Regulators of BCL6 proteolysis and related uses

Abstract

The present invention provides a small molecule therapeutic agent that targets BCL6 and utilizes or enhances the substrate specificity of E3 ubiquitin ligases (e.g., cereblon). [Solution] This specification describes a bifunctional compound that has been found to be useful as a regulator of B-cell lymphoma 6 protein (BCL6; target protein). In particular, the bifunctional compound of this disclosure contains a cerebron ligand that binds to each E3 ubiquitin ligase on one end and a moiety that binds to the target protein on the other end, such that the target protein is positioned in close proximity to the ubiquitin ligase, resulting in the degradation (and inhibition) of the target protein. The bifunctional compound of this disclosure exhibits a wide range of pharmacological activity related to the degradation / inhibition of the target protein. Diseases or disorders resulting from the aggregation or accumulation of the target protein can be treated or prevented using the compounds and compositions of this disclosure.

Claims

1. Chemical structure: CLM-L-PTM, Compounds having, or pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, and heavy It is a hydrogen type, During the ceremony, (a) The CLM is the cereblon E3 ubiquitin ligase binding portion represented as follows And: 【Chemistry 1】 During the ceremony, W is CH2, O, CHR (e.g., CH(CH3)), C=O, NH, or N the law of nature; Each X is independently selected from the non-existent O, S, and CH2; Z is O, S, or CH2; G is H, methyl, or OH; Each of Q1, Q2, Q3, and Q4 is independently replaced by N or R. Represents C; A is H, an unsubstituted or substituted linear or branched alkyl group, Cl, or F. ； n is an integer between 1 and 4 (for example, 1 or 2, 1 to 3, 1, 2, 3 or 4); Each R is independent of bond, H, -OR', -NR'R'', -CR'R''-, non-substituted or The C1-C6 linear alkyl or branched alkyl to be substituted (for example) (Optionally substituted with C1-C3 alkyl and / or one or more halogens) , unsubstituted or substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, p) Ropoxy, pentoxy, or hexoxy, wherein the alkoxyl is optionally one One or more halogens, C1-C3 alkyls, haloalkyls, or C1-C3 fluoroalkyls A 4-6 member cycloalkyl group that is optionally substituted (by kill), optionally Substituting 4-6 member heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN or NO2, where one R is covalently bonded to the L; R' and R'' are, independently, bonded, H, and substituted or unsubstituted C1-C4 atoms. Selected from alkyl (e.g., methyl or ethyl); and 【Chemistry 2】 This represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. (b) The PTM is a B-cell lymphoma 6 protein (BCL6) selected from the following: It is a small molecule containing a targeting moiety: 【Transformation 3】 During the ceremony, RPTM5 is a linear or branched C1-C6 alkyl group that is optionally substituted with H (for example) (C1-C3) Alkyl), C1-C4 alkyl-O-, C1-C4 alkyl-NH(C1-C3 alkyl C1-C4 alkyl-N (C1-C3 alkyl) 2, optionally substituted with C5-C1 0 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C3-C It is a 10-cycloalkyl or optionally substituted C3-C10 heterocycline; Q6 and Q16 are independently N or CH; Q7 and Q14 are independently N or CH; XPTM1 is H, Cl, or F; XPTM2 is H, Cl, F, or CN; Q8 and Q9 【Chemistry 4】 These are single or double bonds, When Q8 and Q9 are connected by a single bond, Q8 is CH2; and Q9 is CH(RPTM3) or N(RPTM3); When Q8 and Q9 are connected by a double bond, Q8 is CH; and Q9 is C(RPTM3); RPTM3 is a linear or optionally substituted molecule: -OH; -Cl; -F; -CN. Branched chain C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., (-OCH3 or -OCH2CH3); optionally substituted. 【Transformation 5】 (For example, linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl; (Optionally substituted with -F, -CN, or -OH); or optionally substituted ru 【Transformation 6】 (For example, linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl, (which can be optionally substituted with -F, -CN, or -OH); RPTM1a and RPTM2a are independently H, and optionally substituted C1-C 4-alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alcohols It is xy (for example, -OCH3 or -OCH2CH3), or CH2OCH3; Each t1 is independently 1, 2, 3, 4, or 5; and Each t2 is independently 0, 1, 2, 3, 4, or 5; RPMT2 is a linear or otherwise optionally substituted molecule containing H, OH, CN, -F, -Cl. Branched chain C1-C4 alkyl, optionally substituted with -NH2 (e.g., -N(C1-) Linearly chains that are optionally substituted with C3 alkyl)2 or -NH(C1-C3 alkyl) Alternatively, a branched-chain -O-C1-C4 alkyl, or a monocyclic or bicyclic compound that can be optionally substituted. Cyclic C3-C12 heterocycloalkyls (e.g., azetidine 1-yl, azetidine 1) -yl-3-ol, pyrrolidine-1-yl, piperidine-1-yl, piperazine-1-yl , or morpholin-4-yl, homopiperazine-1-yl, 【Transformation 7】 Each can be optionally selected as an OH group, a linear or branched C1-C6 alkyl group, or a C1-C6 alkyl group. (Substituted with one or more of the following: coxy, -CN, -F, -Cl, or NH2), optional A monocyclic or bicyclic heterocycloalkyl group with a -O-C3-12 structure that is substituted (for example) If, then, one or more OH groups, a linear or branched C1-C6 alkyl group, or a C1-C6 alkoxy group. (Optionally substituted with -CN, -F, -Cl or NH2), or optionally Substituting C3-C12 cycloalkyl (e.g., OH, straight-chain or branched C1-C) One of the following: 6-alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2 (The above are optionally substituted), C5-C6 heteroaryls that are optionally substituted (e.g.) For example, one or more linear or branched C1-C6 alkyl, C1-C6 alkoxy, - (Optionally substituted with CN, -F, -Cl or NH2), or optionally substituted C5-C6 aryl compounds (for example, one or more linear or branched C1-C6 alkyl compounds) Optionally substituted with C1-C6 alkoxy, -CN, -F, -Cl, or NH2. (to be), and; and The PTM 【Transformation 8】 This indicates the connection point with L; and (c) The L is a chemical linker group that covalently bonds the CLM and the PTM. thing.

2. The PTM has a chemical structure selected from the following: 【Chemistry 9】 In the formula, the PTM 【Chemistry 10】 The compound according to claim 1, wherein is a bonding site with L.

3. The PTM has a chemical structure selected from the following: 【Chemistry 11】 In the formula, the PTM 【Chemistry 12】 The compound according to claim 1, wherein is a bonding site with L.

4. The PTM has a chemical structure selected from the following: 【Chemistry 13】 In the formula, the PTM 【Chemistry 14】 The compound according to claim 1, wherein is a bonding site with L.

5. (a) PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMI R of Ib2, PTMIIb4, PTMIIc1, PTMIIc2, and PTMIIc4 PTM2 is selected from the following: H, OH, NH2, -N(CH3)2, methyl, ethyl 、 【Chemistry 15】 During the ceremony, 【Chemistry 16】 This represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific. 【Chemistry 17】 This indicates the bonding site of the PTM with the aryl or heteroaryl; (c) PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMI RP of Ib2, PTMIIb4, PTMIIc1, PTMIIc2 and PTMIIc4 TM3 is selected from the following: [Chemistry 18] During the ceremony, 【Chemistry 19】 This indicates the binding site between the biheteroaryl or biheterocyclic ring of PTM and RPTM3; also teeth (d) PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMI R of Ib2, PTMIIb4, PTMIIc1, PTMIIc2, and PTMIIc4 PTM5 is selected from the following: H, methyl, CFH2, CF2H, ethyl, propyl, Isopropyl, cyclopropyl, butyl, pentyl, hexyl 【Chemistry 20】 During the ceremony, 【Chemistry 21】 This indicates the bond point between the nitrogen of the biheteroaryl or biheterocyclic PTM and RPTM5. ;or (e) any one of claims 1 to 4, which is at least one of those combinations. The compound described in item 1.

6. PTM is a compound according to any one of claims 1 to 5, represented by the following chemical structure: 【Chemistry 22-1】 【Chemistry 22-2】

7. The PTM is the compound according to any one of claims 1 to 5, as described below: 【Chemistry 23-1】 【Chemistry 23-2】

8. The PTM is the compound according to any one of claims 1 to 5, as described below: 【Chemistry 24】

9. The PTM is the compound according to any one of claims 1 to 5, as described below: 【Chemistry 25】

10. The PTM is the compound according to any one of claims 1 to 5, as described below: 【Chemistry 26】

11. The CLM has the following chemical structure: 【Chemistry 27】 During the ceremony, W is CH2, O, CH(C1-3 alkyl) (e.g., CH(CH3)), or C = O; G is H, methyl, or OH; Each of Q1, Q2, Q3, and Q4 independently represents N, CH, or CR; A is H, an unsubstituted or substituted linear or branched alkyl group, Cl, or F. ； n is an integer between 1 and 4; R represents bond, H, -OR', -NR'R'', -CR'R''-, unsubstituted or substituted. A straight-chain or branched-chain C1-C6 straight-chain alkyl or branched-chain alkyl (for example, C1-C (Optionally substituted with 3 alkyl groups and / or one or more halogens), unsubstituted or substituted alkoxy groups (e.g., methoxy, ethoxy, butoxy, propoxy, Pentoxy or hexoxy, wherein the alkoxyl is optionally one or more hydroxyls Substituted with logen, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl. (to be performed), a 4-6 member cycloalkyl that is optionally substituted, optionally substituted 4-6 member heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or is NO2, and one R is covalently bonded to the aforementioned L; R' and R'' are, independently, bond H and substituted or unsubstituted C1-C4 axol. Selected from methyl or ethyl; 【Chemistry 28】 This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific, A compound described in any one of items 1 to 10.

12. The CLM has the following chemical structure: 【Chemistry 29】 During the ceremony, W is CH2, O, CH(C1-3 alkyl) (e.g., CH(CH3)), or C = O; A is a linear or branched alkyl group that is optionally substituted with H, methyl, or other suitable group. the law of nature; n is an integer between 1 and 4; R can be independently and optionally substituted with H, O, OH, N, NH, NH2, or methyl. Alkyl chains or branched chains (e.g., linear or branched C1- chains that are optionally substituted) C6 alkyl), C1-C6 alkoxy, and -alkyl-aryl (e.g., C1- At least one of C6 alkyl, C4-C7 aryl, or a combination thereof Includes alkylaryls, aryls (e.g., C5-C7 aryls), amines, and amines. Selected from d or carboxy, one R or W is optionally PTM, chemistry Shared linker group (L), ULM, CLM (or CLM') or combination thereof. Modified to be combined; and Equation (g) 【Transformation 30】 This represents a binding that may be stereospecific ((R) or (S)) or non-stereospecific, A compound described in any one of items 1 to 10.

13. The aforementioned chemical linker group comprises a chemical structural unit represented by the following formula: -(AL)q-, During the ceremony, -(AL)q- is a base connected to the CLM or the PTM; q is an integer greater than or equal to 1; Each A is independent of CRL1RL2, O, S, SO, SO2, NRL3, SO2NRL3 ,SONRL3,CONRL3,NRL3CONRL4,NRL3SO2NRL4,CO CRL1 = CRL2, C ≡ C, 1 to 6 RL1 units and / or RL2 units can be arbitrarily selected. Selectively substituted C3-11 monocyclic or bicyclic cycloalkyl groups, 1 to 9 RL1 C5-13 spirocycloalkyl groups optionally substituted with a group and / or an RL2 group C3-11 is optionally replaced with 1 to 6 RL1 groups and / or RL2 groups. Monocyclic or bicyclic heterocyclines, 1 to 8 RL1 and / or RL2 groups A C5-13 spiroheterocyl that is optionally substituted, with 1 to 6 RL1 groups and aryls that are optionally replaced by RL2 units, and 1 to 6 RL1 units and / or heteroaryls optionally substituted with RL2 groups; Rabini RL1, RL2, RL3, RL4, and RL5 are each independently H, halogen, C1-8 alkyl, OC1-8 alkyl, SC1-8 alkyl, NHC1-8 alkyl, N(C1-8 alkyl)2, C3-11 cycloalkyl, 5-membered or 6-membered aryl, Five-membered or six-membered heteroaryls, C3-11 heterocyclyls, OC3-8 cycloaryls Kill, SC3-8 cycloalkyl, NHC3-8 cycloalkyl, N(C3-8 cycloalkyl) Lukil) 2, N(C3-8 cycloalkyl)(C1-8 alkyl), OH, NH2, SH SO2C1-8 alkyl, CC-C1-8 alkyl, CCH, CH=CH(C1-8 alkyl) Lukil), C(C1-8 alkyl)=CH(C1-8 alkyl), C(C1-8 alkyl) ) = C(C1-8 alkyl)2, COC1-8 alkyl, CO2H, CN, CF3, CH F2, CH2F, NO2, SF5, SO2NHC1-8 alkyl, SO2N(C1-8 Lukil) 2, SONHC1-8 alkyl, SON(C1-8 alkyl) 2, CONHC1 -8 alkyl, CON(C1-8 alkyl)2,N(C1-8 alkyl)CONH(C1 -8 alkyl), N(C1-8 alkyl)CON(C1-8 alkyl)2,NHCONH (C1-8 alkyl), NHCON(C1-8 alkyl)2, NHCONH2, N(C1 -8 alkyl)SO2NH(C1-8 alkyl),N(C1-8 alkyl)SO2N(C 1-8 alkyl)2, NH₃SO₂NH₃(C1-8 alkyl), NH₃SO₂N(C1- The following is a description of any one of claims 1 to 12, which is 8 alkyl)2 or NH₃SO₂NH₂. The compound listed.

14. The aforementioned chemical linker group is optionally substituted with a C1-C50 alkyl group (for example, C1 , C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14, C15, C16, C17, C18, C19, C20, C21, C22, C23 , C24, C25, C26, C27, C28, C29, C30, C31, C32, C33 , C34, C35, C36, C37, C38, C39, C40, C41, C42, C43 (including C44, C45, C46, ​​C47, C48, C49, or C50 alkyl), During the ceremony, Each carbon atom can be arbitrarily selected as CRL1RL2, O, S, SO, SO2, NRL3, SO2N RL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4 CO, CRL1=CRL2, C≡C, any 1 to 6 RL1 and / or RL2 units Selectively substituted C3-11 monocyclic or bicyclic cycloalkyl groups, 1 to 9 R groups C5-13 spirocycloalkyl groups optionally substituted with L1 and / or RL2 groups monocyclic or bicyclic rings, optionally substituted with 1 to 6 RL1 and / or RL2 groups. The formula C3-11 heterocyclyl, optionally with 1 to 8 RL1 and / or RL2 groups C5-13 spiroheterocyclyl is substituted with 1 to 6 RL1 and / or RL2 An aryl group optionally substituted with a group, or 1 to 6 RL1 and / or RL2 groups Substituted with a heteroaryl which is optionally substituted; and RL1, RL2, RL3, RL4, and RL5 are each independently H, halogen, C1-8 alkyl, OC1-8 alkyl, SC1-8 alkyl, NHC1-8 alkyl, N(C1-8 alkyl)2, C3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC3-8 cycloalkyl, SC3-8 cycloalkyl, NH C3-8 cycloalkyl, N(C3-8 cycloalkyl)2, N(C3-8 cycloalkyl (C1-8 alkyl), OH, NH2, SH, SO2C1-8 alkyl, CC-C1 -8 alkyl, CCH, CH=CH(C1-8 alkyl), C(C1-8 alkyl)=C H(C1-8 alkyl), C(C1-8 alkyl)=C(C1-8 alkyl)2, COC 1-8alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO 2NHC1-8 alkyl, SO2N(C1-8 alkyl)2, SONHC1-8 alkyl , SON(C1-8 alkyl)2, CONHC1-8 alkyl, CON(C1-8 alkyl 2, N(C1-8 alkyl)CONH(C1-8 alkyl), N(C1-8 alkyl) )CON(C1-8 alkyl)2, NHCONH(C1-8 alkyl), NHCON(C 1-8 alkyl)2,NHCONH2,N(C1-8 alkyl)SO2NH(C1-8 Lukil), N(C1-8 alkyl)SO2N(C1-8 alkyl)2,NH SO2NH (C1-8 alkyl), NH₃SO₂N(C1-8 alkyl)₂, or NH₃SO₂N A compound according to any one of claims 1 to 12, wherein the compound is H2.

15. The aforementioned chemical linker group is selected from the following: 【Chemistry 31】 During the ceremony, 【Chemistry 32】 Each is independently a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl (e.g.) For example, a 4-6 member cycloalkyl or a 4-6 member heterocycloalkyl, and overlapping The ring shown represents a spirocyclic ring; Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; RL is selected from H and C1-3 alkyl groups; The linker may optionally consist of (i) = O and (ii) C1-3 alkyl (for example, 1 to 4 independently selected from methyl and halogens (e.g., F, Cl, or Br) Substituted with at least one of (e.g., 1, 2, 3, or 4) substituents; call 【Transformation 33】 This indicates the connection point with the PTM or the CLM, as described in any one of claims 1 to 14. The compound listed.

16. The aforementioned chemical linker has the following chemical structure: 【Chemistry 34-1】 【Chemistry 34-2】 During the ceremony, 【Chemistry 35】 Each is independently a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl (e.g.) For example, a 4-6 member cycloalkyl or a 4-6 member heterocycloalkyl, and overlapping The ring shown represents a spirocyclic ring; 【Transformation 36】 These include 8-10 member cross-linked cycloalkyl groups, 8-10 member cross-linked heterosylcoalkyl groups, and one- or a 3- to 7-membered heterocycline having two double bonds (for example, one or two double bonds) (3-7 member heterocyclyl having a bond), or 7-10 member condensed bicyclic heterocyclo It is an alkyl group (for example, a 7-9 member condensed bicyclic heterocycloalkyl group); Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; RL is selected from H and C1-3 alkyl groups; The linker may optionally consist of (i) = O and (ii) C1-3 alkyl (for example, Independently selected from methyl, OH, and halogens (e.g., F, Cl, or Br) Substituting with at least one of 1 to 4 substituents (for example, 1, 2, 3, or 4) and 【Chemistry 37】 This indicates the connection point with the PTM or the CLM, as described in any one of claims 1 to 14. The compound listed.

17. The aforementioned chemical linker group is: 【Transformation 38】 And in the formula, The above chemical linker groups that do not contain substituents can optionally be (i) = O and (ii) C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl or Br) One to four substituents (e.g., one, two, three, or four) are independently selected, of which a small number At the very least, it will be replaced by one; * is covalently bonded to the CLM or the PTM, or to the CLM or the front The atoms shared by the PTM (e.g., nitrogen, carbon, or oxygen) are indicated; 【Chemistry 39】 This indicates the connection point with the PTM or the CLM; and m, n, o, and p are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, Any of claims 1 to 16, which is 9 or 10 (preferably 0, 1, 2, or 3). The compound described in item 1.

18. The aforementioned chemical linker group is independently selected from C1-3 alkyl (preferably methyl) groups. or optionally substituted with one or two substituents; p and o are 0, respectively; and The compound according to claim 17, wherein m is 1.

19. The aforementioned chemical linker group is selected from the following: 【Chemistry 40-1】 【Chemistry 40-2】 During the ceremony, The above chemical linker groups that do not contain substituents can optionally be (i) = O and (ii) C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl or Br) One to four substituents (e.g., one, two, three, or four) are independently selected, of which a small number At the very least, it will be replaced by one; * is covalently bonded to the CLM or the PTM, or to the CLM or the front The atoms shared by the PTM (e.g., nitrogen or carbon) are indicated; 【Chemistry 41】 This indicates the connection point with the PTM or the CLM; and m, n, o, and p are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, Any of claims 1 to 16, which is 9 or 10 (preferably 0, 1, 2, or 3). The compound described in item 1.

20. The aforementioned chemical linker group is selected from the following: 【Chemistry 42-1】 【Chemistry 42-2】 【Chemistry 42-3】 【Chemistry 42-4】 【Chemistry 42-5】 【Chemistry 42-6】 【Chemistry 42-7】 【Chemistry 42-8】 During the ceremony, The above chemical linker groups that do not contain substituents can optionally be (i) = O and (ii) C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl or Br) One to four substituents (e.g., one, two, three, or four) are independently selected, of which a small number At the very least, it will be replaced by one; * is covalently bonded to the CLM or the PTM, or to the CLM or the front The atoms shared by the PTM (e.g., nitrogen or carbon) are indicated; 【Chemistry 43】 This indicates the connection point with the PTM or the CLM; and m, n, and o are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3), any one of claims 1 to 16. The compounds described above.

21. The aforementioned chemical linker group is selected from the following: 【Chemistry 44-1】 【Chemistry 44-2】 【Chemistry 44-3】 【Chemistry 44-4】 During the ceremony, The above chemical linker groups that do not contain substituents can optionally be (i) = O and (ii) C1-3 alkyl (e.g., methyl) and halogen (e.g., F, Cl or Br) One to four substituents (e.g., one, two, three, or four) are independently selected, of which a small number At the very least, it will be replaced by one; * is shared with the CLM or the PTM, or the CLM or the P This indicates the atom (e.g., nitrogen or carbon) that is covalently bonded to TM; 【Chemistry 45】 This indicates the connection point with the PTM or the CLM; and m, n, o, and p are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, Any of claims 1 to 16, which is 9 or 10 (preferably 0, 1, 2, or 3). The compound described in item 1.

22. The aforementioned chemical linker has the following chemical structure: 【Chemistry 46】 During the ceremony, XL is either an N group or a CH group; m, n, o, and p are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 (preferably 0, 1, 2, or 3); * is shared with the CLM or the PTM, or the CLM or the P This indicates the atom (e.g., nitrogen or carbon) that is covalently bonded to TM; 【Chemistry 47】 This indicates the connection point with the PTM or the CLM; and The chemical linker has 0 to 4 substituents (preferably 0, 1, or 2 substituents). The claim includes, wherein each substituent is independently a C1-3 alkyl (preferably methyl). A compound described in any one of items 1 to 16.

23. The aforementioned chemical linker has the following chemical structure: 【Chemistry 48】 During the ceremony, XL is either an N or CH group; 【Chemistry 49】 This represents a stereospecific bond, where one side has an (R) structure and the other side has an (S) structure; * is shared with the CLM or the PTM, or the CLM or the P This indicates the atom (e.g., nitrogen or carbon) that is covalently bonded to TM; [Transformation 50] This indicates the connection point with the PTM or the CLM; and The chemical linker has 0 to 4 substituents (preferably 0, 1, or 2 substituents). The claim includes, wherein each substituent is independently a C1-3 alkyl (preferably methyl). A compound described in any one of items 1 to 16.

24. (a) The CLM is, 【Chemistry 51】 It is expressed by, in the formula, The CLM 【Chemistry 52】 This indicates the connection point with L; and N* is a nitrogen atom shared with the aforementioned chemical linker group; (b) The PTM is 【Chemistry 53】 Represented by the PTM 【Chemistry 54】 This indicates the connection point with L; and (c) The above L is, 【Transformation 55】 A chemical linker group selected from the above, where * is covalently bonded to the CLM or PTM. Atoms that are combined with or shared with the CLM or PTM (e.g., carbon or nitrogen) This indicates that 【Transformation 56】 Each of these represents a bonding site with the CLM or the PTM, the compound according to claim 1. 。

25. (a) The CLM is represented by: 【Chemistry 57-1】 【Chemistry 57-2】 【Chemistry 57-3】 【Chemistry 57-4】 During the ceremony, The CLM 【Transformation 58】 indicates the connection point with L; and N* is a nitrogen atom shared with the aforementioned chemical linker group; (b) The PTM is represented by: 【Chemistry 59-1】 【Chemistry 59-2】 【Chemistry 59-3】 【Chemistry 59-4】 In the formula, the PTM 【Transformation 60】 This indicates the connection point with L; (c) The L is a chemical linker group selected from the following: 【Chemistry 61】 In the formula, * is covalently bonded to the CLM or PTM, or to the CLM or P This indicates atoms shared by TM (e.g., carbon, nitrogen, or oxygen). 【Transformation 62】 Each of these indicates a connection point with the CLM or the PTM; or (d) A combination thereof, the compound according to any one of claims 1 to 23.

26. (a) The CLM is represented by: 【Chemistry 63-1】 【Chemistry 63-2】 【Chemistry 63-3】 【Chemistry 63-4】 【Chemistry 63-5】 【Transformation 63-6】 【Chemistry 63-7】 【Transformation 63-8】 During the ceremony, The CLM 【Chemistry 64】 indicates the connection point with L; and N* is a nitrogen atom shared with the aforementioned chemical linker group; (b) The PTM is represented by: 【Chemistry 65-1】 【Chemistry 65-2】 【Chemistry 65-3】 【Chemistry 65-4】 【Transformation 65-5】 In the formula, the PTM 【Chemical Formula 66】 This indicates the connection point with L; (c) The L is a chemical linker group selected from the following: 【Chemistry 67-1】 【Chemistry 67-2】 【Chemistry 67-3】 In the formula, * is covalently bonded to the CLM or PTM, or to the CLM or P This indicates atoms shared by TM (e.g., carbon, nitrogen, or oxygen). 【Transformation 68】 Each of these indicates a connection point with the CLM or the PTM; or (d) A combination thereof, the compound according to any one of claims 1 to 23.

27. The PTM is selected from the compounds in Tables 1 to 3 (for example, selected from compounds 1 to 431). It is a PTM (Professional Training Machine); The CLM is selected from the compounds in Tables 1 to 3 (for example, selected from compounds 1 to 431). (is) CLM; and The aforementioned L is selected from the compounds in Tables 1 to 3 (for example, selected from compounds 1 to 431). The compound according to claim 1, wherein it is at least one of L.

28. The aforementioned compounds are compounds 1-3, 5-9, 11-22, 25-28, 31, 34-29, ４１、４４～５６、５８～６２、６４～６９、７１～１１７、１１９～１４０、１４４～ １４７、１５１、１５５、１５６、１５９～２１２、２１４、２１６～２１９、２２１、 ２２２、２２４～２２７、２２９～２４２、２４４～２４８、２５０～２５５、２５７～ ２６０、２６２～２６９、２７２、２７３、２７５、２７７～２８０、２８２～２８７、 ２８９～２９５、２９７～３０２、３０４～３２９、３３２～３３９、３４２～３５１、 ３５３～３５８、３６０～３６９、３７１～３７７、３７９～３９７、３９９～４０３、 Selected from 405-407, 409-411, and 414-431, as described in claim 1 The compound listed.

29. The aforementioned compounds are compounds 4, 10, 29, 30, 32, 40, 42, 43, 57, 63, ４０、１１８、１５０、１５２、１５４、１５７、１５８、２１３、２１５、２２０、２ ２３、２２８、２４３、２４９、２５６、２６１、２７４、２７６、２８１、２８８、３ ０３、３３０、３３１、３４０、３４１、３５２、３５９、３７０、３７８、４０４、４ A compound according to claim 1, selected from 08, 412, and 413.

30. The aforementioned compounds are derived from compounds 23, 24, 33, 141-143, 148, and 153. A compound selected according to claim 1.

31. The compound is selected from compounds 149, 270, 271, 296, and 398. The compound according to claim 1.

32. An effective amount of the bifunctional compound according to any one of claims 1 to 31, and pharmaceutically acceptable A composition containing a carrier.

33. The composition may be an additional bioactive agent, or another as described in any one of claims 1 to 31. The composition according to claim 32, further comprising at least one of the bifunctional compounds.

34. The composition according to claim 33, wherein the additional bioactive agent is an anticancer agent.

35. A pharmaceutically acceptable carrier for treating a disease or disorder in a subject, and claims A composition comprising an effective amount of at least one compound described in any one of items 1 to 31. The method comprises administering the composition to a subject requiring it, wherein the compound is A composition that is effective in treating or improving at least one symptom of the disease or disorder described above.

36. The disease or disorder is associated with abnormal BCL6 expression and / or activity, according to the claim. The composition described in 35.

37. The disease or disorder is a cancer associated with abnormal BCL6 expression and / or activity. The composition according to claim 35 or 36.

38. The aforementioned disease or disorder is squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, Bladder cancer, intestinal cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer Cancer, lung cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer; leukemia; benign lymphoma Tumor, malignant lymphoma, Burkitt lymphoma, non-Hodgkin lymphoma, benign melanoma, malignant Melanoma, myeloproliferative disorders, sarcomas, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma , sarcoma, peripheral epithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioma Ablastoma, neuroblastoma, ganglion cell tumor, ganglion glioma, medulloblastoma, pineal cell tumor, meninges Tumors, meningiosarcomas, neurofibromas, and schwannomas, prostate cancer, uterine cancer, testicular cancer, thyroid cancer Cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, malformations Cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T cell lymphoma, adult T cell leukemia, precursor B cell ALL, precursor B cell Lymphoma, Large B-cell lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL Philadelphia chromosome-positive CML, follicular lymphoma, intravascular large B-cell lymphoma Claims 35 to 37, which are B-cell leukemia, chronic myeloid leukemia, or non-small cell lung cancer. The composition described in any one of the items.

39. The aforementioned disease or disorder is lymphoma, B-cell non-Hodgkin lymphoma, large B-cell lymphoma B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia The disease is B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, or non-small cell lung cancer. The composition according to any one of claims 35 to 37.

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