes 5 to 6-membered monocycles. In some embodiments, the heterocyclic group includes 0 to 3 double bonds. In any of the foregoing embodiments, the heterocyclic group includes 1, 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR4] + Cl - 、[NR4] + OH -Representative examples of heterocyclic groups include oxirane, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiooxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, oxetanyl, oxetanyl, oxazepin ... yl), oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidine dinonyl, oxazolidine dinonyl, imidazolidine dinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-b]pyridinyl, thiazinyl, phenylthio, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazine thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiopentyl, pyrimidinyl nonyl, pyrimidinyl dione, pyrimidine-2,4-dione, piperazinyl nonyl, piperazinyl dinonyl, pyrazolidinyl imidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo [3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]decan-2-one, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl.Examples of 5-membered heterocyclic groups containing sulfur or oxygen atoms and 1 to 3 nitrogen atoms are thiazolyl (including thiazol-2-yl and thiazol-2-yl N-oxide), thiadiazolyl (including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), oxazolyl (e.g. oxazol-2-yl) and oxadiazolyl (e.g. 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl). Example 5-membered heterocyclic groups containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl and tetrazolyl, such as 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclic groups are benzoxazol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocyclic groups contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, for example pyridyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; pyrimidinyl, such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, especially pyridazin-3-yl and pyrazinyl.

[0069] Therefore, the term heterocycle includes N-heterocyclic groups, as used herein, N-heterocyclic groups refer to heterocyclic groups containing at least one nitrogen, and wherein the point of attachment of the heterocyclic group to the rest of the molecule is through the nitrogen atom in the heterocyclic group. In the scope of not being otherwise specified for any one or more groups in the compound of formula (I), representative examples of N-heterocyclic groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl. The term heterocycle also includes C-heterocyclic groups, as used herein, C-heterocyclic groups refer to heterocyclic groups containing at least one heteroatom, and wherein the point of attachment of the heterocyclic group to the rest of the molecule is through the carbon atom in the heterocyclic group. In the scope of not being otherwise specified, representative examples of C-heterocyclic groups include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl and 2- or 3-pyrrolidinyl. The term heterocycle also includes heterocycloalkyl, as disclosed above, heterocycloalkyl refers to the formula -R c -heterocyclic group, wherein R c The term heterocycle also includes heterocycloalkoxy, which, as used herein, refers to a heterocyclic ring having the formula -OR c - a free radical bonded to the oxygen atom of a heterocyclic group, wherein R c It is an alkylene chain.

[0070] As used herein, the term "aryl" used alone or as part of a larger moiety (e.g., "aralkyl" where the terminal carbon atom on the alkyl group is the point of attachment, such as benzyl, "aralkyloxy" where the oxygen atom is the point of attachment, or "aryloxyalkyl" where the point of attachment is on the aryl group) refers to a group including a monocyclic, bicyclic or tricyclic carbocyclic ring system, including fused rings, wherein at least one ring in the system is aromatic. In some embodiments, the aralkyloxy group is a benzoyloxy group. The term "aryl" can be used interchangeably with the term "aromatic ring". In one embodiment, within the range not otherwise specified, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl include phenyl, naphthyl, anthracenyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthyridinyl, etc., which may be substituted or independently substituted by one or more substituents described herein. A special aryl is phenyl. In some embodiments, within the scope not otherwise specified, aryl includes an aromatic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the free radical or point of attachment is on the aromatic ring.

[0071] Thus, the term aryl includes aralkyl (eg, benzyl), where, as described above, aralkyl refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain, such as methylene or ethylene. In some embodiments, to the extent not otherwise specified for any one or more groups in the compounds of formula (I), aralkyl is an optionally substituted benzyl. The term aryl also includes aralkyloxy, as used herein, which refers to a alkylene group of the formula -OR c - a group bonded to the oxygen atom of an aromatic group, wherein R c is an alkylene chain, such as methylene or ethylene.

[0072] As used herein, the term "heteroaryl", used alone or as part of a larger moiety, for example, "heteroarylalkyl" (also known as "heteroaralkyl") or "heteroarylalkoxy" (also known as "heteroaralkoxy"), refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, within the range not otherwise specified for any one or more groups in the compounds of formula (I), heteroaryl includes 5- to 6-membered monocyclic aromatic groups, wherein one or more ring atoms are independently optionally substituted nitrogen, sulfur or oxygen. Representative examples of heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinyl, imidazolylpyridinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazolyl, tetrazo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzophenone ... The term "heteroaryl" also includes groups in which the heteroaryl group is fused to one or more (e.g., 1, 2, or 3) cyclic (e.g., carbocyclyl or heterocyclyl) rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothiophenyl, benzophenylthio, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnozinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic or tricyclic. In some embodiments, heteroaryl includes a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic), wherein the radical or point of attachment is on the heteroaryl ring, and in some embodiments, wherein the point of attachment is a heteroatom contained in the heterocyclic ring.

[0073] Thus, the term heteroaryl also includes N-heteroaryl, which as used herein refers to a heteroaryl as described above and which contains at least one nitrogen atom and wherein the point of attachment of the N-heteroaryl to the rest of the molecule is through a nitrogen atom in the heteroaryl. The term heteroaryl also includes C-heteroaryl, which as used herein refers to a heteroaryl as described above and wherein the point of attachment of the heteroaryl to the rest of the molecule is through a carbon atom in the heteroaryl. The term heteroaryl also includes heteroarylalkyl, which as described above refers to a heteroaryl of the formula— c -heteroaryl radical, wherein R c is an alkylene chain as described above. The term heteroaryl also includes heteroaralkoxy (or heteroarylalkoxy) groups, which as used herein refer to groups of the formula --O--R c - a group bonded to the oxygen atom of a heteroaryl group, wherein R c is an alkylene chain as defined above.

[0074] Representative examples of substituents may thus include, to the extent not otherwise specified with respect to any one or more groups in the compounds of formula (I), alkyl, substituted alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), -C2, C1), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclyl (e.g., C3-C 12 , C5-C6), substituted cyclic groups (e.g., C3-C 12 , C5-C6), carbocyclic rings (e.g., C3-C 12 , C5-C6), substituted carbocyclic rings (e.g., C3-C 12 , C5-C6), heterocyclic (e.g. C3-C 12 , C5-C6), substituted heterocycles (e.g., C3-C 12, C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidinyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidinyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxy, aryloxy (e.g., C6-C 12 , C6), substituted aryloxy (e.g. C6-C 12 , C6), thioalkyl (e.g. C1-C6), substituted thioalkyl (e.g. C1-C6), arylthio (e.g. C6-C 12 , C6), substituted arylthio (e.g. C6-C 12 , C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptidyl.

[0075] In one aspect, the compounds of the present disclosure are represented by formula (I):

[0076]

[0077] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0078] is phenyl or pyridyl;

[0079] yes

[0080] X is a bond, (C3-C6)carbocyclyl, (C3-C6)carbocyclyl(C=O) or SO2;

[0081] X0 is N or CCN;

[0082] X1 is CH2, S, CHF, CHCl, CHOH or CF2;

[0083] R1 is (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, (C3-C6) carbocyclyl, 4- to 6-membered heterocyclyl, (C1-C6) alkyl-(C3-C6) carbocyclyl or (C1-C6) alkyl-4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 1a Group substitution, where R 1ais deuterium, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl;

[0084] R2 and R 2’ are each independently H, (C1-C3)alkyl, (C1-C3)hydroxyalkyl or (C1-C3)aminoalkyl,

[0085] or R2 and R 2' Together with the same carbon atom to which they are attached, they form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 2a Group substitution, where R 2a is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl;

[0086] R3 and R 3’ are each independently H, (C1-C3)alkyl, (C1-C3)hydroxyalkyl or (C1-C3)aminoalkyl, or

[0087] R3 and R 3' , together with the same carbon atom to which they are attached, form C=O, (C3-C6) carbocyclyl, 4-membered to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 3a group substituted, where each R 3a are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl, or two of them 3a The groups, together with the same carbon atom to which they are attached, form C=O,

[0088] or R2 or R 2' and R3 or R 3' , together with the same carbon atom to which they are attached, form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 2a group substitution;

[0089] R4 is H, OH, NH-(C1-C6) alkyl, NH-(C1-C6) hydroxyalkyl, NH-(C1-C6) aminoalkyl, NH-(C3-C6) carbocyclyl, NH-4- to 6-membered heterocyclyl, NH-(C1-C6) alkyl-(C3-C6) carbocyclyl, NH-(C1-C6) alkyl-4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 4a group substituted, where each R 4a is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl;

[0090] R5 is halogen or (C 1- C3) alkoxy;

[0091] R6 and R 6' are each independently H or halogen;

[0092] R7 is H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, CN, NO2, OH, (C2-C4)alkenyl, (C2-C4)alkynyl, or -R 7a -R 7b , where R 7a Does not exist or is O, N (R 7a1 )(CR 7a1 R 7a2 ) q ,S,SO,SO2,C(O),C(O)O,OC(O),C(O)N(R 7a1 )、N(R 7a1 )C(O), N(R 7a1 )C(O)N(R 7a2 )、N(R 7a1 )C(O)O、OC(O)N(R 7a1 )、S(O)2N(R 7a1 )、N(R 7a1 )SO2, where R 7a1 and R 7a2 are each independently H or (C1-C4) alkyl, and q is 0, 1, 2, and R 7b is H, (C1-C6) alkyl, (C6-C 10)aryl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C1-C4)alkynyl, (C3-C6)cycloalkenyl, wherein the alkyl, aryl, cycloalkyl, alkenyl, alkynyl or cycloalkenyl is further optionally substituted with one or more substituents independently selected from the group consisting of oxo, (C1-C4)alkyl, (C1-C4)cycloalkyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, amino, CN, OH, amido, carboxyl, carbamoyl, sulfamoyl, thiol, C(O)NR 7b1 R 7b2 , R 7b1 R 7b2 OR 7b1 , where R 7b1 and R 7b2 Each is independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, wherein the oxo, alkyl, cycloalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, amino, CN, OH, amide, carboxyl, carbamoyl, sulfamoyl or thiol is optionally further substituted by R 7b3 -R 7b4 Substitution, where R 7b3 is absent or is (C1-C5)alkylene which is optionally substituted by one or more substituents selected from (C1-C2)alkyl or oxo, and R 7b4 Yes (C6-C 10 )aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, (C3-C6)carbocyclyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, CN, OH, (C1-C4)alkoxy, C(O)R 7b4a 、COOR 7b4b 、C(O)NR 7b4a R 7b4b or NR 7b4a R 7b4b , where: R 7b4a and R 7b4b each independently selected from H or (C1-C4) alkyl; the aryl, heteroaryl, heterocyclic or carbocyclic radical is optionally further substituted by one or more substituents independently selected from (C1-C4) alkyl, halogen, (C1-C4) haloalkyl, amino, CN or OH; and the heterocyclic or heteroaryl radical contains at least one nitrogen atom and is connected via nitrogen, wherein the heterocyclic radical is optionally and independently substituted by one or more identical or different groups independently selected from R9, and the heteroaryl radical is optionally and independently substituted by one or more independently selected from R 10 The same or different groups are substituted;

[0093] R8 is halogen or CN;

[0094] R9 is =O, CN, C≡CH, OH, COOH, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, 5-membered or 6-membered heteroaryl, phenyl, N(R 11 R 12 )、C(O)-R 13 、C(O)N(R 14 R 15 ) or a 5- to 8-membered heterocyclyl, wherein the (C1-C6)alkyl is optionally substituted by COOH, OH, COO-(C1-C6)alkyl, -CON((C1-C6)alkyl)2, (C1-C6)alkoxy, N((C1-C3)alkyl)2, phenyl or a 5- or 6-membered heterocyclyl, and the heteroaryl, phenyl or heterocyclyl is optionally substituted by a group selected from (C1-C6)alkyl;

[0095] R 10 COOH, (C1-C6) alkyl, C(O)-R 16 or C(O)N(R 17 )(R 18 );

[0096] R 11 is H or (C 1- C4) alkyl;

[0097] R 12 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 6-membered heterocyclyl or 6-membered heteroaryl;

[0098] R 13 is (C1-C3)alkyl-N(C1-C3)alkyl)2 or 5-membered or 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by (C1-C3)alkyl;

[0099] R 14 is hydrogen or (C 1- C3) alkyl;

[0100] R 15 is (C1-C6)alkyl optionally substituted by NH2, (C1-C6)alkoxy, O-(C1-C6)alkyl-NH2 or O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, or R 15 is a 6-membered heterocyclic group optionally substituted by a (C1-C3)alkyl group;

[0101] R 16 is a 6-membered heterocyclic group optionally substituted by a (C1-C3)alkyl group;

[0102] R 17 and R 18Each is independently H or (C1-C3) alkyl;

[0103] R 19 is H, =O, -CN, –C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, acylamino, carboxyl, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclic group, –NR 20 R 21 , –C(O)R 22 , –C(O)NR 23 R 24 or L1Y1, wherein the alkyl, phenyl or heterocyclyl is optionally substituted with one or more groups selected from halo, –COOH, –OH, –NH2, (C1-C6)alkyl, –C(O)O–(C1-C6)alkyl, –C(O)N(C1-C6alkyl)2, –O–(C1-C6)alkyl, –N(C1-C3alkyl)2, phenyl and 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is optionally substituted with one or more groups selected from halo and (C1-C6)alkyl;

[0104] L1 is absent, (C1-C6) alkylene or (C3-C7) carbocyclyl; wherein the alkylene or carbocyclyl is further optionally replaced by one or more identical or different R 25 or L1 is the same as R 26 (C2-C4)alkylene group combined to form a 4- to 6-membered heterocyclic group; and

[0105] Y1 is –CN, –OH, halo, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, 4- to 7-membered heterocyclyl, (C3-C6)carbocyclyl, –NR 26 R 27 , –C(O)R 22 , –C(O)NR 23 R 24 ; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C4)alkyl, halo, (C1-C4)haloalkyl, –CN, –OH and –NH2;

[0106] R 19 'Not present, H, -CN, -C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, amide, carboxyl, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclic group, -NR 20 R21 、-C(O)R 22 or -C(O)NR 23 R 24 wherein the alkyl, phenyl or heterocyclic group is further optionally replaced by one or more identical or different R 25 Group substitution, or

[0107] R 19 ' and L1 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclic group or a 4- to 7-membered heterocyclic group; wherein the carbocyclic group or heterocyclic group is further optionally replaced by one or more identical or different R 25 Group substitution;

[0108] R 20 is hydrogen, (C1-C4)alkyl or (C3-C6)cycloalkyl;

[0109] R 21 is hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl or 6-membered heterocyclyl;

[0110] R 22 is -(C1-C3)alkyl-N(C1-C3alkyl)2, (C3-C6)cycloalkyl or 5- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by (C1-C3)alkyl;

[0111] R 23 is hydrogen, (C1-C3)alkyl or (C3-C6)cycloalkyl;

[0112] R 24 is (C3-C6)cycloalkyl or (C1-C6)alkyl, which is optionally substituted with –NH2, –O-(C1-C6)alkyl, –O-(C1-C6)alkyl-NH2 or –O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2;

[0113] Each R 25and alkyl. The alkyl radicals are independently oxo, alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloalkyloxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, N-alkyl -N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido or phosphinyl;

[0114] R 26 and R 27 are independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl or monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein the alkyl, carbocyclic, heterocyclic, aryl or heteroaryl is further optionally replaced by one or more identical or different R 25 Group substitution, or

[0115] R 26 and R 27 Together with the nitrogen atom to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the heterocyclic group is further optionally substituted by one or more identical or different R 25 Group substitution;

[0116] m is 0, 1, or 2;

[0117] n is 0, 1, 2 or 3; and

[0118] o is either 0 or 1.

[0119] In some embodiments, wherein It is phenyl and yes The compounds of the present disclosure are represented by structure I-1a:

[0120]

[0121] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0122] In some embodiments, wherein is pyridyl and yes The compounds of the present disclosure are represented by any one of structures I-2a to I-4a:

[0123]

[0124] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0125] In some embodiments, R7 is optionally substituted (C1-C4) alkyl. In some embodiments, R7 is methyl or

[0126] In some embodiments, R7 is amino or OH.

[0127] In some embodiments, wherein It is phenyl and yes The compounds of the present disclosure are represented by structure I-1b:

[0128]

[0129] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0130] In some embodiments, wherein is pyridyl and yes The compounds of the present disclosure are represented by any of structures I-2b to I-4b:

[0131]

[0132] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0133] In some embodiments, X2 is CH2, CHF, CHOH, or CF2.

[0134] In some embodiments, R 19 and R 19 'are independently H, OH, methyl, amino,

[0135]

[0136] In some embodiments, R8 is halogen. In some embodiments, R8 is Cl or F.

[0137] In some embodiments, R1 is optionally substituted (C1-C6) alkyl. In some embodiments, R1 is methyl.

[0138] In some embodiments, R1 is optionally substituted (C1-C6)hydroxyalkyl.

[0139] In some embodiments, R1 is optionally substituted (C1-C6)aminoalkyl.

[0140] In some embodiments, R1 is an optionally substituted 4- to 6-membered heterocyclyl. In some embodiments, R1 is

[0141] In some embodiments, R1 is optionally substituted (C1-C6)alkyl-4- to 6-membered heterocyclyl.

[0142] In some embodiments, X is a bond or (C3-C6)carbocyclyl, m is 0 or 1, and o is 0 or 1.

[0143] In some embodiments, wherein It is phenyl. yes X is a bond, m is 0 or 1, and o is 1, the compounds of the present disclosure are represented by structure I-1a1 or I-1b1:

[0144]

[0145] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0146] In some embodiments, wherein It is phenyl. yes X is a bond, m is 0 or 1, and o is 1, the compounds of the present disclosure are represented by structure I-1a2 or I-1b2:

[0147]

[0148] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0149] In some embodiments, wherein Pyridyl, yes X is a bond, m is 0 or 1, and o is 1, the compounds of the present disclosure are represented by any one of structures I-2a1 to I-4a1 and I-2b1 to I-4b1:

[0150]

[0151] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0152] In some embodiments, wherein Pyridyl, yes X is a bond, m is 0 or 1, and o is 1, the compounds of the present disclosure are represented by any of structures I-2a2 to I-4a2 and I-2b2 to I-4b2:

[0153]

[0154] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0155] In some embodiments, R2 and R 2’ Each independently is H or methyl. In some embodiments, R2 and R 2’ In some embodiments, R2 and R 2’ Together with the same carbon atom to which they are attached they form a cyclopropyl group.

[0156] In some embodiments, R3 and R 3’ Each independently is H or methyl. In some embodiments, R3 and R 3’ Together with the same carbon atom to which they are attached, they form C=O. In some embodiments, R3 and R 3’ Together with the same carbon atom to which they are attached, they form an optionally substituted 4- to 6-membered heterocyclyl. 3a The groups together with the same carbon atom to which they are attached form C=O. In some embodiments, the optionally substituted 4-membered heterocyclyl is oxetane or N-methylazetidine. In some embodiments, the optionally substituted 5-membered or 6-membered heterocyclyl is carbamate. In some embodiments, R2 or R 2’ and R3 or R3 together with the same carbon atom to which they are attached form a (C3-C6) carbocyclyl;

[0157] In some embodiments, R4 is OH or H.

[0158] In some embodiments, R2 and R 2’ are each independently H or methyl; R3 and R 3’ are each independently H or methyl; and R4 is OH or H. In some embodiments, R2 and R 2’ Both are H; R3 and R 3’ are each independently H or methyl; and R4 is OH.

[0159] In some embodiments, wherein It is phenyl. yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compound of the present disclosure is represented by structure I-1c1:

[0160]

[0161] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0162] In some embodiments, wherein It is phenyl. yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compounds of the present disclosure are represented by structure I-1c2:

[0163]

[0164] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0165] In some embodiments, wherein is pyridyl, yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compounds of the present disclosure are represented by any one of structures I-2c1 to I-4c1:

[0166]

[0167] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0168] In some embodiments, wherein is pyridyl, yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compounds of the present disclosure are represented by any one of structures I-2c2 to I-4c2:

[0169]

[0170] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0171] In some embodiments, wherein It is phenyl. yes X is SO2, m is 1 or 2, and o is 0, the compounds of the present disclosure are represented by structure I-1d1:

[0172]

[0173] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0174] In some embodiments, wherein It is phenyl. yes X is SO2, m is 1 or 2, and o is 0, the compounds of the present disclosure are represented by structure I-1d2:

[0175]

[0176] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0177] In some embodiments, wherein is pyridyl, yes X is SO2, m is 1 or 2, and o is 0, the compounds of the present disclosure are represented by any one of structures I-2d1 to I-4d1:

[0178]

[0179] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0180] In some embodiments, wherein Pyridyl, yes X is SO2, m is 1 or 2, and o is 0, the compounds of the present disclosure are represented by any one of structures I-2d2 to I-4d2:

[0181]

[0182] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0183] In some embodiments, R4 is optionally substituted NH-(C1-C6)alkyl. In some embodiments, R4 is NH-methyl. In some embodiments, R4 is OH.

[0184] In some embodiments, R4 is optionally substituted NH-(C1-C6)hydroxyalkyl.

[0185] In some embodiments, R4 is optionally substituted NH-(C1-C6)aminoalkyl.

[0186] In some embodiments, R4 is optionally substituted NH-4-membered to 6-membered heterocyclyl. In some embodiments, R4 is

[0187] In some embodiments, R4 is optionally substituted NH-(C1-C6)alkyl-4- to 6-membered heterocyclyl.

[0188] In some embodiments, n is 0 or 1.

[0189] In some embodiments, R5 is F. In some embodiments, R5 is methoxy.

[0190] In some embodiments, R6 and R 6’ are H or F. In some embodiments, R6 is H and R 6’ It's F.

[0191] In some embodiments, X0 is N.

[0192] In some embodiments, the compounds of the present disclosure are represented by any of the following structures:

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0207] The compounds of the present disclosure may be in the form of free acids or free bases or pharmaceutically acceptable salts. For example, pharmaceutically acceptable salts of the compounds of the present disclosure may be formed by reacting the appropriate free base of the compounds of the present invention with an appropriate pharmaceutically acceptable acid in a suitable solvent under standard conditions known in the art. See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4: 427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66: 1-19, (1977).

[0208] The compounds of the present disclosure may have at least one chiral center, and therefore may be in the form of stereoisomers, which as used herein include all isomers of each compound, differing only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (including enantiomers of the (R-) or (S-) configuration of the compound), mirror image isomer mixtures of compounds (physical mixtures and racemates or racemic mixtures of enantiomers), geometric (cis / trans or E / Z, R / S) isomers of compounds, and compound isomers (diastereomers) with more than one chiral center that are not mirror images of each other. The chiral center of the compound may undergo epimerization in vivo; therefore, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Therefore, the compounds of the present disclosure may be manufactured and used in the form of a single isomer and substantially free of other isomers, or manufactured and used in the form of a mixture of various isomers, for example, a racemic mixture of stereoisomers.

[0209] In some embodiments, the compound of formula (I) is an isotopic derivative because it has at least one desired atomic isotope substitution in an amount greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound includes deuterium or multiple deuterium atoms. As used herein, the term "compound" includes isotopic derivatives.

[0210] The compounds of formula (I) may also be in the form of N-oxides, crystalline forms (also known as polymorphs), co-crystals, active metabolites of compounds having the same type of activity, prodrugs, tautomers, and non-solvated forms of the compounds as well as solvated (e.g., hydrated) forms using pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). As used herein, the term "compound" includes all of these forms.

[0211] The compound of formula (I) can be prepared by crystallization under different conditions, and can exist as a kind of crystal form or polymorph combination of compound.For example, by crystallization at different temperatures, or by using various cooling modes (from very fast to very slow cooling) in the crystallization process, different solvents or different solvent mixtures are used to recrystallize to identify and / or prepare different polymorphs.Polymorphs can also be obtained by heating or melting the compound, and then gradually or rapidly cooling.The presence of polymorphs can be determined by solid probe NMR spectrum, IR spectrum, differential scanning calorimetry, powder X-ray diffraction pattern and / or other known technologies.

[0212] In some embodiments, the pharmaceutical composition comprises a co-crystal of a compound of formula (I). As used herein, the term "co-crystal" refers to a stoichiometric multi-component system comprising a compound of formula (I) and a co-crystal former, wherein the compound of formula (I) and the co-crystal former are linked by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that is capable of forming intermolecular interactions with a compound of formula (I) and co-crystalizing therewith. Representative examples of cocrystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexanoic acid, 2-hydroxyhexanoic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridyl para-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, pyrogallol, isoniazid, theophylline, adenine, theobromine, phenacetin, antipyrine, ethophylline, and phenobarbital.

[0213] Synthesis method

[0214] On the other hand, the present disclosure relates to a method for manufacturing a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. In a broad sense, a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof can be prepared by any process known to be suitable for preparing chemically related compounds. In conjunction with the synthesis schemes described in the various working examples, the compound of formula (I) can be better understood, and these schemes illustrate non-limiting methods by which compounds of formula (I) can be prepared.

[0215] Pharmaceutical composition

[0216] Another aspect of the present invention relates to a pharmaceutical composition, which includes a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier", as known in the art, refers to a pharmaceutically acceptable material, composition or carrier suitable for administering a compound of the present disclosure to a mammal. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases and combinations thereof (e.g., semisolids) and gases, the function of which is to carry or transport a compound from one organ or part of the body to another organ or another part of the body. The carrier is "acceptable", i.e., physiologically inert and compatible with the other ingredients of the preparation, and harmless to the subject or patient. Depending on the type of preparation, the composition may also include one or more pharmaceutically acceptable excipients.

[0217] In a broad sense, the compounds of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof can be formulated into a given type of composition according to conventional pharmaceutical practices, such as conventional mixing, dissolving, granulating, dragee making, pulverizing, emulsifying, encapsulating, encapsulating and tableting processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which can include enteral (e.g., oral, buccal, sublingual, and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection, or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). In general, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous because the compound can be administered relatively quickly, for example, in the case of single-dose treatment and / or acute discomfort.

[0218] In some embodiments, the compounds of Formula (I) are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0219] Thus, the compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible particles, capsules, cachets, and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions, and solutions containing liposomes, micelles or nanoparticles, syrups, and elixirs); semisolid compositions (e.g., gels, suspensions, and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for immediate release, intermediate release, or sustained release.

[0220] Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate and other carriers or excipients such as a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as cross-linked polymers (such as cross-linked polyethylene glycol) and sucrose. The dosage form may also include a buffering agent. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings. They may also contain opacifiers.

[0221] In some embodiments, the compound of formula (I) can be formulated into hard gelatin or soft gelatin capsules. Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose. The gelatin shell can include gelatin, titanium dioxide, iron oxide and a coloring agent.

[0222] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs. In addition to the compound, the liquid dosage form may contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters and mixtures thereof. Oral compositions may also include excipients, such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents and aromatics.

[0223] Injectable preparations for parenteral administration may include sterile aqueous solutions or oily suspensions. They can be formulated using suitable dispersants or wetting agents and suspending agents according to standard techniques. Sterile injectable preparations are also sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions dissolved in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are used to prepare injections. The injection preparation is sterilized, for example, by filtering through a bacterial retention filter, or by incorporating a sterilizing agent into a sterile solid composition form, which can be dissolved or dispersed in sterile water or other sterile injection media before use. The effect of the compound can be prolonged by slowing down its absorption, which can be achieved by using a liquid suspension or crystalline or amorphous material with poor water solubility. Prolonged absorption of a compound from a parenterally administered preparation may also be accomplished by suspending the compound in an oil vehicle.

[0224] In certain embodiments, the compound of formula (I) can be administered in a local rather than systemic manner, for example, by injecting the conjugate directly into an organ, usually in the form of a depot preparation or a sustained-release preparation. In a specific embodiment, the long-acting preparation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Injectable long-acting dosage forms are manufactured by forming a microcapsule matrix in a biodegradable polymer (e.g., polylactic acid-polyglycolic acid, polyorthoesters, and polyanhydrides). The release rate of the compound can be controlled by changing the ratio of the compound to the polymer and the properties of the specific polymer used. Injectable long-acting preparations are also prepared by encapsulating the compound in a liposome or microemulsion compatible with body tissues. In addition, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, delivered in a liposome coated with an organ-specific antibody. In such an embodiment, the liposome targets the organ and is selectively taken up by the organ.

[0225] The composition may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0226] The compound of formula (I) can be formulated for inhalation administration. The various forms suitable for inhalation administration include aerosols, sprays or powders. The pharmaceutical composition can be delivered from a pressurized package or atomizer in the form of an aerosol spray using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases). In some embodiments, the dosage unit of a pressurized aerosol can be determined by providing a valve to deliver a metered amount. In some embodiments, a capsule and cartridge (e.g., for an inhaler or insufflator) comprising gelatin can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0227] The compounds of formula (I) may be formulated for topical administration, which as used herein means administration of the formulation intradermally to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0228] Representative examples of carriers for formulating topical compounds include solvents (e.g., alcohols, polyols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffers (e.g., hypotonic or buffered saline). For example, saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl alcohol, or oleyl alcohol can be used to formulate creams. Creams can also contain nonionic surfactants such as polyoxyl (40) stearate.

[0229] In some embodiments, topical preparations may also include excipients, examples of which are penetration enhancers. These preparations can transport pharmacologically active compounds through the stratum corneum and into the epidermis or dermis, preferably with little or no systemic absorption. The effectiveness of various compounds in improving the skin penetration rate of drugs has been evaluated. See, for example, Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995) (which investigated the use and testing of various skin penetration enhancers) and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (Eds.), Interpharm Press Inc., Buffalo Grove, Ill.

[0230] (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe-vera gel), ethanol, isopropyl alcohol, octylphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0231] Representative examples of other excipients that may be included in topical formulations and other types of formulations (to the extent that they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, benzoates and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol and chelating agents such as EDTA and citric acid. Suitable humectants include glycerol, sorbitol, polyethylene glycol, urea and propylene glycol. Suitable buffers include citric acid, hydrochloric acid and lactic acid buffer. Suitable solubilizers include quaternary ammonium hydrochloride, cyclodextrins, benzyl benzoate, lecithin and polysorbate. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerol, vaseline and zinc oxide.

[0232] Transdermal preparations usually adopt transdermal delivery devices and transdermal delivery patches, wherein the compound is formulated into a lipophilic emulsion or a buffered aqueous solution that is dissolved in and / or dispersed in a polymer or adhesive. Patch can be constructed to deliver medicaments continuously, pulsed or on demand. The transdermal delivery of a compound can be achieved by an iontophoresis patch. A transdermal patch can provide controlled delivery of a compound, wherein by using a rate-controlled membrane or by slowing down absorption rate by trapping the compound in a polymer matrix or a gel. Absorption enhancers can be used to increase absorption, and examples thereof include absorbable pharmaceutically acceptable solvents that contribute to passing through the skin.

[0233] Ophthalmic preparations include eye drops.

[0234] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinyl pyrrolidone, PEG, etc. Compositions for rectal or vaginal administration may also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the compound.

[0235] dose

[0236] As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing the desired therapeutic response in a specific patient suffering from a disease or condition mediated by abnormal BCL6 activity. Therefore, the term "therapeutically effective amount" includes an amount of a compound or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, induces a positive change in the disease or condition to be treated, or is sufficient to prevent the development or progression of the disease or condition, or alleviates one or more symptoms of the disease or condition being treated in the subject to some extent, or simply kills or inhibits the growth of diseased (such as cancer) cells, or reduces the amount of BCL6 in diseased cells.

[0237] The total daily dose of the compound of formula (I) and its usage can be determined according to standard medical practice, for example, by the attending physician using reasonable medical judgment. The specific therapeutically effective dose of any particular subject may depend on a variety of factors, including the disease or condition being treated and its severity (e.g., its current status); the age, weight, general health, sex and diet of the subject; the administration time, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the compound; and similar factors known to the medical community (see, for example, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).

[0238] How to use

[0239] In certain aspects, the present disclosure is intended to treat cancer characterized or mediated by abnormal (e.g., elevated BCL6 levels or other functional abnormalities, e.g., dysfunctional BCL6 levels) BCL6 activity relative to a non-pathological state. The method requires administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need thereof.

[0240] As used herein, the term "subject" (or "patient") includes all members of the animal kingdom susceptible to or suffering from the disease or condition. In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. The method is also applicable to companion animals, such as dogs and cats. According to the present disclosure, a subject "in need of" treatment may "suffer from or be suspected of suffering from" a specific disease or condition, may have been diagnosed positive or otherwise exhibit a sufficient number of risk factors or a sufficient number of signs or symptoms, or a combination thereof, so that a medical professional can diagnose or suspect that the subject suffers from the disease or condition. Therefore, subjects suffering from a specific disease or condition and subjects suspected of suffering from a specific disease or condition are not necessarily two different groups.

[0241] The method involves treating a subject with cancer. This includes adult tumors / cancers and pediatric tumors / cancers. The cancer can be vascularized, or a tumor that is not substantially vascularized or non-vascularized.

[0242] In some embodiments, the methods relate to treating a subject having a lymphoid malignancy.

[0243] In some embodiments, the malignant lymphoma is peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia / lymphoma (ALL), cutaneous T-cell lymphoma, chronic myeloid leukemia, or B-cell non-Hodgkin lymphoma.

[0244] In some embodiments, the methods of the present disclosure relate to treating a subject having a cell proliferative disease or disorder of the hematological system.

[0245] The compound of formula (I) can be administered to a patient, such as a cancer patient, as a monotherapy or by means of a combination therapy. The treatment can be "front / first-line", that is, as the initial treatment for patients who have not previously received an anticancer treatment regimen, whether used alone or in combination with other treatments; or "second-line", as the treatment of patients who have previously received an anticancer treatment regimen, whether used alone or in combination with other treatments; or as a "third line", "fourth line" and other treatments, whether used alone or in combination with other treatments. Treatment can also be performed on patients who have been unsuccessful or partially successful in previous treatments but are unresponsive or intolerant to a particular treatment. Treatment can also be given as an adjuvant therapy, that is, to prevent cancer recurrence in patients who are currently undetectable for the disease or after surgical resection of the tumor. Therefore, in some embodiments, the compound can be administered to patients who have received another treatment such as chemotherapy, radioimmunotherapy, surgical treatment, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0246] The disclosed method may need to administer a compound of formula (I) or its pharmaceutical composition to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the frequency of administration may range from once a day to approximately once every eight weeks. In some embodiments, the frequency of administration ranges from approximately once a day for 1, 2, 3, 4, 5 or 6 weeks, while in other embodiments, at least one 28-day cycle is required, which includes daily administration for 3 weeks (21 days), followed by a 7-day "drug withdrawal" period. In other embodiments, the compound may be administered twice a day (BID) (a total of 5 doses) or once a day (QD) (a total of 2 doses) in a two-day course of treatment. In other embodiments, the compound may be administered once a day (QD) in a 5-day course of treatment.

[0247] Combination therapy

[0248] Formula (I) compound and its pharmaceutically acceptable salt or stereoisomer can be combined with at least one other active agent, such as anticancer agent or anticancer scheme or use simultaneously, to treat diseases and conditions. In this context, the terms "combination" and "simultaneous" refer to agents by the same or separate dosage form, and by the same or different modes of administration, or sequentially, for example, as part of the same treatment regimen, or by a continuous treatment regimen, co-administered, which includes substantially simultaneous administration. Therefore, if sequentially administered, at the beginning of administration of the second compound, in some cases, the first of the two compounds is still detectable at an effective concentration at the treatment site. The order and time interval can be determined so that they can work together (e.g., synergistically) to provide greater benefits than otherwise administered. For example, therapeutic agents can be administered sequentially in any order simultaneously or at different time points; however, if not administered simultaneously, they can be administered in sufficiently close time to provide the desired therapeutic effect, which can be a synergistic manner. Therefore, these terms are not limited to administering active agents at exactly the same time.

[0249] In some embodiments, the treatment regimen may include administering a compound of formula (I) in combination with one or more other therapeutic agents known to treat a disease or condition (e.g., cancer). The dosage of the other therapeutic agent may be the same as or even lower than the known or recommended dosage. See Hardman et al., eds., Goodman & Gilman's the Pharmacological Basis of Basis of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anticancer agents suitable for use in combination with the compound are known in the art. See, for example, U.S. Pat. No. 9,101,622 (Section 5.2 therein) and U.S. Pat. No. 9,345,705 B2 (Columns 12-18 therein). Representative examples of additional anti-cancer agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, anti-hormones, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, anti-androgens, signal transduction pathway inhibitors, anti-microtubule agents, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0250] In some embodiments, the compound of Formula (I) and the other (e.g., anticancer) therapeutic agent can be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 hour apart, about 2 hours apart, about 3 hours apart, about 4 hours apart, about 4 hours apart, about 5 hours apart, about 5 hours apart, about 6 hours apart, about 7 hours apart, about 8 hours apart, about 9 hours apart, about 9 hours apart, about 10 hours apart, about 10 hours apart, about 11 hours apart, about 12 hours apart, about 12 hours apart, 18 hours apart, 24 hours apart, 24 hours apart, 36 hours apart, 36 hours apart, 48 hours apart, 52 hours apart, 52 hours apart, 60 hours apart, 72 hours apart, 72 hours apart, 84 hours apart, 84 hours apart, or 96 hours apart. 120 hours apart. Two or more (eg, anti-cancer) therapeutic agents can be administered in the same patient visit.

[0251] When the active ingredients of the composition are not administered in the same pharmaceutical composition, it is understood that they can be administered to a subject in need thereof in any order. For example, the compounds of the present disclosure can be administered to a subject in need thereof before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks before), simultaneously or afterwards (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks after) the additional therapeutic agent is administered. In various aspects, the therapeutic agent is administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, 6 to 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, 11 to 12 hours, no more than 24 hours, or no more than 48 hours. In one example, the (e.g., anticancer) therapeutic agent is administered at the same visit. In another example, the combination anticancer therapeutic agent can be administered at intervals of 1 minute to 24 hours.

[0252] In some embodiments involving cancer treatment, the compound of formula (I) and other anticancer agents or therapeutic agents are administered cyclically. Cyclic therapy includes administering an anticancer therapeutic agent for a period of time, then administering a second anticancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycling, to reduce the occurrence of resistance to one or both anticancer therapeutic agents, avoid or reduce the side effects of one or both anticancer therapeutic agents, and / or improve the efficacy of treatment. In one example, cyclic therapy includes administering a first anticancer therapeutic agent for a period of time, then administering a second anticancer therapeutic agent for a period of time, optionally, then administering a third anticancer therapeutic agent for a period of time, and so on, and repeating this sequential administration, i.e., cycling, to reduce the occurrence of resistance to an anticancer therapeutic agent, avoid or reduce the side effects of an anticancer therapeutic agent, and / or improve the efficacy of an anticancer therapeutic agent.

[0253] In some embodiments, the compounds of the present disclosure may be used in combination with additional anticancer agents, examples of which include etoposide (e.g., lymphomas and non-lymphocytic leukemias), vincristine (e.g., leukemias), daunorubicin (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), rituximab (e.g., non-Hodgkin's lymphoma), alemtuzumab (e.g., chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL), and T-cell lymphomas), bortezomib (e.g., multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., acute lymphoblastic leukemia), (such as Hodgkin lymphoma) and dexamethasone (such as acute multiple myeloma).

[0254] In some embodiments, the additional anticancer agent is an enhancer of an inhibitor of zeste homolog 2 (EZH2), examples of which include tazetostat, GSK126, lirametostat (CPI-1205), CPI-0209, PF-06821497, SHR2554, HH2853, valmetosstat (DS3201), MAK-683, and FTX-6058.

[0255] These and other aspects of the present disclosure will be further understood upon consideration of the following examples, which are intended to illustrate certain specific embodiments of the present disclosure, but are not intended to limit the scope as defined by the claims. Example

[0256] Example 1: 3-(7-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-4- Synthesis of methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-N-methylpropanamide (1).

[0257]

[0258] 3-Bromo-N-methylpropionamide

[0259] To a mixture of 3-bromopropionyl chloride (2 g, 11.67 mmol, 1.18 mL, 1 eq.) in DCM (35 mL) was added MeNH2 (2 M in THF, 11.67 mL, 2 eq.) dropwise at 0 °C and N2 atmosphere. The mixture was then allowed to warm to 15 °C and stirred for 12 hours. The mixture was concentrated in vacuo. The resulting residue was then diluted with saturated (sat.) NaHCO3 (50 mL) and extracted with DCM (50 mL*2). The combined organic phases were further washed with sat. NaHCO3 (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 3-bromo-N-methylpropionamide (1.2 g, 4.05 mmol, yield 34.69%, purity 56%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δ = 5.83 (s, 1H), 3.64 (t, J = 6.4Hz, 2H), 2.84 (d, J = 4.8Hz, 3H), 2.76 (t, J = 6.4Hz, 2H).

[0260]

[0261] 1-Methyl-6-nitroquinoxaline-2,3(1H,4H)-dione

[0262] A mixture of N1-methyl-4-nitrobenzene-1,2-diamine (3 g, 17.95 mmol, 1 eq.) and oxalic acid (3.23 g, 35.89 mmol, 3.17 mL, 2 eq.) in 4N HCl water (aq.) solution (150 mL) was stirred at 120 ° C for 3 hours. The mixture was cooled to 15 ° C, and precipitation was observed. The mixture was filtered, and the separated filter cake was washed with water (50 mL * 2) and concentrated in vacuo to give a brown solid 1-methyl-6-nitroquinoxaline-2,3 (1H, 4H) -dione (3 g, 13.42 mmol, yield 74.9%, purity 98.9%). 1 HNMR (400MHz, DMSO-d6) δ = 12.27 (s, 1H), 8.00 (dd, J = 2.8, 9.2Hz, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.52 (d, J = 9.2Hz, 1H), 3.53 (s, 3H). LCMS: [M+H + ]=222.1.

[0263]

[0264] 6-Amino-1-methylquinoxaline-2,3(1H,4H)-dione

[0265] To a solution of 4-methyl-7-nitro-1H-quinoxaline-2,3-dione (1 g, 4.52 mmol, 1 eq.) in DMF (50 mL) was added Pd / C (0.2 g, 10% purity) under argon. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25 °C for 12 h. The mixture was stirred by The mixture was filtered and the filtrate was concentrated in vacuo to give 6-amino-1-methylquinoxaline-2,3(1H,4H)-dione (900 mg, crude) as a yellow solid. LCMS: [M+H + ]=192.1.

[0266]

[0267] 6-((2,5-dichloropyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione

[0268] To a mixture of 2,4,5-trichloropyrimidine (863.46 mg, 4.71 mmol, 2 eq.) in DMF (5 mL) was added N,N-diisopropylethylamine (DIPEA) (608.4 mg, 4.71 mmol, 819.9 μL, 2 eq.). The reaction mixture was stirred at 15 °C for 10 minutes, and then a solution of 7-amino-4-methyl-1H-quinoxaline-2,3-dione (450 mg, 2.35 mmol, 1 eq.) in DMF (10 mL) was added dropwise. The resulting mixture was stirred at 15 °C for 12 hours. Water (20 mL) was added to the mixture to obtain a precipitate. The resulting mixture was filtered, and the separated filter cake was washed with water (30 mL), and then washed with EtOAc (50 mL). The residual solvent was removed in vacuo to give 6-((2,5-dichloropyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione (300 mg, 789.59 μmol, yield 33.6%, purity 89.0%) as a gray solid. 1 HNMR (400MHz, DMSO-d6) δ = 8.34 (s, 1H), 7.44-7.31 (m, 3H), 3.54 (s, 3H). LCMS:[M+H + ]=338.0.

[0269]

[0270] 6-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione

[0271] To a mixture of 7-[(2,5-dichloropyrimidin-4-yl)amino]-4-methyl-1H-quinoxaline-2,3-dione (100 mg, 295.73 μmol, 1 eq) and (3S,5R)-3,5-dimethylpiperidine (40.17 mg, 354.87 μmol, 1.2 eq) in DMF (2 mL) was added DIPEA (76.44 mg, 591.5 μmol, 103.0 μL, 2 eq) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 1 hour. The resulting mixture was concentrated in vacuo, and the separated residue was purified by preparative high performance liquid chromatography (prep-HPLC) (column: Waters TM Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 40%-70%, 10min) to obtain a white solid 6-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione (purity 99%, 26.2mg). 1 HNMR (400MHz, DMSO-d6) δ=12.09(s,1H),8.87(s,1H),8.02(s,1H),7.49-7.43(m,2H),7.34-7.28(m,1H),4.48(d,J=10.8Hz,2H) ,3.52(s,3H),2.25(t,J=12.4Hz,2H),1.76(d,J=13.2Hz,1H),1.57-1.43(m,2H),0.85(d,J=6.4Hz,6H),0.77(q,J=12.0Hz,1H). LCMS:[M+H + ]=415.1.

[0272]

[0273] To a mixture of 7-[[5-chloro-2-[(3S,5R)-3,5-dimethyl-1-piperidinyl]pyrimidin-4-yl]amino]-4-methyl-1H-quinoxaline-2,3-dione (100 mg, 241.03 μmol, 1 eq) in DMSO (10 mL) were added 3-bromo-N-methylpropionamide (44.02 mg, 265.13 μmol, 1.1 eq), K2CO3 (39.98 mg, 289.23 μmol, 1.2 eq) and KI (20.01 mg, 120.51 μmol, 0.5 eq). The mixture was stirred at 60 °C for 12 h, concentrated in vacuo, and filtered to remove solids. The separated mixture was purified by prep-HPLC (column: WatersTM Xbridge BEH C18 100*25mm*5μm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 35%-65%, 10min) to give a white solid 3-(7-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)-N-methylpropanamide (51.5mg, yield 42.7%). 1 H NMR (400MHz, DMSO-d6) δ = 8.87 (s, 1H), 8.05 (s, 1H), 7.94 (dd, J = 2.0, 3.6Hz, 1H), 7.7 9-7.71(m,1H),7.65(s,1H),7.38(d,J=8.8Hz,1H),4.53-4.49(m,2H),4.31-4.21(m ,2H),3.53(s,3H),2.55(d,J=4Hz,3H),2.48-2.43(m,2H),2.27(t,J=12.0Hz,2H),1 .81-1.72(m,1H),1.59-1.44(m,2H),0.86(d,J=6.4Hz,6H),0.77(q,J=12.0Hz,1H). LCMS:[M+H + ]=500.1.

[0274] Example 2: 2-(7-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidine-4- Synthesis of 4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-N-methylacetamide (56).

[0275]

[0276] 6-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione

[0277] A mixture of 7-[(2,5-dichloropyrimidin-4-yl)amino]-4-methyl-1H-quinoxaline-2,3-dione (2 g, 5.91 mmol, 1 eq.), (3S,5R)-4,4-difluoro-3,5-dimethylpiperidine (2.02 g, 7.69 mmol, 1.3 eq., TFA) and DIPEA (1.53 g, 11.83 mmol, 2.06 mL, 2 eq.) in DMSO (20 mL) was stirred at 100 °C under nitrogen atmosphere for 3 hours. Water (20 mL) was added to the mixture to obtain a precipitate. The resulting mixture was filtered and the separated filter cake was washed with water (50 mL) and then with EtOAc (50 mL). The separated residue was dried under reduced pressure to give 7-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidinyl]pyrimidin-4-yl]amino]-4-methyl-1H-quinoxaline-2,3-dione (2.2 g, 4.60 mmol, yield 77.8%, purity 94.1%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.10 (br s, 1H), 8.98 (s, 1H), 8.07 (s, 1H), 7.46 (d, J = 2.0Hz, 1H), 7.43-7.37 (m, 1H), 7.34-7.28 (m, 1H), 4.49 (br d,J=11.6Hz,2H),3.51(s,3H),2.64(br t,J=12.8Hz,2H),2.12-1.92(m,2H),0.96(d,J=6.4Hz,6H).

[0278]

[0279] To a mixture of 7-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidinyl]pyrimidin-4-yl]amino]-4-methyl-1H-quinoxaline-2,3-dione (100 mg, 221.79 μmol, 1 eq) and 2-bromo-N-methylacetamide (50.57 mg, 332.69 μmol, 1.5 eq) in DMSO (1.5 mL) were added K2CO3 (61.31 mg, 443.59 μmol, 2 eq) and KI (18.41 mg, 110.90 μmol, 0.5 eq), and the mixture was stirred at 60 ° C for 4 hours. Water was added to the reaction mixture to obtain a precipitate. The resulting mixture was filtered, and the separated filter cake was washed with water (15 mL*2), and then with EtOAc (15 mL*2). The residual solvent was removed under reduced pressure, and the resulting residue was triturated with DMSO (2 ml) at 15° C. for 10 minutes, and then the mixture was filtered. The separated filter cake was concentrated under reduced pressure to give 2-[7-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidinyl]pyrimidin-4-yl]amino]-4-methyl-2,3-dioxo-quinoxalin-1-yl]-N-methylacetamide (37 mg, purity 96.7%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ=8.98(s,1H),8.10(s,1H),8.03(brd,J=4.4Hz,1H),7.75(br d,J=8.8Hz,1H),7.41(br d,J=8.8Hz,1H),7.38(br s,1H),4.63(br s,2H),4.51(br d,J=10.4Hz,2H),3.57(s,3H),2.68(br t,J=12.8Hz,2H),2.57(br d,J=4Hz,3H),2.13-1.95(m,2H),0.98(br d,J=6.8Hz,6H). LCMS:[M+H + ]=522.18.

[0280] Example 3: Degradation activity in SU-DHL-4 cells.

[0281] HiBiT Solution

[0282] According to the cell degradation assay of Su-DHL-4 cells (HiBiT, Promega TM )Determine DC 50(Concentration to achieve 50% degradation) values ​​(Table 1). Endogenous BCL6 was labeled with 11-amino acid SmBiT by CRISPR / Cas9 gene editing and single cell clone selection. After 24 hours of compound treatment, the cells were lysed and incubated with LgBiT protein to reconstitute the complete nanoluciferase. The substrate was then added and the relative luciferase units were measured. The degradation level of each treatment is expressed as a percentage relative to the control 100% DMSO (Prism).

[0283] Table 1. DCs in SU-DHL-4 cells 50 and MS data

[0284] Compound <![CDATA[MS[M+H + ]]]> <![CDATA[HiBiT SU-DHL-4DC 50 (μM)]]> 1 500.1 0.025 8 591.2 ＞10 9 605.3 0.22 11 605.2 3.1 12 619.3 1.8 18 593.3 0.45 19 607.3 0.5 28 578.1 0.032 29 592.2 0.071 31 592.1 0.16 32 606.2 0.15 56 522.2 0.014 57 579.2 0.34 58 577.2 0.87 59 591.2 0.97 60 605.2 1.12 68 564.2 0.1 73 594.2 0.13 75-1 562.1 0.29 75-2 562.1 0.1 80 565.2 ＞10 81 565.2 0.25 82 537.1 0.084 83 537.1 0.92 84 538.1 N / A 85 538.1 0.094 86 523.2 0.12 87 523.2 0.23 106 487.2 0.041 107 487.2 0.047 108 517.1 0.043 109 517.1 0.004 110 517.2 0.018 111 531.2 0.034 112 533.2 0.025 117 532.2 0.13 118 532.2 0.12 119 541.1 0.013 120 590.1 1.9 121 590.1 0.071 122 505.1 0.019 123 505.2 0.023

[0285] The HiBiT assay data in SU-DHL-4 (B cell lymphoma) cells listed in Table 1 show that the DC 50 The value was 0.1 μM or lower.

[0286] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which the present disclosure pertains. All of these publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0287] Although the present disclosure has been described with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. Therefore, it should be understood that many modifications may be made to these illustrative embodiments and other arrangements may be designed without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A compound having a structure represented by Formula I: or a pharmaceutically acceptable salt or stereoisomer thereof, in: is phenyl or pyridyl; yes X is a bond, (C3-C6)carbocyclyl, (C3-C6)carbocyclyl(C=O) or SO2; X0 is N or CCN; X1 is CH2, S, CHF, CHCl, CHOH or CF2; R1 is (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) aminoalkyl, (C3-C6) carbocyclyl, 4- to 6-membered heterocyclyl, (C1-C6) alkyl-(C3-C6) carbocyclyl or (C1-C6) alkyl-4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different R 1a Group substitution, where R 1a is deuterium, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl; R2 and R 2’ are each independently H, (C1-C3)alkyl, (C1-C3)hydroxyalkyl or (C1-C3)aminoalkyl, or R2 and R 2' Together with the same carbon atom to which they are attached, they form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 2a Group substitution, where R 2a is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl; R3 and R 3’ are each independently H, (C1-C3)alkyl, (C1-C3)hydroxyalkyl or (C1-C3)aminoalkyl, or R3 and R 3' Together with the same carbon atom to which they are attached, they form C=O, (C3-C6) carbocyclyl, 4-membered to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 3a group substituted, where each R 3a are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl, or two of them 3a The groups, together with the same carbon atom to which they are attached, form C=O, or R2 or R 2' and R3 or R 3' , together with the same carbon atom to which they are attached, form a (C3-C6) carbocyclyl or a 4- to 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by one or more identical or different R 2a Group substitution; R4 is H, OH, NH-(C1-C6) alkyl, NH-(C1-C6) hydroxyalkyl, NH-(C1-C6) aminoalkyl, NH-(C3-C6) carbocyclyl, NH-4- to 6-membered heterocyclyl, NH-(C1-C6) alkyl-(C3-C6) carbocyclyl, NH-(C1-C6) alkyl-4- to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl or heterocyclyl is further optionally replaced by one or more identical or different R 4a group substituted, where each R 4a is independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxy, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl or 4- to 6-membered heterocyclyl; R5 is halogen or (C 1- C3) alkoxy; R6 and R 6' are each independently H or halogen; R7 is H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, CN, NO2, OH, (C2-C4)alkenyl, (C2-C4)alkynyl, or -R 7a -R 7b , where R 7a Does not exist or is O, N (R 7a1 )(CR 7a1 R 7a2 ) q ,S,SO,SO2,C(O),C(O)O,OC(O),C(O)N(R 7a1 )、N(R 7a1 )C(O), N(R 7a1 )C(O)N(R 7a2 )、N(R 7a1 )C(O)O、OC(O)N(R 7a1 )、S(O)2N(R 7a1 )、N(R 7a1 )SO2, where R 7a1 and R 7a2 are each independently H or (C1-C4) alkyl, and q is 0, 1, 2, and R 7b is H, (C1-C6) alkyl, (C6-C 10 )aryl, (C3-C6)cycloalkyl, (C2-C4)alkenyl, (C1-C4)alkynyl, (C3-C6)cycloalkenyl, wherein the alkyl, aryl, cycloalkyl, alkenyl, alkynyl or cycloalkenyl is further optionally substituted with one or more substituents independently selected from the group consisting of oxo, (C1-C4)alkyl, (C1-C4)cycloalkyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, amino, CN, OH, amido, carboxyl, carbamoyl, sulfamoyl, thiol, C(O)NR 7b1 R 7b2 , R 7b1 R 7b2 OR 7b1 , where R 7b1 and R 7b2 Each is independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, wherein the oxo, alkyl, cycloalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, amino, CN, OH, amide, carboxyl, carbamoyl, sulfamoyl or thiol is optionally further substituted by R 7b3 -R 7b4 Substitution, where R 7b3 is absent or is (C1-C5)alkylene which is optionally substituted by one or more substituents selected from (C1-C2)alkyl or oxo, and R 7b4 Yes (C6-C 10 )aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclyl, (C3-C6)carbocyclyl, halogen, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, CN, OH, (C1-C4)alkoxy, C(O)R 7b4a 、COOR 7b4b 、C(O)NR 7b4a R 7b4b or NR 7b4a R 7b4b , where: R 7b4a and R 7b4b each independently selected from H or (C1-C4) alkyl; the aryl, heteroaryl, heterocyclic or carbocyclic radical is optionally further substituted by one or more substituents independently selected from (C1-C4) alkyl, halogen, (C1-C4) haloalkyl, amino, CN or OH; and the heterocyclic or heteroaryl radical contains at least one nitrogen atom and is connected via nitrogen, wherein the heterocyclic radical is optionally and independently substituted by one or more identical or different groups independently selected from R9, and the heteroaryl radical is optionally and independently substituted by one or more independently selected from R 10 The same or different groups are substituted; R8 is halogen or CN; R9 is =O, CN, C≡CH, OH, COOH, halogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, 5-membered or 6-membered heteroaryl, phenyl, N(R 11 R 12 )、C(O)-R 13 、C(O)N(R 14 R 15 ) or a 5- to 8-membered heterocyclyl, wherein the (C1-C6)alkyl is optionally substituted by COOH, OH, COO-(C1-C6)alkyl, -CON((C1-C6)alkyl)2, (C1-C6)alkoxy, N((C1-C3)alkyl)2, phenyl or a 5- or 6-membered heterocyclyl, and the heteroaryl, phenyl or heterocyclyl is optionally substituted by a group selected from (C1-C6)alkyl; R 10 COOH, (C1-C6) alkyl, C(O)-R 16 or C(O)N(R 17 )(R 18 ); R 11 is H or (C 1- C4) alkyl; R 12 is H, (C1-C4)alkyl, (C1-C4)haloalkyl, 6-membered heterocyclyl or 6-membered heteroaryl; R 13 is (C1-C3)alkyl-N(C1-C3)alkyl)2 or 5-membered or 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by (C1-C3)alkyl; R 14 is hydrogen or (C 1- C3) alkyl; R 15 is (C1-C6)alkyl optionally substituted by NH2, (C1-C6)alkoxy, O-(C1-C6)alkyl-NH2 or O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, or R 15 is a 6-membered heterocyclic group optionally substituted by a (C1-C3)alkyl group; R 16 is a 6-membered heterocyclic group optionally substituted by a (C1-C3)alkyl group; R 17 and R 18 Each is independently H or (C1-C3) alkyl; R 19 H, =O, -CN, –C≡CH, -OH, -SH, -NH2, -COOH, halogen, (C1- C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, acylamino, carboxyl, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclic group, –NR 20 R 21 , –C(O)R 22 , –C(O)NR 23 R 24 or L1Y1, wherein the alkyl, phenyl or heterocyclyl is optionally substituted by one or more groups selected from halo, –COOH, –OH, –NH2, (C1-C6)alkyl, –C(O)O–(C1-C6)alkyl, –C(O)N(C1-C6alkyl)2, –O–(C1-C6)alkyl, –N(C1-C3alkyl)2, phenyl and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted by one or more groups selected from halo and (C1-C6)alkyl; L1 is absent, (C1-C6) alkylene or (C3-C7) carbocyclyl; wherein the alkylene or carbocyclyl is further optionally replaced by one or more identical or different R 25 or L1 is the same as R 26 (C2-C4)alkylene group combined to form a 4- to 6-membered heterocyclic group; and Y1 is –CN, –OH, halo, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, 4- to 7-membered heterocyclyl, (C3-C6)carbocyclyl, –NR 26 R 27 , –C(O)R 22 , –C(O)NR 23 R 24 ; wherein the alkyl, carbocyclyl or heterocyclyl is further optionally substituted by one or more identical or different groups selected from (C1-C4)alkyl, halo, (C1-C4)haloalkyl, –CN, –OH and –NH2; R 19 'Not present, H, -CN, -C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, amide, carboxyl, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclic group, -NR 20 R 21 、-C(O)R 22 or -C(O)NR 23 R 24 wherein the alkyl, phenyl or heterocyclic group is further optionally replaced by one or more identical or different R 25 Group substitution, or R 19 ' and L1 together with the same carbon atom to which they are attached form a spiro (C3-C7) carbocyclic group or a 4- to 7-membered heterocyclic group; wherein the carbocyclic group or heterocyclic group is further optionally replaced by one or more identical or different R 25 Group substitution; R 20 is hydrogen, (C1-C4)alkyl or (C3-C6)cycloalkyl; R 21 is hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl or 6-membered heterocyclyl; R 22 is -(C1-C3)alkyl-N(C1-C3alkyl)2, (C3-C6)cycloalkyl or 5- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with (C1-C3)alkyl; R 23 is hydrogen, (C1-C3)alkyl or (C3-C6)cycloalkyl; R 24 is (C3-C6)cycloalkyl or (C1-C6)alkyl, which is optionally substituted with –NH2, –O-(C1-C6)alkyl, –O-(C1-C6)alkyl-NH2 or –O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2; Each R 25 and alkyl. In some embodiments, the present invention relates to alkyl, alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cycloalkyloxy, heterocycloalkyloxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkenyloxy, alkynyloxy, amino, alkylamino, cycloalkylamino, heterocycloalkylamino, arylamino, heteroarylamino, aralkylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-alkyl-N-aralkylamino, hydroxyalkyl, aminoalkyl, alkylthio, haloalkylthio, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, heterocycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, alkylaminosulfonyl, cycloalkylaminosulfonyl, heterocycloalkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl alkyl, N-alkyl-N-arylaminosulfonyl, N-alkyl-N-heteroarylaminosulfonyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, amino, alkylsulfonylamino, haloalkylsulfonylamino, cycloalkylsulfonylamino, heterocycloalkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, alkylcarbonylamino, haloalkylcarbonylamino, cycloalkylcarbonylamino, heterocycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylsulfonylamino, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, N-alkyl-N-heteroarylaminocarbonyl, cyano, nitro, azido or phosphinyl; R 26 and R 27 are each independently hydrogen, (C1-C6) alkyl, (C3-C7) carbocyclyl, 4- to 7-membered heterocyclyl, (C6-C 10 ) aryl or monocyclic or bicyclic 5- to 10-membered heteroaryl; wherein the alkyl, carbocyclic, heterocyclic, aryl or heteroaryl is further optionally replaced by one or more identical or different R 25 Group substitution, or R 26 and R 27 Together with the nitrogen atom to which they are attached, they form a 3- to 7-membered heterocyclic group, wherein the heterocyclic group is further optionally substituted by one or more identical or different R 25 Group substitution; m is 0, 1, or 2; n is 0, 1, 2 or 3; and o is either 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl and yes And the compound is represented by structure I-1a:

3. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is pyridyl and yes And the compound is represented by any one of structures I-2a to I-4a:

4. The compound of claim 1, wherein R7 is optionally substituted (C1-C4)alkyl.

5. The compound according to claim 4, wherein R7 is methyl or The compound according to claim 1 , wherein R 7 is amino or OH.

7. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl and yes And the compound is represented by structure I-1b:

8. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is pyridyl and yes And the compound is represented by any one of structures I-2b to I-4b:

9. The compound according to claim 7, wherein X1 is CH2, CHF, CHOH or CF2.

10. The compound according to claim 7, wherein R 19 and R 19 'are independently H, OH, methyl, amino, 11. The compound according to claim 1, wherein R8 is halogen.

12. The compound according to claim 11, wherein R8 is Cl or F.

13. The compound of claim 1, wherein R1 is optionally substituted (C1-C6)alkyl.

14. The compound according to claim 13, wherein R1 is methyl.

15. The compound of claim 1, wherein R1 is optionally substituted (C1-C6)hydroxyalkyl.

16. The compound according to claim 15, wherein R1 is 17. The compound of claim 1, wherein R1 is optionally substituted (C1-C6)aminoalkyl.

18. The compound according to claim 17, wherein R1 is 19. The compound according to claim 1, wherein R1 is an optionally substituted 4- to 6-membered heterocyclyl.

20. The compound according to claim 19, wherein R1 is 21. The compound of claim 1, wherein R1 is an optionally substituted (C1-C6)alkyl-4- to 6-membered heterocyclyl.

22. The compound according to claim 21, wherein R1 is 23. The compound of claim 1, wherein X is a bond or a (C3-C6)carbocyclyl, m is 0 or 1, and o is 0 or 1.

24. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is phenyl and yes And the compound is represented by structure I-1a1 or I-1b1:

25. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl. yes X is a bond, m is 0 or 1, and o is 1, and the compound is represented by structure I-1a2 or I-1b2:

26. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is pyridyl, yes And the compound is represented by any one of structures I-2a1 to I-4a1 and I-2b1 to I-4b1:

27. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Pyridyl, yes X is a bond, m is 0 or 1, and o is 1, and the compound is represented by any one of structures I-2a2 to I-4a2 and I-2b2 to I-4b2:

28. The compound according to claim 24, wherein R2 and R 2’ Each is independently H or methyl.

29. The compound according to claim 24, wherein R2 and R 2’ All are H.

30. The compound according to claim 24, wherein R2 and R 2’ Together with the same carbon atom to which they are attached they form a cyclopropyl group.

31. The compound according to claim 23, wherein R3 and R 3’ Together with the same carbon atom to which they are attached they form C=O.

32. The compound according to claim 23, wherein R3 and R 3’ Together with the same carbon atom to which they are attached, they form an optionally substituted 4- to 6-membered heterocyclyl.

33. The compound of claim 32, wherein the optionally substituted 4-membered heterocyclyl is oxetane or N-methylazetidine.

34. The compound of claim 32, wherein the optionally substituted 4- to 6-membered heterocyclyl is a carbamate.

35. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl. yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compound is represented by structure I-1c1:

36. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl. yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compound is represented by structure I-1c2:

37. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Pyridyl, yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compound is represented by any one of structures I-2c1 to I-4c1:

38. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is pyridyl, yes X is a C4 carbocyclic group (C=O), and m and o are 0, and the compound is represented by any one of structures I-2c2 to I-4c2:

39. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl. yes X is SO2, m is 1 or 2, and o is 0, and the compound is represented by structure I-1d1:

40. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein It is phenyl. yes X is SO2, m is 1 or 2, and o is 0, and the compound is represented by structure I-1d2:

41. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is pyridyl, yes X is SO2, m is 1 or 2, and o is 0, and the compound is represented by any one of structures I-2d1 to I-4d1:

42. The compound according to claim 1, wherein is pyridyl, yes X is SO2, m is 1 or 2, and o is 0, and the compound is represented by any one of structures I-2d2 to I-4d2:

43. The compound of claim 1, wherein R4 is optionally substituted NH-(C1-C6)alkyl.

44. The compound of claim 43, wherein R4 is NH-methyl.

45. The compound of claim 1, wherein R4 is H or OH.

46. ​​The compound of claim 1, wherein R4 is optionally substituted NH-(C1-C6)hydroxyalkyl.

47. The compound according to claim 46, wherein R4 is 48. The compound of claim 1, wherein R4 is optionally substituted NH-(C1-C6)aminoalkyl.

49. The compound according to claim 48, wherein R4 is 50. The compound of claim 1, wherein R4 is an optionally substituted -NH-4- to 6-membered heterocyclyl.

51. The compound according to claim 50, wherein R4 is 52. The compound of claim 1, wherein R4 is an optionally substituted NH-(C1-C6)alkyl-4- to 6-membered heterocyclyl.

53. The compound according to claim 52, wherein R4 is 54. The compound of claim 1, wherein n is 0 or 1.

55. The compound of claim 1, wherein R5 is F.

56. The compound of claim 1, wherein R5 is methoxy.

57. The compound according to claim 1, wherein R6 and R 6’ All are H or F.

58. The compound of claim 1, wherein X0 is N.

59. The compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is any one of the following structures:

60. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or stereoisomer according to any one of claims 1 to 59, and a pharmaceutically acceptable carrier.

61. The pharmaceutical composition of claim 60, which is in liquid or solid form.

62. A method of treating a cancer characterized by aberrant B-cell lymphoma 6 (BCL6) activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-59, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 60.

63. The method of claim 62, wherein the cancer is a lymphoid malignancy.

64. The method of claim 63, wherein the lymphoid malignancy is peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia / lymphoma (ALL), or cutaneous T-cell lymphoma.

65. The method of claim 62, further comprising administering an additional anticancer agent.

66. The method of claim 65, wherein the additional anti-cancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor.

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