Quinoxalinone and pyrido[2,3-b]pyrazine-2,3-dione B-cell lymphoma 6 (BCL6) degrading agents and uses thereof

Abstract

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

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 390,482, filed Jul. 19, 2022, the entire disclosure of which is hereby incorporated by reference herein.

Background Art

[0002] BCL6 is a promising drug target in non-Hodgkin lymphoma 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, as a result of somatic BCL6 translocations, exon mutations, promoter mutations, or mutations in regulatory pathways, 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)). BCL6 acts as a master transcriptional repressor that enables rapid expression in germinal center (GC) B cells and resistance to genomic instability caused by hypermutation and class switch recombination of immunoglobulin genes (Hatzi et al., Trends Mol. Med. 20:343-352 (2014)). BCL6 suppresses a wide range of genes involved in DNA damage response (Ranuncolo et al., Blood Cells Mol. Dis. 41:95-99 (2008)), cell cycle checkpoint (Tunyaplin et al., J. Immunol. 173:1158-1165 (2004)), and differentiation (Phan et al., Nat. Immunol. 6:1054-1060 (2005)).

[0003] Knockout of BCL6 in lymphocytes results in tumor stasis (Schlager et al., Oncotarget 11:875-890 (2020)). Some peptides and small molecule inhibitors targeting BCL6 have shown efficacy in vivo, but only at high concentrations, which limited their conversion to clinical therapeutic agents (Cerchietti et al., Cancer Cell 17:400-411 (2010); Cardenas et al., J. Clin. Invest. 126:3351-3362 (2016)). Summary of the Invention Means for Solving the Problems

[0004] The first aspect of the present disclosure is formula I: [Chemical formula] [Wherein: [Chemical formula] is phenyl or pyridyl; [Chemical formula] is [Chemical formula] and X is a bond, (C3-C6) carbocyclic, (C3-C6) carbocyclic (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 said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl is selected from the group consisting of one or more of the same or different R 1a may be further substituted by groups, R 1a is deuterium, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxyl, (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 form a (C-C) carbocyclyl or a 4- to 6-membered heterocyclyl, and said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl may be optionally joined by one or more of the same or different R 2a may be substituted by a group, R 2a is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxyl, (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, form C=O, (C3-C6) carbocyclyl, 4- to 6-membered heterocyclyl, wherein said carbocyclyl or heterocyclyl may be substituted by one or more identical or different R 3a groups, and each R 3a is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-(C1-C3) alkoxy, halogen, amino, hydroxyl, (C1-C6) haloalkyl, NH-(C1-C6) alkyl, N((C1-C6) alkyl)2, (C3-C6) carbocyclyl, or 4- to 6-membered heterocyclyl, or two R 3a 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 (C3-C6) carbocyclyl or 4- to 6-membered heterocyclyl, wherein said carbocyclyl or heterocyclyl may be substituted by one or more identical or different R 2a groups; 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 said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl may be further substituted by one or more identical or different R 4a groups, where each R 4a is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkyl-(C1-C3) alkoxy, halogen, amino, hydroxyl, (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 (C1-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 wherein R 7a is absent 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, wherein R 7a1 and R 7a2 are each independently H or (C1-C4) alkyl, 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 said alkyl, aryl, cycloalkyl, alkenyl, alkynyl, or cycloalkenyl is optionally oxo, (C1-C4) alkyl, (C1-C4) cycloalkyl, halogen, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, amino, CN, OH, amide, carboxy, carbamoyl, sulfamoyl, mercapto, C(O)NR 7b1 R 7b2 , R 7b1 R 7b2 , or OR 7b1may be further substituted by one or more substituents independently selected therefrom, wherein R 7b1 and R 7b2 are each independently selected from hydrogen, (C1-C4)alkyl, (C3-C6)cycloalkyl, said oxo, alkyl, cycloalkyl, haloalkyl, haloalkoxy, hydroxyalkyl, amino, CN, OH, amide, carboxy, carbamoyl, sulfamoyl, or mercapto may be further substituted by R 7b3 -R 7b4 wherein R 7b3 is absent or is (C1-C5)alkylene optionally substituted by one or more substituents selected from (C1-C2)alkyl or oxo, R 7b4 is (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 wherein: R 7b4a and R 7b4b are each independently selected from H or (C1-C4)alkyl; said aryl, heteroaryl, heterocyclyl, or carbocyclyl may each independently be further substituted by one or more substituents selected from (C1-C4)alkyl, halogen, (C1-C4)haloalkyl, amino, CN or OH; said heterocyclyl or heteroaryl contains at least one nitrogen atom and is linked via nitrogen, said heterocyclyl group may be optionally and independently substituted by one or more identical or different groups independently selected from R9, said heteroaryl group may be optionally and independently substituted by one or more identical or different groups independently selected from R 10 ; R8 is halogen or CN; R9 is =O, CN, C≡CH, OH, COOH, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, 5- or 6-membered heteroaryl, phenyl, N(R 11 R 12 ), C(O)-R 13 , C(O)N(R 14 R 15 ), or 5- to 8-membered heterocyclyl, wherein the (C1-C6)alkyl may be substituted with COOH, OH, COO-(C1-C6)alkyl, -CON((C1-C6)alkyl)2, (C1-C6)alkoxy, N((C1-C3)alkyl)2, phenyl, or 5- or 6-membered heterocyclyl, and the heteroaryl, phenyl, or heterocyclyl may be substituted with one group selected from (C1-C6)alkyl; R 10 is COOH, (C1-C6)alkyl, C(O)-R 16 , or C(O)N(R 17 )(R 18 ); R 11 is H or (C1-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- or 6-membered heterocyclyl, and the heterocyclyl may be substituted with (C1-C3)alkyl; R 14 is hydrogen or (C1-C3)alkyl; R 15 is (C1-C6)alkyl optionally substituted with NH2, (C1-C6)alkoxy, O-(C1-C6)alkyl-NH2, or O-(C1-C6)alkyl-O-(C1-C6)alkyl-NH2, or R 15 is 6-membered heterocyclyl optionally substituted with (C1-C3)alkyl; R 16 is a 6-membered heterocyclyl which may be substituted with (C1-C3) alkyl; R 17 and R 18 are each independently H or (C1-C3) alkyl; R 19 is H, =O, -CN, -C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6) alkyl, -O-(C1-C6) alkyl, (C1-C6) haloalkyl, amide, carboxy, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclyl, -NR 20 R 21 , -C(O)R 22 , -C(O)NR 23 R 24 , or L1Y1, wherein the alkyl, phenyl, or heterocyclyl may be 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-C6 alkyl)2, -O-(C1-C6) alkyl, -N(C1-C3 alkyl)2, phenyl, and 4- to 6-membered heterocyclyl which may be substituted with one or more groups selected from halo and (C1-C6) alkyl; L1 is absent, (C1-C6) alkylene, or (C3-C7) carbocyclic; wherein the alkylene or carbocyclic may be further substituted with one or more identical or different R 25 groups, or L1 is (C2-C4) alkylene which binds to R 26 to form a 4- to 6-membered heterocyclyl group; Y1 is -CN, -OH, halo, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, 4- to 7-membered heterocyclyl, (C3-C6) carbocyclic, -NR 26 R 27 , -C(O)R 22 , -C(O)NR 23 R 24and the alkyl, carbocyclic, or heterocyclic group may be further substituted by one or more identical or different groups selected from (C1-C4)alkyl, halo, (C1-C4)haloalkyl, -CN, -OH, and -NH2; R 19’ is absent or is H, -CN, -C≡CH, -OH, -SH, -NH2, -COOH, halo, (C1-C6)alkyl, -O-(C1-C6)alkyl, (C1-C6)haloalkyl, amide, carboxy, carbamoyl, sulfamoyl, phenyl, 5- to 8-membered heterocyclyl, -NR 20 R 21 , -C(O)R 22 , or -C(O)NR 23 R 24 ; where the alkyl, phenyl, or heterocyclyl may be further substituted by one or more identical or different R 25 groups, 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; the carbocyclic or heterocyclic group may be further substituted by one or more identical or different R 25 groups; 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, the heterocyclyl may be substituted by (C1-C3)alkyl; R 23 is hydrogen, (C1-C3)alkyl, or (C3-C6)cycloalkyl; R 24is (C3-C6) cycloalkyl or (C1-C6) alkyl, which may be substituted with -NH2, -O-(C1-C6) alkyl, -O-(C1-C6) alkyl-NH2, or -O-(C1-C6) alkyl-O-(C1-C6) alkyl-NH2; each R 25is, independently, oxo, alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocyclic, heterocyclic, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, 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, carboxy, 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, azide, or phosphinyl; R 26 and R 27is, independently of each other, 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; said alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl may be further substituted by one or more identical or different R 25 groups, or R 26 and R 27 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl, said heterocyclyl may be further substituted by one or more identical or different R 25 groups; m is 0, 1, or 2; n is 0, 1, 2, or 3; o is 0 or 1], a compound having the structure represented thereby, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0005] Another aspect of the present disclosure is directed 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.

[0006] A further aspect of the present disclosure is a method of treating cancer characterized by or mediated by abnormal B-cell lymphoma 6 (BCL6) activity, the method comprising 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.

[0007] In some embodiments, the cancer is a lymphoid malignancy. In some embodiments, 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), cutaneous T-cell lymphoma, chronic myelogenous leukemia, or B-cell non-Hodgkin lymphoma.

Best Mode for Carrying Out the Invention

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. As used in this specification and the appended claims, unless the context clearly dictates otherwise, the following terms have the meanings set forth below to facilitate understanding of the disclosure.

[0009] As used in this specification 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 the like.

[0010] Unless otherwise specified, the term “about” means within 10% (e.g., within 5%, 2%, or 1%) of a specified value modified by the term “about.”

[0011] The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or non-limiting and does not exclude additional, unrecited elements or method steps. In contrast, the transitional term “consisting of” excludes elements, steps, or components not specified in the claims. The transitional term “consisting essentially of” limits the claims to the specific materials or steps of the claimed invention, “and those that do not substantially affect the basic and novel characteristics.”

[0012] For the compounds of the present disclosure and to the extent that the following terms are used herein to further describe them, the following definitions apply.

[0013] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group. In some embodiments, unless otherwise specified with respect to any one or more of the groups in the compounds of formula (I), the alkyl radical is a C1-C4 group. In other embodiments, the alkyl radical is a C0-C4, C0-C3, C1-C4, C1-C3 or C1-C2 group (C0 alkyl refers to a bond). Representative examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, and 2-methyl-2-propyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C3-C5 branched-chain alkyl group.

[0014] As used herein, the term "alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain consisting of only carbon and hydrogen that links the rest of the molecule to a radical group. The alkylene chain may be bonded to the rest of the molecule via a single bond or to the radical group via a single bond. In some embodiments, unless otherwise specified with respect to any one or more of the groups in the compounds of formula (I), the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene (e.g., methylene, ethylene, propylene, and n-butylene)). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0015] As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon group having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, unless otherwise specified with respect to any one or more groups in the compounds of formula (I), the alkenyl radical is a C2-C6 group. In other embodiments, the alkenyl radical 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, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl and hexa-1,3-dienyl.

[0016] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined above to which an oxygen radical is attached. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbyl groups covalently bonded by oxygen. Thus, the alkyl substituent that makes an alkyl into an ether is an alkoxyl or is similar to an alkoxyl and can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0017] As used herein, the term "alkoxylene" refers to a general formula (-O-C n H 2nrefers to a saturated monovalent aliphatic group and includes both straight-chain and branched-chain radicals. The alkoxylene chain may be bonded to the remainder of the molecule via a single bond or to a radical group via a single bond. In some embodiments, and unless otherwise specified with respect to any one or more of the groups in the compound of formula (I), the alkoxylene group contains 1 to 3 carbon atoms (-O-C1-C3 alkoxylene). In other embodiments, the alkoxylene group contains 1 to 5 carbon atoms (-O-C1-C5 alkoxylene).

[0018] As used herein, the term "cyclic group" is used alone or as part of a larger moiety and broadly refers to any group that includes a saturated, partially saturated or aromatic ring system, such as a carbocyclic group (cycloalkyl, cycloalkenyl), a heterocyclic group (heterocycloalkyl, heterocycloalkenyl), an aryl group and a heteroaryl group. The cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, unless otherwise specified with respect to any one or more of the groups in the compound of formula (I), the cyclic group may include one or more (e.g., 1, 2, or 3) carbocyclic groups, heterocyclic groups, aryl groups or heteroaryl groups.

[0019] As used herein, the term "carbocycle" (also "carbocyclyl") is used alone or as part of a larger moiety and refers to a group that is alone or part of a larger moiety and includes a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms (e.g., an alk carbocyclic group). The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused ring systems, bridged ring systems, and spiro ring systems, and combinations thereof. Unless otherwise specified with respect to any one or more of the groups in the compound of formula (I), in one embodiment, the carbocyclyl contains 3 to 15 carbon atoms (C3-C 15 )). In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C3-C 12 ). In another embodiment, the carbocyclyl is C3-C8, C3-C 10 or C5-C 10includes. In another embodiment, the carbocyclic ring is, as a monocyclic ring, including C3-C8, C3-C6 or C5-C6. In some embodiments, the carbocyclic ring is, as a bicyclic ring, C7-C 12 includes. In another embodiment, the carbocyclic ring is, as a spiro system, C5-C 12 includes. Representative examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuterocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclic rings having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclic rings include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. The term carbocyclic ring includes aryl ring systems as defined herein. The term carbocyclic ring also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic or spiro carbocyclic rings). The term carbocyclic group also includes a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl or heterocycle), where the radical or point of attachment is on the carbocyclic ring.

[0020] As used herein, the term "heterocyclyl" is used alone or as part of a larger moiety and includes saturated, partially unsaturated or aromatic ring systems, where one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, N(O), S, S(O) or S(O)2), and refers to "carbocyclyl". The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused ring, bridged ring, and spiro ring systems, as well as combinations thereof. In some embodiments, unless otherwise specified with respect to any one or more of the groups in 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 heteroaryl ring system such as a 5- to 14-membered heteroaryl ring system. The term heterocyclyl also includes C3-C8 heterocycloalkyl which is a saturated or partially unsaturated monocyclic, bicyclic, or spiro ring system containing 3 to 8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

[0021] In some embodiments, the heterocyclyl group contains 3 to 12 ring atoms, including monocyclic, bicyclic, tricyclic and spiro ring systems, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur or oxygen. In some embodiments, unless otherwise specified, the heterocyclyl contains a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In some embodiments, the heterocyclyl contains a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In some embodiments, the heterocyclyl contains a 3-membered monocyclic ring. In some embodiments, the heterocyclyl contains a 4-membered monocyclic ring. In some embodiments, the heterocyclyl contains a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group contains 0 to 3 double bonds. In any of the foregoing embodiments, the heterocyclyl contains 1, 2, 3 or 4 heteroatoms. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4] + Cl - , [NR4] + OH -)). Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 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, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, l,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1] Examples include octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-one only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyl containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms include 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 such as oxazol-2-yl, and oxadiazolyl such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered ring heterocyclyl 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 heterocyclyl are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Examples of 6-membered heterocyclyl contain 1 to 3 nitrogen atoms and optionally a sulfur or oxygen atom, such as pyridyl including pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl; triazinyl such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; particularly pyridazinyl such as pyridazin-3-yl and pyrazinyl.

[0022] Accordingly, as used herein, the term heterocyclic ring includes an N - heterocyclyl group that refers to a heterocyclyl group containing at least one nitrogen, where the point of attachment of the heterocyclyl group to the remainder of the molecule is through a nitrogen atom in the heterocyclyl group. Unless otherwise specified for any one or more of the groups in the compound of formula (I), representative examples of the N - heterocyclyl group include 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. As used herein, the term heterocyclic ring also includes a C - heterocyclyl group that refers to a heterocyclyl group containing at least one heteroatom, where the point of attachment of the heterocyclyl group to the remainder of the molecule is through a carbon atom in the heterocyclyl group. Unless otherwise specified, representative examples of the C - heterocyclyl group include 2 - morpholinyl, 2 - or 3 - or 4 - piperidinyl, 2 - piperazinyl, and 2 - or 3 - pyrrolidinyl. As disclosed above, the term heterocyclic ring, where R c is an alkylene chain, of the formula - R c also includes a heterocyclylalkyl group that refers to a heterocyclyl group. As used herein, the term heterocyclic ring, where R c is an alkylene chain, of the formula - O - R c also includes a heterocyclylalkoxy group that refers to a radical attached through an oxygen atom of the heterocyclyl group.

[0023] As used herein, the term "aryl" (e.g., "aralkyl" where the terminal carbon atom on an alkyl group is the point of attachment, such as a benzyl group, "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an aryl group), whether used alone or as part of a larger moiety, refers to a group containing a monocyclic, bicyclic, or tricyclic carbocyclic system including a fused ring, with at least one ring in the system being aromatic. In some embodiments, the aralkoxy group is a benzyloxy group. The term "aryl" may be used interchangeably with the term "aryl ring". In one embodiment, unless 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 groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4 - tetrahydronaphthalenyl, 1H - indenyl, 2,3 - dihydro - 1H - indenyl, naphthyridinyl, etc., which may be substituted or independently substituted with one or more of the substituents described herein. A particular aryl is phenyl. In some embodiments, unless otherwise specified, the aryl group includes an aryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., a carbocyclic or heterocyclic ring), where the radical or point of attachment is on the aryl ring.

[0024] Thus, the term aryl, as disclosed above, refers to an aralkyl group (e.g., benzyl) of the formula -R c -aryl where R is an alkylene chain such as methylene or ethylene. In some embodiments, unless otherwise specified with respect to any one or more of the groups in the compound of formula (I), the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, also includes an aralkoxy group that refers to a group attached through an oxygen atom of the formula -O-R c -aryl where R is an alkylene chain such as methylene or ethylene. c -aryl where R is an alkylene chain such as methylene or ethylene. c -aryl where R is an alkylene chain such as methylene or ethylene.

[0025] As used herein, the term "heteroaryl", used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also referred to as "heteroaralkyl"), or "heteroarylalkoxy" (also referred to 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, unless otherwise specified with respect to any one or more of the groups in the compounds of formula (I), heteroaryl includes a 5- to 6-membered monocyclic aromatic group in which one or more of the ring atoms are independently optionally substituted nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more (e.g., 1, 2 or 3) cyclic (e.g., carbocyclic or heterocyclic) rings and the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group includes a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring), where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0026] The term heteroaryl also, as used herein, refers to a heteroaryl group as defined above and includes an N-heteroaryl group that contains at least one nitrogen atom and the point of attachment of the N-heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl further includes a C-heteroaryl group that, as used herein, refers to a heteroaryl group as defined above, where the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl, as disclosed above, where R c is an alkylene chain as defined above, refers to a heteroarylalkyl group of the formula --R c -heteroaryl. The term heteroaryl also, as used herein, where R c is an alkylene group as defined above, refers to a heteroaralkoxy (or heteroarylalkoxy) group of the formula --O--R c -heteroaryl attached through an oxygen atom.

[0027] Unless otherwise disclosed with respect to any one or more groups in the compound of formula (I), representative examples of substituents include 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), 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), cyclic (e.g., C3-C 12 、C5-C6), substituted cyclic (e.g., C3-C 12 、C5-C6), carbocyclic (e.g., C3-C 12 、C5-C6), substituted carbocyclic (e.g., C3-C 12 、C5-C6), heterocyclic (e.g., C3-C 12 、C5-C6), substituted heterocyclic (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 pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C 12 、C6), substituted aryloxy (e.g., C6-C 12 、C6), alkylthio (e.g., C1-C6), substituted alkylthio (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 peptide groups may be included.

[0028] In one aspect, the compounds of the present disclosure have the formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0029] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0030] In some embodiments,

Chemical formula

[0031] In some embodiments, R7 is optionally substituted (C1-C4) alkyl. In some embodiments, R7 is methyl, or [Chemistry] is.

[0032] In some embodiments, R7 is amino or OH.

[0033] In some embodiments, [Chemistry] is phenyl [Chemistry] is [Chemistry] and the compounds of the present disclosure are represented by Structure I-1b: [Chemistry] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0034] In some embodiments, [Chemistry] is pyridyl [Chemistry] is [Chemistry] and the compounds of the present disclosure have the structures I-2b to I-4b: [Chemistry] is represented by any one of them, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0035] In some embodiments, X1 is CH2, CHF, CHOH, or CF2.

[0036] In some embodiments, R 19 and R 19 ' are each independently H, OH, methyl, amino, [Chemistry] is.

[0037] In some embodiments, R8 is halogen. In some embodiments, R8 is Cl or F.

[0038] In some embodiments, R1 is optionally substituted (C1-C6) alkyl. In some embodiments, R1 is methyl.

[0039] In some embodiments, R1 is optionally substituted (C1-C6) hydroxyalkyl. In some embodiments, R1 is [Chemistry] is.

[0040] In some embodiments, R1 is optionally substituted (C1-C6) aminoalkyl. In some embodiments, R1 is

Chemical formula

[0041] In some embodiments, R1 is optionally substituted 4- to 6-membered heterocyclyl. In some embodiments, R1 is

Chemical formula

[0042] In some embodiments, R1 is optionally substituted (C1-C6) alkyl-4- to 6-membered heterocyclyl. In some embodiments, R1 is

Chemical formula

[0043] In some embodiments, X is a bond or (C3-C6) carbocyclyl, m is 0 or 1, and o is 0 or 1.

[0044] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0045] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0046] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0047] In some embodiments,

Chemical formula

Chem.

Chem.

Chem.

[0048] In some embodiments, R2 and R 2’ are each independently H or methyl. In some embodiments, both R2 and R2 are H. In some embodiments, R2 and R2 together with the same carbon atom to which they are attached form cyclopropyl.

[0049] In some embodiments, R3 and R 3’ are each independently H or methyl. In some embodiments, R3 and R 3’ together with the same carbon atom to which they are attached form C=O. In some embodiments, R3 and R 3’ together with the same carbon atom to which they are attached form an optionally substituted 4- to 6-membered heterocyclyl. In some embodiments, two R 3a 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- or 6-membered heterocyclyl is carbamate. In some embodiments, R2 or R 2’ and R3 or R 3’They combine with the same carbon atom to which they are attached to form a (C3-C6) carbocyclic ring.

[0050] In some embodiments, R4 is OH or H.

[0051] In some embodiments, R2 and R 2’ are each independently H or methyl; R3 and R 3’ are each independently H or methyl; R4 is OH or H. In some embodiments, R2 and R 2’ are each H; R3 and R 3’ are each independently H or methyl; R4 is OH.

[0052] In some embodiments

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0053] In some embodiments,

Chemical formula

Chemical formula

Chemical formula

[0054] In some embodiments, [Chemical formula] is pyridyl, [Chemical formula] is [Chemical formula] wherein X is C4 carbocyclic (C=O), m and o are 0, and the compounds of the present disclosure have the structures I-2c1 to I-4c1: [Chemical formula] represented by any one of or a pharmaceutically acceptable salt or stereoisomer thereof.

[0055] In some embodiments, [Chemical formula] is pyridyl, [Chemical formula] is [Chemical formula] wherein X is C4 carbocyclic (C=O), m and o are 0, and the compounds of the present disclosure have the structures I-2c2 to I-4c2: [Chemical formula] is represented by any one of them, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0056] In some embodiments, [Chemical formula] is phenyl, [Chemical formula] is [Chemical formula] where X is SO2, m is 1 or 2, o is 0, and the compound of the present disclosure has the structure I-1d1: [Chemical formula] is represented by any one of them, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0057] In some embodiments, [Chemical formula] is phenyl, [Chemical formula] is [Chemical formula] where X is SO2, m is 1 or 2, o is 0, and the compound of the present disclosure has the structure I-1d2: [Chemical formula] is represented by any one of them, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0058] In some embodiments, [Chemical formula] is pyridyl,

Chem.

Chem.

Chem.

[0059] In some embodiments,

Chem.

Chem.

Chem.

Chem.

[0060] In some embodiments, R4 is optionally substituted NH-(C1-C6)alkyl. In some embodiments, R4 is NH-methyl. In some embodiments, R4 is OH.

[0061] In some embodiments, R4 is optionally substituted NH-(C1-C6)hydroxyalkyl. [ka] is.

[0062] In some embodiments, R4 is optionally substituted NH-(C1-C6)aminoalkyl. [ka] is.

[0063] In some embodiments, R4 is optionally substituted NH-4-6 membered heterocyclyl. [ka] [ka] is.

[0064] In some embodiments, R4 is an optionally substituted NH-(C1-C6)alkyl-4-6 membered heterocyclyl. [ka] is.

[0065] In some embodiments, n is 0 or 1.

[0066] In some embodiments, R5 is F. In some embodiments, R5 is methoxy.

[0067] In some embodiments, R and R 6’ are both H or F. In some embodiments, R is H and R is F.

[0068] In some embodiments, X0 is N.

[0069] In some embodiments, the compounds of the present disclosure have the following structure:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0070] The compounds of the present disclosure may be in the form of the free acid or free base, or a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of the compounds of the present disclosure can be formed, for example, by reacting the appropriate free base of the compound of the invention with an appropriate pharmaceutically acceptable acid in an appropriate solvent under standard conditions well known in the art. See, for example, Gould, P.L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, R.J., et al., “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4:427-435 (2000); and Berge, S.M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0071] The compounds of the present disclosure may have at least one chiral center and thus may be in the form of stereoisomers, and as used herein, include all isomers of the individual compounds that differ only in the orientation of their atoms in space. The term stereoisomers includes enantiomers (including (R-) or (S-) configurations of the compound), mixtures of enantiomers of the compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of the compound, and isomers of compounds having more than one chiral center that are not mirror images of each other (diastereoisomers). The chiral centers of the compounds can undergo epimerization in vivo; thus, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the compounds of the present disclosure can be made and used in the form of the individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0072] In some embodiments, the compounds of formula (I) are isotope derivatives in that they have at least one desired isotope substitution of an atom in an amount exceeding the natural abundance of the isotope, i.e., are enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. As used herein, the term "compound" encompasses isotope derivatives.

[0073] The compounds of formula (I) may also be in the form of N-oxides of the compounds, crystalline forms (also known as polymorphs), co-crystals, active metabolites of compounds having the same type of activity, prodrugs, tautomers, and non-solvated and solvated forms such as hydrated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. As used herein, the term "compound" encompasses all of these forms.

[0074] The compounds of formula (I) can be prepared by crystallization under different conditions and can exist as one or a combination of polymorphs of the compound. For example, different polymorphs can be identified and / or prepared by performing crystallization at different temperatures using different solvents or different solvent mixtures for recrystallization, or by using various cooling modes ranging from very fast cooling to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compound followed by slow or rapid cooling. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction patterns, and / or other known techniques.

[0075] In some embodiments, the pharmaceutical composition comprises a co-crystal of the compound of formula (I). As used herein, the term "co-crystal" refers to a stoichiometric multi-component system comprising the compound of formula (I) and a co-crystal former, wherein the compound of formula (I) and the co-crystal former are connected by non-covalent interactions. As used herein, the term "co-crystal former" refers to a compound that can form an intermolecular interaction with the compound of formula (I) and co-crystallize therewith. Representative examples of co-crystal formers include benzoic acid, succinic acid, fumaric acid, glutaric acid, trans-cinnamic acid, 2,5-dihydroxybenzoic acid, glycolic acid, trans-2-hexenoic acid, 2-hydroxycaproic acid, lactic acid, sorbic acid, tartaric acid, ferulic acid, suberic acid, picolinic acid, salicylic acid, maleic acid, saccharin, 4,4'-bipyridine p-aminosalicylic acid, nicotinamide, urea, isonicotinamide, methyl 4-hydroxybenzoate, adipic acid, terephthalic acid, resorcinol, pyrogallol, phloroglucinol, hydroxyquinol, isoniazid, theophylline, adenine, theobromine, phenacetin, phenazone, etophylline, and phenobarbital.

[0076] Synthesis method In another aspect, the present disclosure is directed to a method of making a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. Generally, the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof can be prepared by any process known to be applicable to the preparation of chemically related compounds. The compound of formula (I) will be better understood in connection with the synthetic schemes described in various examples that illustrate non-limiting methods for preparing the compound of formula (I).

[0077] Pharmaceutical composition 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. The term "pharmaceutically acceptable carrier" as known in the art refers to a pharmaceutically acceptable material, composition or vehicle suitable for administering the compounds of the present disclosure to a mammal. Suitable carriers include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (such as semi-solids), and gases, which function to transport or convey the compound from one organ or part of the body to another organ or part of the body. The carrier is "acceptable" in the sense that it is physiologically inert with respect to the other components of the formulation, compatible, and not harmful to the subject or patient. Depending on the type of formulation, the composition may also include one or more pharmaceutically acceptable excipients.

[0078] Generally, the compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be formulated into a given type of composition according to conventional pharmaceutical practices such as conventional mixing, dissolving, granulating, tablet coating, trituration, emulsifying, encapsulating, entrapping and compression 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 may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.) and intracardiac injection or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, intranasal, intratracheal instillation, bronchial instillation and inhalation) and topical (e.g., transdermal). Generally, the most appropriate route of administration depends on various 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 can also be advantageous in that the compound can be administered relatively rapidly, such as in the case of single-dose treatment and / or acute conditions.

[0079] In some embodiments, the compounds of formula (I) are formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0080] Accordingly, the compounds of formula (I) can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, 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); semi-solid compositions (e.g., gels, suspensions and creams); and gases (e.g., propellants for aerosol compositions). The compounds can also be formulated for rapid, medium or sustained release.

[0081] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with carriers such as sodium citrate or dicalcium phosphate, and a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrants such as cross-linked polymers, for example, cross-linked polyvinylpyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) additional carriers or excipients such as lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of the same type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings. They may further contain opacifying agents.

[0082] In some embodiments, the compounds of formula (I) can be formulated in hard or soft gelatin capsules. Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystalline cellulose, and croscarmellose sodium. The gelatin shell can contain gelatin, titanium dioxide, iron oxide, and coloring agents.

[0083] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to the compound, the liquid dosage forms can contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions can also contain excipients such as wetting agents, suspending agents, coloring agents, sweetening agents, flavoring agents, and fragrances.

[0084] Injectable preparations for parenteral administration can include sterile aqueous solutions or oily suspensions. They can be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile fixed oils have conventionally been used as a solvent or suspending medium. For this purpose, any non-irritating, non-volatile oil containing synthetic mono- or diglycerides can be used. Further, fatty acids such as oleic acid are used in injectable preparations. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. The effect of the compound can be prolonged by delaying its absorption, which can be achieved by using a liquid suspension of low water solubility or a crystalline or amorphous material. Prolonged absorption of the compound from parenterally administered formulations can also be achieved by suspending the compound in an oily vehicle.

[0085] In certain embodiments, the compounds of formula (I) can be administered, not systemically but locally, for example, by direct injection of the conjugate into an organ, often in depot or sustained release formulations. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides). The rate of release of the compound can be controlled by varying the ratio of the compound to the polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Further, in other embodiments, the compounds are delivered in a targeted drug delivery system, for example, liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ.

[0086] The composition may be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0087] The compounds of formula (I) can be formulated for administration by inhalation. Suitable forms for administration by inhalation include aerosols, mists, or powders. The pharmaceutical composition can be delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges containing gelatin for use in, for example, inhalers or insufflators can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0088] The compounds of formula (I), as used herein, can be formulated for topical administration, which refers to intradermal administration of the formulation to the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0089] Representative examples of carriers useful for formulating the compounds for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffer solutions (e.g., hypotonic or buffered saline). Creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants such as polyoxy-40-stearate.

[0090] In some embodiments, the topical formulation may also include excipients, examples of which are penetration enhancers. These agents can transport a pharmacologically active compound through the stratum corneum and into the epidermis or dermis, preferably with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the rate of drug penetration through the skin. See, for example, Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton, Florida (1995), which reviews 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 T. K., Pfister W. R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo grove, Illinois (1997). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octitriphenyl polyethylene 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.

[0091] Representative examples of other excipients that may be included (to the extent they are compatible) in depot and other types of formulations include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, 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 glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citrate buffer, hydrochloride buffer, and lactate buffer. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate. Suitable skin protectants include vitamin E oil, allantoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0092] Transdermal formulations typically use a transdermal delivery device and a transdermal patch, where the compound is formulated in a lipophilic emulsion or buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive. The patch can be constructed for continuous, pulsatile, or on-demand delivery of the pharmaceutical. Transdermal delivery of the compound can be achieved by an iontophoresis patch. The transdermal patch can provide controlled delivery of the compound, where the absorption rate is slowed by using a rate-controlling membrane or by trapping the compound in a polymer matrix or gel. Absorption can be increased using absorption enhancers, examples of which include absorbent pharmaceutically acceptable solvents that aid in skin penetration.

[0093] Ophthalmic formulations include eye drops.

[0094] 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 polyvinylpyrrolidone and PEG. Compositions for rectal or vaginal administration can be formulated as suppositories 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 thus melt within the rectal or vaginal cavity to release the compound.

[0095] Dosage 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 to produce a desired therapeutic response in a particular patient afflicted with a disease or disorder mediated by abnormal BCL6 activity. Thus, 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 modification in the disease or disorder being treated, or prevents the onset or progression of the disease or disorder, or is sufficient to alleviate to some extent one or more of the symptoms of the disease or disorder being treated in a subject, or simply kills or inhibits the growth of diseased cells such as cancer cells, or reduces the amount of BCL6 in diseased cells.

[0096] The total daily dosage and the method of use of the compound of formula (I) can be determined in accordance with standard medical practice, for example by the attending physician, using sound medical judgment. The specific therapeutically effective dosage for any particular subject depends on various factors including the disease or disorder being treated and its severity (e.g., its current state); the age, weight, general health, sex and diet of the subject; the time of administration, the route of administration, and the rate of excretion of the specific compound being used; the duration of the treatment; drugs used in combination with or simultaneously with the compound; and similar factors well known in the medical arts (see, e.g., 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).

[0097] Method of Use In some embodiments, the present disclosure is directed to treating a cancer characterized by, or mediated by, abnormal (e.g., elevated levels of BCL6, or otherwise functionally abnormal, e.g., deregulated levels of BCL6) BCL6 activity as compared to a non-pathological state. The method 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.

[0098] As used herein, the term "subject" (or "patient") includes all members of the animal kingdom that are susceptible to, or have, the indicated disease or disorder. In some embodiments, the subject is a mammal, such as a human or non-human mammal. The methods are also applicable to companion animals such as dogs and cats. A subject "in need of" treatment according to the disclosure may have "or be suspected of having" a particular disease or disorder, may have been diagnosed positive, or otherwise exhibit a sufficient number of risk factors or a sufficient number or combination of signs or symptoms such that a medical professional can diagnose or suspect that the subject has the disease or disorder. Thus, subjects having a particular disease or disorder and subjects suspected of having a particular disease or disorder are not necessarily two distinct groups.

[0099] The method is directed to treating a subject having cancer. Both adult tumors / cancers and pediatric tumors / cancers are included. The cancer can be a tumor that is vascularized, substantially non-vascularized, or avascular.

[0100] In some embodiments, the method relates to treating a subject having a lymphatic malignancy.

[0101] In some embodiments, the lymphatic 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), cutaneous T cell lymphoma, chronic myelogenous leukemia, or B cell non-Hodgkin lymphoma.

[0102] In some embodiments, the methods of the disclosure involve treating a subject having a hematopoietic cell proliferative disease or disorder.

[0103] The compounds of formula (I) can be administered to a patient, e.g., a cancer patient, as a monotherapy or in combination therapy. The treatment can be "front / first choice", i.e., as the first treatment in patients who have not received a previous anti-cancer treatment regimen, either alone or in combination with other treatments; or "second choice" as a treatment in patients who have received a previous anti-cancer treatment regimen, either alone or in combination with other treatments; or it can be a "third choice", "fourth choice", etc. treatment, either alone or in combination with other treatments. The treatment can also be given to patients who have previously received an unsuccessful or partially successful treatment but have become non-responsive or intolerant to a particular treatment. The treatment can also be given as an adjuvant treatment, i.e., to prevent cancer recurrence in patients who currently have no detectable disease or after surgical removal of a tumor. Thus, in some embodiments, the compound may be administered to patients who have received another therapy such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0104] The methods of the present disclosure may require administering a compound of formula (I) or a pharmaceutical composition thereof 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 dosing frequency can range from once a day to about once every 8 weeks. In some embodiments, the dosing frequency ranges from about once a day to 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments, it involves at least one 28-day cycle that includes daily dosing for 3 weeks (21 days) followed by a 7-day "off" period. In other embodiments, the compound may be administered twice a day (BID) for 2.5 days (a total of 5 doses) or once a day (QD) for 2 days (a total of 2 doses). In other embodiments, the compound can be administered once a day (QD) for 5 days.

[0105] Combination therapy The compounds of formula (I) and their pharmaceutically acceptable salts and stereoisomers can be used in combination with, or simultaneously with, at least one other active agent, for example, an anti-cancer agent or regimen, in the treatment of diseases and disorders. The terms "in combination with" and "simultaneously with" in this context mean that the agents are administered concomitantly, which includes substantially contemporaneous administration by the same or different dosage forms 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. Thus, when administered sequentially, at the start of the administration of the second compound, the first of the two compounds is still detectable at an effective concentration at the site of treatment in some cases. The order and time intervals can be determined such that they act together (e.g., synergistically) to provide a greater benefit than if they were administered in a different manner. For example, the therapeutic agents can be administered simultaneously or sequentially in any order at different times, but if not administered simultaneously, they can be administered at times close enough to provide the desired therapeutic effect in a synergistic manner. Thus, these terms are not limited to the exact simultaneous administration of the active agents.

[0106] In some embodiments, the treatment regimen may include administration of a compound of formula (I) in combination with one or more additional therapeutic agents known to be used in treating a disease or condition (e.g., cancer). The dosage of the additional therapeutic agent may be the same as or 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, anti-cancer agents that may be suitable for use in combination with the compounds are known in the art. See, for example, U.S. Patent No. 9,101,622 (section 5.2 thereof) and U.S. Patent No. 9,345,705 B2 (columns 12-18 thereof). 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), immunomodulatory agents, therapeutic antibodies (e.g., monospecific antibodies and bispecific antibodies), and CAR-T therapy.

[0107] In some embodiments, the compound of formula (I) and an additional (e.g., anti-cancer) therapeutic agent can be administered at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 to about 3 hours, about 3 to about 4 hours, about 4 to about 5 hours, about 5 to about 6 hours, about 6 to about 7 hours, about 7 to about 8 hours, about 8 to about 9 hours, about 9 to about 10 hours, about 10 to about 11 hours, about 11 to about 12 hours, about 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more (e.g., anti-cancer) therapeutic agents can be administered within the same patient visit.

[0108] If the active ingredients of the combination 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 with, or after (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 administration of an additional therapeutic agent. In various embodiments, the therapeutic agents are 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, less than 24 hours, or less than 48 hours. In one example, (e.g., anti-cancer) therapeutic agents are administered within the same outpatient visit time. In another example, the combination anti-cancer therapeutic agents can be administered at intervals of 1 minute to 24 hours.

[0109] In some embodiments, including cancer treatment, the compounds of formula (I) and additional anti-cancer or therapeutic agents are administered periodically. Cyclic therapy involves administering one anti-cancer therapeutic agent for a period, followed by administering a second anti-cancer therapeutic agent for a period, and repeating this sequential administration, i.e., the cycle, to reduce the development of resistance to one or both of the anti-cancer therapeutic agents, avoid or reduce side effects of one or both of the anti-cancer therapeutic agents, and / or improve the efficacy of the treatment. In one example, cyclic therapy involves administering a first anti-cancer therapeutic agent for a period, then a second anti-cancer therapeutic agent for a period, optionally then a third anti-cancer therapeutic agent for a period, etc., and repeating this sequential administration, i.e., the cycle, to reduce the development of resistance to one of the anti-cancer therapeutic agents, avoid or reduce side effects of one of the anti-cancer therapeutic agents, and / or improve the effectiveness of the anti-cancer therapeutic agents.

[0110] In some embodiments, the compounds of the present disclosure can be used in combination with other anti-cancer agents, examples of which include etoposide (e.g., for lymphoma and non-lymphocytic leukemia), vincristine (e.g., for leukemia), daunorubicin (e.g., for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and Kaposi's sarcoma), rituximab (e.g., for non-Hodgkin lymphoma), alemtuzumab (e.g., for chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma), bortezomib (e.g., for multiple myeloma and mantle cell lymphoma), pegaspargase (e.g., for acute lymphoblastic leukemia), Keytruda® (e.g., for Hodgkin lymphoma), and dexamethasone (e.g., for acute multiple myeloma).

[0111] In some embodiments, the additional anti-cancer agent is an enhancer of zeste homolog 2 (EZH2) inhibitor, examples of which include tazemetostat, GSK126, lirametostat (CPI-1205), CPI-0209, PF-06821497, SHR2554, HH2853, valemetostat (DS3201), MAK-683, and FTX-6058.

[0112] These and other aspects of the present disclosure are intended to illustrate certain embodiments of the present disclosure, but are not intended to limit its scope as defined by the claims. It will be further understood by considering the following examples.

Example

[0113] Example 1: Synthesis of 3-(7-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-N-methylpropanamide (1).

Chemical formula

[0114] 3-bromo-N-methylpropanamide To a mixture of 3-bromopropanoyl chloride (2 g, 11.67 mmol, 1.18 mL, 1 equiv) in DCM (35 mL), MeNH2 (2 M in THF, 11.67 mL, 2 equiv) was added dropwise at 0 °C under a N2 atmosphere. The mixture was then warmed to 15 °C and stirred for 12 h. The mixture was concentrated under vacuum. The resulting residue was diluted with saturated NaHCO3 (50 mL) and extracted with DCM (50 mL × 2). The combined organic phases were further washed with saturated NaHCO3 (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 3-bromo-N-methylpropanamide (1.2 g, 4.05 mmol, yield 34.69%, purity 56%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 5.83 (s, 1H), 3.64 (t, J = 6.4 Hz, 2H), 2.84 (d, J = 4.8 Hz, 3H), 2.76 (t, J = 6.4 Hz, 2H).

Chemical formula

[0115] 1-Methyl-6-nitroquinoxaline-2,3(1H,4H)-dione A mixture of N1-methyl-4-nitro-benzene-1,2-diamine (3 g, 17.95 mmol, 1 equiv) and oxalic acid (3.23 g, 35.89 mmol, 3.17 mL, 2 equiv) in 4N HCl aqueous solution (150 mL) was stirred at 120 °C for 3 h. The mixture was cooled to 15 °C and a precipitate was observed. The mixture was filtered, and the isolated cake was washed with water (50 mL×2) and concentrated in vacuo to give 1-methyl-6-nitroquinoxaline-2,3(1H,4H)-dione (3 g, 13.42 mmol, yield 74.9%, purity 98.9%) as a brown solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 12.27 (s, 1H), 8.00 (dd, J = 2.8, 9.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 3.53 (s, 3H). LCMS: [M+H + =222.1.

Chem.

[0116] -6-Amino-1-methylquinoxaline-2,3(1H,4H)-dione To a solution of 4-methyl-7-nitro-1H-quinoxaline-2,3-dione (1 g, 4.52 mmol, 1 equiv) in DMF (50 mL) was added Pd / C (0.2 g, purity 10%) under argon. The suspension was degassed under vacuum and purged several times with hydrogen. Then, the mixture was stirred at 25 °C for 12 h under hydrogen (15 psi). The mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give 6-amino-1-methylquinoxaline-2,3(1H,4H)-dione (900 mg, crude) as a yellow solid. LCMS: [M+H+]=192.1.

Chem.

[0117] 6-((2,5-Dichloropyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione 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). After stirring the reaction mixture at 15 °C for 10 min, 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 h. Water (20 mL) was added to the mixture to obtain a precipitate. The resulting mixture was filtered and the isolated cake was washed with water (30 mL) and then 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 H NMR (400 MHz, DMSO-d6) δ = 8.34 (s, 1H), 7.44 - 7.31 (m, 3H), 3.54 (s, 3H). LCMS: [M+H + = 338.0.

Chemical Structure

[0118] 6-((5-Chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione A mixture of 7-[(2,5-dichloropyrimidin-4-yl)amino]-4-methyl-1H-quinoxaline-2,3-dione (100 mg, 295.73 μmol, 1 equiv) and (3S,5R)-3,5-dimethylpiperidine (40.17 mg, 354.87 μmol, 1.2 equiv) in DMF (2 mL) was added with DIPEA (76.44 mg, 591.5 μmol, 103.0 μL, 2 equiv) under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 1 h. The resulting mixture was concentrated under vacuum, and the isolated residue was purified by preparative high performance liquid chromatography (preparative HPLC) (column: Waters™ Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40% - 70%, 10 min) to obtain 6-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-methylquinoxaline-2,3(1H,4H)-dione (purity 99%, 26.2 mg) as a white solid. 1 H NMR (400 MHz, 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 = 10.8 Hz, 2H), 3.52 (s, 3H), 2.25 (t, J = 12.4 Hz, 2H), 1.76 (d, J = 13.2 Hz, 1H), 1.57 - 1.43 (m, 2H), 0.85 (d, J = 6.4 Hz, 6H), 0.77 (q, J = 12.0 Hz, 1H). LCMS: [M+H+] = 415.1.

Chemical Structure

[0119] To a mixture of 7-[[5-chloro-2-[(3S,5R)-3,5-dimethyl-1-piperidyl]pyrimidin-4-yl]amino]-4-methyl-1H-quinoxaline-2,3-dione (100 mg, 241.03 μmol, 1 equiv) in DMSO (10 mL) were added 3-bromo-N-methyl-propanamide (44.02 mg, 265.13 μmol, 1.1 equiv), K2CO3 (39.98 mg, 289.23 μmol, 1.2 equiv) and KI (20.01 mg, 120.51 μmol, 0.5 equiv). The mixture was stirred at 60 °C for 12 h, concentrated under vacuum and filtered to remove solids. The isolated mixture was purified by preparative HPLC (column: Waters™ Xbridge BEH C18 100*25mm*5μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 35% - 65%, 10 min) to give 3-(7-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-N-methylpropanamide (51.5 mg, yield 42.7%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.87 (s, 1H), 8.05 (s, 1H), 7.94 (dd, J = 2.0, 3.6 Hz, 1H), 7.79 - 7.71 (m, 1H), 7.65 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 4.53 - 4.49 (m, 2H), 4.31 - 4.21 (m, 2H), 3.53 (s, 3H), 2.55 (d, J = 4 Hz, 3H), 2.48 - 2.43 (m, 2H), 2.27 (t, J = 12.0 Hz, 2H), 1.81 - 1.72 (m, 1H), 1.59 - 1.44 (m, 2H), 0.86 (d, J = 6.4 Hz, 6H), 0.77 (q, J = 12.0 Hz, 1H). LCMS: [M+H+] = 500.1.

[0120] Example 2: Synthesis of 2-(7-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-4-methyl-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)-N-methylacetamide 56). [Chem.]

[0121] 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 A mixture of 7-[(2,5-dichloropyrimidin-4-yl)amino]-4-methyl-1H-quinoxaline-2,3-dione (2 g, 5.91 mmol, 1 equiv), (3S,5R)-4,4-difluoro-3,5-dimethyl-piperidine (2.02 g, 7.69 mmol, 1.3 equiv, TFA), and DIPEA (1.53 g, 11.83 mmol, 2.06 mL, 2 equiv) in DMSO (20 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. Water (20 mL) was added to the mixture to obtain a precipitate. The resulting mixture was filtered, and the isolated cake was washed with water (50 mL) and then with EtOAc (50 mL). The isolated residue was dried under reduced pressure to give 7-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]pyrimidin-4-yl]amino]-4-methyl-1H-quinoxaline-2,3-dione (2.2 g, 4.60 mmol, 77.8% yield, 94.1% purity) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 8.98 (s, 1H), 8.07 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.34 - 7.28 (m, 1H), 4.49 (br d, J = 11.6 Hz, 2H), 3.51 (s, 3H), 2.64 (br t, J = 12.8 Hz, 2H), 2.12 - 1.92 (m, 2H), 0.96 (d, J = 6.4 Hz, 6H). [Chem.]

[0122] 7-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]pyrimidin-4-yl]amino]-4-methyl-1H-quinoxaline-2,3-dione (100 mg, 221.79 μmol, 1 eq) and 2-bromo-N-methyl-acetamide (50.57 mg, 332.69 μmol, 1.5 eq) in DMSO (1.5 mL) were added with K2CO3 (61.31 mg, 443.59 μmol, 2 eq) and KI (18.41 mg, 110.90 μmol, 0.5 eq), and stirred at 60 °C for 4 h. Water was added to the reaction mixture to obtain a precipitate. The resulting mixture was filtered, and the isolated cake was washed with water (15 mL * 2), then with EtOH (15 mL * 2). The residual solvent was removed under reduced pressure, and the obtained residue was triturated with DMSO (2 mL) at 15 °C for 10 min, and then the mixture was filtered. The isolated cake was concentrated under reduced pressure to obtain 2-[7-[[5-chloro-2-[(3S,5R)-4,4-difluoro-3,5-dimethyl-1-piperidyl]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 (400 MHz, DMSO-d6) δ = 8.98 (s, 1H), 8.10 (s, 1H), 8.03 (br d, J = 4.4 Hz, 1H), 7.75 (br d, J = 8.8 Hz, 1H), 7.41 (br d, J = 8.8 Hz, 1H), 7.38 (br s, 1H), 4.63 (br s, 2H), 4.51 (br d, J = 10.4 Hz, 2H), 3.57 (s, 3H), 2.68 (br t, J = 12.8 Hz, 2H), 2.57 (br d, J = 4 Hz, 3H), 2.13 - 1.95 (m, 2H), 0.98 (br d, J = 6.8 Hz, 6H). LCMS: [M + H+] = 522.18.

[0123] Example 3: Degradation activity in SU-DHL-4 cells.

[0124] HiBiT protocol

[0125] DC 50The value (concentration at which 50% degradation is reached) was determined from a cell lysis assay (HiBiT, Promega (trademark)) in Su-DHL-4 cells (Table 1). Through CRISPR / Cas9 gene editing and single-cell clone selection, endogenous BCL6 was tagged with SmBiT of 11 amino acid residues. After 24 hours of compound treatment, the cells were lysed and incubated with LgBiT protein to reconstitute intact nanoluciferase. Then, the substrate was added and the relative luciferase units were measured. The degradation level of each treatment was obtained as a percentage compared to 100% DMSO (Prism) as the control.

Table 1

[0126] The data of the HiBiT assay in SU-DHL-4 (B-cell lymphoma) cells described in Table 1 show that the compound of formula I has a DC 50 value of 0.1 μM or less.

[0127] All patent publications and non-patent documents indicate the technical level of those skilled in the art to which the present disclosure pertains. All of these publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.

[0128] Although the disclosure herein 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. Accordingly, it should be understood that numerous modifications can be made to the exemplary embodiments and other configurations can be devised without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony 【Chemistry 2】 is phenyl or pyridyl; 【Transformation 3】 teeth 【Chemistry 4】 And; X is a combination, (C ３ -C ６ ) Carbocyclyl, (C ３ -C ６ ) Carbocyclyl (C=O), or SO ２ And; X ０ is N or CCN; X １ is CH ２ , S, CHF, CHCl, CHOH, or CF ２ ; R １ is, (C １ -C ６ ) alkyl, (C １ -C ６ ) Hydroxyalkyl, (C １ -C ６ ) Aminoalkyl, (C ３ -C ６ ) Carbocyclyl, 4-6 member heterocyclyl, (C １ -C ６ ) Alkyl-(C ３ -C ６ ) Carbocyclyl, or (C １ -C ６ ) an alkyl-4 to 6-membered heterocycline, where the alkyl, hydroxyalkyl, aminoalkyl, carbocykyl, or heterocycline is one or more identical or different R １ａ It may be further substituted by the group R １ａ is deuterium, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Alkyl-(C １ -C ３ ) Alkoxy, halogen, amino, hydroxyl, (C １ -C ６ ) Haloalkyl, NH-(C １ -C ６ ) alkyl, N((C １ -C ６ )alkyl) ２ , (C ３ -C ６ ) Carbocyclyl, or 4-6 membered heterocyclyl; R ２ and R ２’ These are H and (C) respectively, independently. １ -C ３ ) alkyl, (C １ -C ３ ) Hydroxyalkyl, or (C １ -C ３ ) It is an aminoalkyl, or R ２ and R ２’ They, together with the same carbon atom to which they are bonded, (C ３ -C ６ ) form a carbocyclyl or a 4-6 membered heterocyclyl, and the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl is one or more identical or different R ２ａ It may be substituted by the group R ２ａ is, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Alkyl-(C １ -C ３ ) Alkoxy, halogen, amino, hydroxyl, (C １ -C ６ ) Haloalkyl, NH-(C １ -C ６ ) alkyl, N((C １ -C ６ )alkyl) ２ , (C ３ -C ６ ) Carbocyclyl, or 4-6 membered heterocyclyl; R ３ and R ３’ These are H and (C) respectively, independently. １ -C ３ ) alkyl, (C １ -C ３ ) Hydroxyalkyl, or (C １ -C ３ ) is an aminoalkyl, or R ３ and R ３’ together with the same carbon atom to which they are attached form C=O, (C ３ -C ６ ) carbocyclic, 4- to 6-membered heterocyclic, and said carbocyclic or heterocyclic may be substituted by one or more identical or different R ３ａ groups, and each R ３ａ is independently (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-(C １ -C ３ ) alkoxy, halogen, amino, hydroxyl, (C １ -C ６ ) haloalkyl, NH-(C １ -C ６ ) alkyl, N((C １ -C ６ ) alkyl) ２ , (C ３ -C ６ ) carbocyclic, or 4- to 6-membered heterocyclic, or two R ３ａ groups together with the same carbon atom to which they are attached form C=O, Or, R ２ or R ２’ and R ３ or R ３’ They, together with the same carbon atom to which they are bonded, (C ３ -C ６ ) form a carbocyclyl or a 4-6 membered heterocyclyl, where the carbocyclyl or heterocyclyl is one or more identical or different R ２ａ It may also be substituted by the element; R ４ H, OH, NH-(C １ -C ６ ) Alkyl, NH-(C １ -C ６ ) Hydroxyalkyl, NH-(C １ -C ６ ) Aminoalkyl, NH-(C ３ -C ６ ) Carbocyclyl, NH-4 to 6-membered heterocyclyl, NH-(C １ -C ６ ) Alkyl-(C ３ -C ６ ) Carbocyclyl, NH-(C １ -C ６ ) an alkyl-4 to 6-membered heterocycline, where the alkyl, hydroxyalkyl, aminoalkyl, carbocykyl, or heterocycline is one or more identical or different R ４ａ The base may be further substituted, where each R ４ａ (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Alkyl-(C １ -C ３ ) Alkoxy, halogen, amino, hydroxyl, (C １ -C ６ ) Haloalkyl, NH-(C １ -C ６ ) alkyl, N((C １ -C ６ )alkyl) ２ , (C ３ -C ６ ) Carbocyclyl, or 4-6 membered heterocyclyl; R ５ is halogen or (C １ -C ３ ) is an alkoxy; R ６ and R ６’ Each of these is independently either H or a halogen; R ７ H, halogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) Alkoxy, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Haloalkoxy, CN, NO ２ ,OH,(C ２ -C ４ ) Alkenil, (C ２ -C ４ ) Alkinyl, or -R ７ａ -R ７ｂ And here, R ７ａ It does not exist, or O, N(R) ７ａ１ ) (CR ７ａ１ R ７ａ２ ) ｑ S, SO, SO ２ , 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 ) SO ２ And here, R ７ａ１ and R ７ａ２ These are, independently, H or (C １ -C ４ ) is alkyl, and q is 0, 1, or 2, R ７ｂ is H, (C １ -C ６ ) alkyl, (C ６ -C １０ ) Aryl, (C ３ -C ６ ) Cycloalkyl, (C ２ -C ４ ) Alkenil, (C １ -C ４ ) Alkinnil, (C ３ -C ６ ) A cycloalkenyl, where the alkyl, aryl, cycloalkyl, alkenyl, alkynyl, or cycloalkenyl is oxo, (C １ -C ４ ) alkyl, (C １ -C ４ ) Cycloalkyl, halogen, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Haloalkoxy, (C １ -C ４ Hydroxyalkyl, amino, CN, OH, amide, carboxy, carbamoyl, sulfamoyl, mercapto, C(O)NR ７ｂ１ R ７ｂ２ , R ７ｂ１ R ７ｂ２ , or OR ７ｂ１ It may be further substituted by one or more substituents independently selected from R, where R ７ｂ１ and R ７ｂ２ These are, independently, hydrogen and (C １ -C ４ ) alkyl, (C ３ -C ６ ) Selected from cycloalkyl, the oxo, alkyl, cycloalkyl, haloalkyl, haloalkoxy, hydroxyalkyl (hydroxyalkyl), amino, CN, OH, amide, carboxy, carbamoyl, sulfamoyl, or mercapto, R ７ｂ３ -R ７ｂ４ It may be further substituted by, where R ７ｂ３ It does not exist, or (C １ -C ２ ) optionally substituted with one or more substituents selected from alkyl or oxo (C １ -C ５ ) is alkylene, R ７ｂ４ is, (C ６ -C １０ )aryl, 5-12 member heteroaryl, 4-12 member heterocyclyl, (C ３ -C ６ ) Carbocyclyl, halogen, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Haloalkoxy, CN, OH, (C １ -C ４ ) Alkoxy, C(O)R ７ｂ４ａ COOR ７ｂ４ｂ , C(O)NR ７ｂ４ａ R ７ｂ４ｂ , or NR ７ｂ４ａ R ７ｂ４ｂ And here: R ７ｂ４ａ and R ７ｂ４ｂ These are, independently, H or (C １ -C ４ ) Selected from alkyl groups; the aryl, heteroaryl, heterocyclyl, or carbocykrill is independently (C １ -C ４ ) alkyl, halogen, (C １ -C ４ ) may be further substituted by one or more substituents selected from haloalkyl, amino, CN, or OH; and the heterocyclyl or heteroaryl contains at least one nitrogen atom and is linked via nitrogen, and the heterocyclyl group is optionally and independently substituted by one or more identical or different groups independently selected from R9, and the heteroaryl group is R １０ It is optionally and independently replaced by one or more identical or different bases selected independently from it; R ８ is a halogen or CN; R ９ is = O, CN, C≡CH, OH, COOH, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) 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 5-8 member heterocycline, and the above (C １ -C ６ Alkyl groups are COOH, OH, COO-(C １ -C ６ ) Alkyl, -CON((C １ -C ６ )alkyl) ２ , (C １ -C ６ ) Alkoxy, N((C １ -C ３ )alkyl) ２ The heteroaryl, phenyl, or heterocyclyl may be substituted with (C １ -C ６ ) It may be substituted with one group selected from alkyl groups; R １０ COOH, (C １ -C ６ ) Alkyl, C(O)-R １６ , or C(O)N(R) １７ ) (Caution １８ ) and; R １１ is H or (C １ -C ４ ) is alkyl; R １２ H, (C １ -C ４ ) alkyl, (C １ -C ４ ) are haloalkyl, six-membered heterocyclyl, or six-membered heteroaryl; R １３ is, (C １ -C ３ ) Alkyl-N ((C １ -C ３ Alkyl) ２ or a 5-membered or 6-membered heterocyclyl, wherein the heterocyclyl is (C １ -C ３ ) may also be substituted with alkyl. R １４ is hydrogen or (C １ -C ３ ) is alkyl; R １５ NH ２ , (C １ -C ６ ) Alkoxy, O-(C １ -C ６ ) Alkyl-NH ２ , or O-(C １ -C ６ ) Alkyl-O-(C １ -C ６ ) Alkyl-NH ２ (C １ -C ６ ) Alkyl or R １５ is, (C １ -C ３ ) A six-membered heterocycline optionally substituted with alkyl; R １６ is, (C １ -C ３ ) A six-membered heterocycline optionally substituted with alkyl; R １７ and R １８ These are, independently, H or (C １ -C ３ ) is alkyl; R １９ H, =O, -CN, -C≡CH, -OH, -SH, -NH ２ ,-COOH, halo, (C １ -C ６ ) alkyl, -O-(C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, amide, carboxy, carbamoyl, sulfamoyl, phenyl, 5-8 membered heterocyclyl, -NR ２０ R ２１ , -C(O)R ２２ , -C(O)NR ２３ R ２４ , or L １ Y １ The alkyl, phenyl, or heterocyclyl is a halo, -COOH, -OH, -NH ２ , (C １ -C ６ ) alkyl, -C(O)O-(C １ -C ６ ) Alkyl, -C(O)N(C １ -C ６ Alkyl) ２ , -O-(C １ -C ６ ) alkyl, -N(C １ -C ３ Alkyl) ２ , phenyl, and halo and (C １ -C ６ ) A 4- to 6-membered heterocycline optionally substituted with one or more groups selected from alkyl groups, L １ It does not exist, or (C １ -C ６ ) Alkylene or (C ３ -C ７ ) is a carbocyclyl; where the alkylene or carbocyclyl is one or more identical or different R ２５ It may be further substituted by the group, or L １ R ２６ (C) ２ -C ４ ) are alkylenes; and Y １ is -CN, -OH, halo, (C １ -C ４ ) Alkoxy, (C １ -C ４ ) Haloalkyl, (C １ -C ４ ) Haloalkoxy, 4-7 membered heterocyclyl, (C ３ -C ６ ) Carbocyclyl, -NR ２６ R ２７ , -C(O)R ２２ , -C(O)NR ２３ R ２４ The alkyl, carbocyacrylic, or heterocyclyl is (C １ -C ４ ) alkyl, halo, (C １ -C ４ ) Haloalkyl, -CN, -OH, and -NH ２ They may be further substituted by one or more identical or different groups selected from; R １９’ It does not exist, or H, -CN, -C≡CH, -OH, -SH, -NH ２ ,-COOH, halo, (C １ -C ６ ) alkyl, -O-(C １ -C ６ ) alkyl, (C １ -C ６ ) Haloalkyl, amide, carboxy, carbamoyl, sulfamoyl, phenyl, 5-8 membered heterocyclyl, -NR ２０ R ２１ , -C(O)R ２２ , or -C(O)NR ２３ R ２４ And; where the alkyl, phenyl, or heterocyclyl is one or more identical or different R ２５ It may be further substituted by the group, or R １９’ and L １ They, together with the same carbon atom to which they are bonded, form a spiro (C ３ -C ７ ) A carbocykyl group or a 4- to 7-membered heterocyclyl group; the carbocykyl or heterocyclyl is one or more identical or different R ２５ It may also be further substituted by the base; R ２０ is hydrogen, (C １ -C ４ ) alkyl, or (C ３ -C ６ ) It is a cycloalkyl; R ２１ is hydrogen, (C １ -C ４ ) alkyl, (C １ -C ４ ) Haloalkyl, (C ３ -C ６ ) Cycloalkyl or 6-membered heterocyclyl; R ２２ is, -(C １ -C ３ ) Alkyl-N(C １ -C ３ Alkyl) ２ , (C ３ -C ６ ) A cycloalkyl or a 5-6 membered heterocycline, wherein the heterocycline is (C １ -C ３ ) may also be substituted with alkyl; R ２３ is hydrogen, (C １ -C ３ ) alkyl, or (C ３ -C ６ ) It is a cycloalkyl; R ２４ is, -NH ２ , -O-(C １ -C ６ ) alkyl, -O-(C １ -C ６ ) Alkyl-NH ２ , or -O-(C １ -C ６ ) Alkyl-O-(C １ -C ６ ) Alkyl-NH ２ It may be replaced with (C ３ -C ６ ) Cycloalkyl or (C １ -C ６ ) is alkyl; Each R ２５ These are independently oxo, alkyl, alkenyl, alkynyl, halo, haloalkyl, carbocykyl, heterocyclyl, hydroxy, alkoxy, cycloalkoxy, heterocycloalkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylenyloxy, 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, carboxy, 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, azide, or phosphinyl; R ２６ and R ２７ These are, independently, hydrogen and (C １ -C ６ ) alkyl, (C ３ -C ７ ) Carbocyclyl, 4-7 member heterocyclyl, (C ６ -C １０ ) aryl, or monocyclic or bicyclic 5-10 membered heteroaryl; the alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl is one or more identical or different R ２５ It may be further substituted by the group, or R ２６ and R ２７ These, together with the nitrogen atoms to which they are bonded, form a 3- to 7-membered heterocycline, and the heterocycline has one or more identical or different R ２５ It may also be further substituted by the base; m is 0, 1, or 2; n is 0, 1, 2, or 3; A compound having a structure represented by [o is 0 or 1], or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 2】 【Chemistry 5】 It is phenyl, 【Transformation 6】 but 【Transformation 7】 The compound has structure I-1a: 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 3】 【Chemistry 9】 That is pyridyl, 【Chemistry 10】 but 【Chemistry 11】 The compound has structures I-2a to I-4a: 【Chemistry 12】 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula].

4. R ７ However, it was replaced as needed (C １ -C ４ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is alkyl.

5. R ７ However, methyl or 【Chemistry 14】 The compound according to claim 4, or a pharmaceutically acceptable salt or stereoisomer thereof.

6. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is an amino or an OH group. 【Request Item 7】 【Chemistry 15】 It is phenyl, 【Chemistry 16】 but 【Chemistry 17】 The compound has structure I-1b: [Chemistry 18] The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 8】 【Chemistry 19】 That is pyridyl, 【Chemistry 20】 but 【Chemistry 21】 The compound has structures I-2b to I-4b: 【Chemistry 22】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. X １ However, CH ２ CHF, CHOH, or CF ２ The compound according to claim 7, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. R １９ and R １９’ However, each independently, H, OH, methyl, amino, 【Chemistry 23】 The compound according to claim 7, or a pharmaceutically acceptable salt or stereoisomer thereof.

11. R ８ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a halogen.

12. R ８ The compound according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is Cl or F.

13. R １ However, it was replaced as needed (C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is alkyl.

14. R １ The compound according to claim 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is methyl.

15. R １ However, it was replaced as needed (C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a hydroxyalkyl compound.

16. R １ but, 【Chemistry 24】 The compound according to claim 15, or a pharmaceutically acceptable salt or stereoisomer thereof.

17. R １ However, it was replaced as needed (C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is an aminoalkyl compound.

18. R １ but, 【Chemistry 25】 The compound according to claim 17, or a pharmaceutically acceptable salt or stereoisomer thereof.

19. R １ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a 4- to 6-membered heterocycline that is substituted as necessary.

20. R １ but, 【Chemistry 26】 The compound according to claim 19, or a pharmaceutically acceptable salt or stereoisomer thereof.

21. R １ However, it was replaced as needed (C １ -C ６ The compound according to claim 1, which is an alkyl-4 to 6-membered heterocycline, or a pharmaceutically acceptable salt or stereoisomer thereof.

22. R １ but, 【Chemistry 27】 The compound according to claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

23. X is combined or (C ３ -C ６ The compound according to claim 1, wherein the compound is a carbocyclyl, m is 0 or 1, and o is 0 or 1, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 24】 【Chemistry 28】 It is phenyl, 【Chemistry 29】 but 【Transformation 30】 The compound is structure I-1a1 or I-1b1: 【Chemistry 31】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 25】 【Chemistry 32】 It is phenyl, 【Transformation 33】 but 【Transformation 34】 The compound is structure I-1a2 or I-1b2, where X is a bond, m is 0 or 1, o is 1, and the compound is structure I-1a2 or I-1b2: 【Chemistry 35】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 26】 【Chemistry 36】 That is pyridyl, 【Chemistry 37】 but 【Transformation 38】 The compound has structures I-2a1 to I-4a1 and I-2b1 to I-4b1: 【Chemistry 39】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 27】 【Chemistry 40】 That is pyridyl, 【Chemistry 41】 but 【Chemistry 42】 The compound is structure I-2a2 to I-4a2 and I-2b2 to I-4b2: 【Chemistry 43】 【Chemistry 44】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof.

28. R ２ The compound according to claim 24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2' and R 2' are independently H or methyl.

29. R ２ and R ２’ The compound according to claim 24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein both atoms are H.

30. R ２ and R ２’ The compound according to claim 24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein they combine with the same carbon atom to which they are bonded to form a cyclopropyl group.

31. R ３ The compound according to claim 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3' and R 3' together with the same carbon atom to which they are bonded to form C=O.

32. R ３ The compound according to claim 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3' and R 3' together with the same carbon atom to which they are bonded form a substituted 4- to 6-membered heterocycline.

33. The compound according to claim 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the optionally substituted four-membered heterocyclyl is oxetane or N-methylazetidine.

34. The compound according to claim 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the substituted 4-6 membered heterocyclyl is a carbamate. 【Request Item 35】 【Chemistry 45】 It is phenyl, 【Chemistry 46】 but 【Chemistry 47】 And X is C ４ It is a carbocyclyl (C=O), m and o are 0, and the compound has structure I-1c1: 【Chemistry 48】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 36】 【Chemistry 49】 It is phenyl, [Transformation 50] but 【Chemistry 51】 And X is C ４ It is a carbocyclyl (C=O), m and o are 0, and the compound has structure I-1c2: 【Chemistry 52】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 37】 【Chemistry 53】 That is pyridyl, 【Chemistry 54】 but 【Transformation 55】 And X is C ４ It is a carbocyclyl (C=O), m and o are 0, and the compound has structures I-2c1 to I-4c1: 【Transformation 56】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 38】 【Chemistry 57】 That is pyridyl, 【Chemistry 58】 but 【Chemistry 59】 And X is C ４ It is a carbocyclyl (C=O), m and o are 0, and the compound has structures I-2c2 to I-4c2: 【Transformation 60】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 39】 【Chemistry 61】 It is phenyl, 【Transformation 62】 but 【Transformation 63】 And X is SO ２ The compound is structure I-1d1: 【Chemistry 64】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. [Request Item 40] [Chemistry 65] It is phenyl, 【Chemical Formula 66】 but 【Transformation 67】 And X is SO ２ The compound is structure I-1d2, where m is 1 or 2, o is 0, and the compound is structure I-1d2: 【Transformation 68】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as represented by [the specified formula]. 【Request Item 41】 【Chemistry 69】 That is pyridyl, 【Transformation 70】 but 【Chemistry 71】 And X is SO ２ The compound is structure I-2d1 to I-4d1, where m is 1 or 2, o is 0, and the compound is structure I-2d1 to I-4d1: 【Chemistry 72】 【Transformation 73】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 42】 【Chemistry 74】 That is pyridyl, 【Chemistry 75】 but 【Transformation 76】 And X is SO ２ The compound is structure I-2d2 to I-4d2, where m is 1 or 2, o is 0, and the compound is structure I-2d2 to I-4d2: 【Chemical Formula 77】 The compound according to claim 1, represented by any one of the following, or a pharmaceutically acceptable salt or stereoisomer thereof.

43. R ４ However, NH-(C) may be substituted as needed. １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is alkyl.

44. R ４ The compound according to claim 43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is NH-methyl.

45. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is H or OH.

46. R ４ However, NH-(C) may be substituted as needed. １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a hydroxyalkyl compound.

47. R ４ but, 【Transformation 78】 The compound according to claim 46, or a pharmaceutically acceptable salt or stereoisomer thereof.

48. R ４ However, NH-(C) may be substituted as needed. １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is an aminoalkyl compound.

49. R ４ but, 【Chemistry 79】 The compound according to claim 48, or a pharmaceutically acceptable salt or stereoisomer thereof.

50. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is a -NH- 4-membered to 6-membered heterocycline as necessary.

51. R ４ but, 【Chemistry 80】 The compound according to claim 50, or a pharmaceutically acceptable salt or stereoisomer thereof.

52. R ４ However, NH-(C) may be substituted as needed. １ -C ６ The compound according to claim 1, which is an alkyl-4 to 6-membered heterocycline, or a pharmaceutically acceptable salt or stereoisomer thereof.

53. R ４ but, 【Chemistry 81】 The compound according to claim 52, or a pharmaceutically acceptable salt or stereoisomer thereof.

54. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 0 or 1.

55. R ５ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein F is present.

56. R ５ The compound according to claim 1, wherein is methoxy, or a pharmaceutically acceptable salt or stereoisomer thereof.

57. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein both R 6' and R 6' are H or F.

58. X ０ The compound according to claim 1, wherein is N, or a pharmaceutically acceptable salt or stereoisomer thereof.

59. The following structure: 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Chemistry 87】 【Chemical 88】 【Chemical 89】 [Chemical 90] 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, which is any one of the above.

60. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemical 95】

61. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemistry 96】

62. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemistry 97】

63. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chem.98】

64. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chem.99】

65. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemistry 100】

66. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemistry 101】

67. The following compounds, or pharmaceutically acceptable salts or stereoisomers thereof. 【Chemical Engineering 102】

68. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 67, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

69. The pharmaceutical composition according to claim 68, which is in the form of a liquid or a solid.

70. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 67, or a pharmaceutically acceptable salt or stereoisomer thereof, and rituximab.

71. Use of a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 67, or a pharmaceutically acceptable salt or stereoisomer thereof, in combination with rituximab.

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