Selective BCL-XL PROTAC Compounds and Methods of Use

Abstract

The present disclosure provides a PROTAC compound represented by formula (A): DL-DSM (A), where DSM is a degradation signaling compound (e.g., an E3 ubiquitin ligase recruiting ligand, e.g., a CRBN ligand or a VHL ligand) covalently attached to a linker L, L is a linker covalently attaching DSM to D, and D is a Bcl-xL inhibitor compound of formula (I) or formula (II) (wherein the definitions for the variables are provided herein) covalently attached to a linker L, or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts. Pharmaceutical compositions comprising and methods of use and making the PROTAC compounds of the present disclosure are also provided. [Formula 1] TIFF2024505562000781.tif7491

Description

[Technical field]

[0001] Related Applications This application claims the benefit of and priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 144,577, filed on February 2, 2021, the entire contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to compounds that include a Bcl-xL inhibitory moiety covalently linked to a degradation signaling moiety (DSM) that binds to a degradative protein or degradative protein complex, such as an E3 ubiquitin ligase or an E3 ubiquitin ligase complex. The present disclosure further relates to methods and compositions useful for treating cancers that respond to reduced expression and / or activity of Bcl-xL. [Background technology]

[0003] Apoptosis (programmed cell death) is an evolutionarily conserved pathway essential for tissue homeostasis, development, and elimination of damaged cells. Deregulation of apoptosis contributes to human diseases, including malignancies, neurodegenerative disorders, diseases of the immune system, and autoimmune diseases (Hanahan and Weinberg, Cell. 2011 Mar 4;144(5):646-74; Marsden and Strasser, Annu Rev Immunol. 2003; 21:71-105; Vaux and Flavell, Curr Opin Immunol. 2000 Dec;12(6):719-24). Evasion of apoptosis is recognized as a hallmark of cancer and is involved in tumor progression and persistent spread, as well as resistance to anticancer treatments (Hanahan and Weinberg, Cell. 2000 Jan 7;100(1):57-70).

[0004] The Bcl-2 protein family includes key regulators of cell survival, which can suppress (e.g., Bcl-2, Bcl-xL, Mcl-1) or promote (e.g., Bad, Bax) apoptosis (Gross et al., Genes Dev. 1999 Aug 1; 13(15): 1899-911; Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan; 9(1): 47-59). When faced with stress stimuli, whether a cell survives or undergoes apoptosis depends on the degree of pairing between Bcl-2 family members that promote cell death and those that promote cell survival. In most cases, these interactions involve docking of the Bcl-2 homology 3 (BH3) domain of the proapoptotic family member into a groove on the surface of the prosurvival member. The presence of Bcl-2 homology (BH) domains defines membership of the Bcl-2 family, which is divided into three major groups depending on the particular BH domains present in the protein: Pro-survival members, such as Bcl-2, Bcl-xL, and Mcl-1, contain BH domains 1-4, whereas Bax and Bak, the pro-apoptotic effectors of mitochondrial outer membrane permeabilization during apoptosis, contain BH domains 1-3 (Youle and Strasser, Nat. Rev. Mol. Cell Biol. 2008 Jan;9(1):47-59).

[0005] Overexpression of pro-survival members of the Bcl-2 family is a hallmark of cancer, and these proteins have been shown to play important roles in tumor initiation, maintenance, and resistance to anticancer therapy (Czabotar et al., Nat. Rev. Mol. Cell Biol. 2014 Jan;15(1):49-63). Bcl-xL (also called BCL2L1 for BCL2-like 1) is frequently amplified in cancer (Beroukhim et al., Nature 2010 Feb 18;463(7283):899-905), and its expression has been shown to inversely correlate with sensitivity to over 120 anticancer therapeutic molecules in a representative panel of cancer cell lines (NCI-60) (Amundson et al., Cancer Res. 2000 Nov 1;60(21):6101-10).

[0006] In addition, several studies using transgenic knockout mouse models and transgenic overexpression of Bcl-2 family members have highlighted the importance of these proteins in diseases of the immune system and autoimmune diseases (for review see Merino et al., Apoptosis 2009 Apr;14(4):570-83. doi: 10.1007 / s10495-008-0308-4. PMID: 19172396). Transgenic overexpression of Bcl-xL in the T cell compartment confers resistance to apoptosis induced by glucocorticoids, g-radiation and CD3 crosslinking. This suggests that transgenic Bcl-xL overexpression may reduce apoptosis in resting and activated T cells (Droin et al., Biochim Biophys Acta 2004 Mar 1;1644(2-3):179-88. doi: 10.1016 / j.bbamcr. 2003.10.011. PMID: 14996502).

[0007] Sustained or high expression of anti-apoptotic Bcl-2 family proteins has been observed in patient samples (Pope et al., Nat Rev Immunol. 2002 Jul;2(7):527-35. doi: 10.1038 / nri846.PMID: 12094227). In particular, T cells isolated from the joints of patients with rheumatoid arthritis showed increased Bcl-xL expression and were resistant to spontaneous apoptosis (Salmon et al., J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172 / JCI119178.PMID: 9022077). The use of BH3 mimetics has also shown benefit in preclinical models of immune system and autoimmune diseases. Treatment with ABT-737 (a Bcl-2, Bcl-xL, and Bcl-w inhibitor) resulted in potent inhibition of lymphocyte proliferation in vitro. Importantly, in animal models of arthritis and lupus, mice treated with ABT-737 showed a marked reduction in disease severity (Bardwell et al., J Clin Invest. 1997 Feb 1;99(3):439-46. doi: 10.1172 / JCI119178.PMID: 9022077). In addition, ABT-737 has been shown to interfere with allogeneic T cell activation, proliferation and cytotoxicity in vitro and inhibit allogeneic T and B cell responses after skin grafting with high selectivity for lymphoid cells (Cippa et al.,.Transpl Int. 2011 Jul;24(7):722-32. doi: 10.1111 / j.1432-2277.2011.01272.x. Epub 2011 May 25. PMID: 21615547).

[0008] These findings presented above motivated the discovery and development of a new class of drugs called BH3 mimetics. These molecules can disrupt the interaction between pro- and anti-apoptotic members of the Bcl-2 family and are potent inducers of apoptosis. This new class of drugs includes inhibitors of Bcl-2, Bcl-xL, Bcl-w and Mcl-1. The first BH3 mimetics described were ABT-737 and ABT-263, which target Bcl-2, Bcl-xL and Bcl-w (Park et al., J. Med. Chem. 2008 Nov 13;51(21):6902-15, Roberts et al., J. Clin. Oncol. 2012 Feb 10;30(5):488-96). Subsequently, selective inhibitors of Bcl-2 (ABT-199 and S55746 - Souers et al., Nat Med. 2013 Feb;19(2):202-8; Casara et al., Oncotarget 2018 Apr 13;9(28):20075-20088), Bcl-xL (A-1155463 and A-1331852 - Tao et al., ACS Med Chem Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci Transl Med. 2015 Mar 18;7(279):279ra40) and Mcl-1 (A-1210477, S63845, S64315, AMG-176 and AZD-5991 - Leverson et al., Sci Transl Med. 2015 Mar 18;7(279):279ra40) were used to treat rheumatoid arthritis. al., Cell Death Dis. 2015 Jan 15;6:e1590., Kotschy et al., Nature 2016, 538, 477-482, Maragno et al., AACR 2019, Poster #4482, Kotschy et al., WO No. 2015 / 097123, Caenepeel et al., Cancer Discov. 2018 Dec;8(12):1582-1597, Tron et al., Nat. Commun. 2018 Dec 17;9(1):5341) were also discovered.ABT-199, a selective Bcl-2 inhibitor, is currently approved for the treatment of patients with CLL and AML in combination therapy, while other inhibitors are still in preclinical or clinical development. In preclinical models, ABT-263 has shown activity in several hematological malignancies and solid tumors (Shoemaker et al., Clin. Cancer Res. 2008 Jun 1;14(11):3268-77; Ackler et al., Cancer Chemother. Pharmacol. 2010 Oct;66(5):869-80; Chen et al., Mol. Cancer Ther. 2011 Dec;10(12):2340-9). In clinical studies, ABT-263 has demonstrated promising antitumor activity in lymphoid malignancies (Wilson et al., Lancet Oncol. 2010 Dec;11(12):1149-59; Roberts et al., J. Clin. Oncol. 2012 Feb 10;30(5):488-96), and its activity is being explored in solid tumors and in combination with several therapies. Selective Bcl-xL inhibitors A-1155463 or A-1331852 have shown in vivo activity in preclinical models of T-ALL (T-cell acute lymphoblastic leukemia) and different types of solid tumors (Tao et al., ACS Med. Chem. Lett. 2014 Aug 26;5(10):1088-93; Leverson et al., Sci. Transl. Med. 2015 Mar 18;7(279):279ra40). Selective Mcl-1 inhibitors have shown promising in vivo activity in several types of hematological cell malignancies in preclinical models, three of which, S64315, AMG176 and AZD5991, are currently being investigated in clinical trials (Yang et al., Eur. J. Med. Chem. 2019 May 8;177:63-75). Therefore, BH3 mimetics represent a highly attractive approach for the development of novel therapeutics in the fields of oncology and immune and autoimmune diseases.

[0009] To advance the development of alternative BH3 mimetics, new approaches can include their use as both protein binders and inhibitors. Indeed, BH3 mimetics, more specifically Bcl-xL inhibitors, can be upgraded by converting their mode of action from inhibition to degradation via PROTACs (Proteolysis Targeting Chimeras) due to medical needs. These degraders are small molecules that contain (i) a ligand that targets the protein of interest (BH3) for degradation, (ii) an E3 ubiquitin ligase recruitment ligand (mainly Cereblon (CRBN) or von Hippel-Lindau (VHL) ligands), and (iii) a chemical linker that connects the two ligands. Upon PROTAC-mediated heterodimerization of the two bound proteins, the target protein is ubiquitinated and degraded by the proteasome (Sakamoto et al., PNAS 2001 17;98(15):8554-8559; Schneekloth et al., J. Am. Chem. Soc. 2004 31;126(12):3748-3754.).

[0010] This method has several advantages. First, potency can be improved by taking advantage of the potential benefits from the catalytic process of the PROTAC approach compared to stoichiometric inhibition (Bondeson et al., Cell Chem. Biol. 2018 Jan 18;25(1):78-87; Qin et al., J. Med. Chem. 2018 61(15) 6685-6704). Furthermore, selectivity can be achieved by site-specific expression of E3 ligases (Schapira et al., Nat. Rev. Drug Discov. 2019 Dec;18(12):949-963). Finally, the first PROTAC, ARV-110, entered clinical trials in Q1-2019. This orally available compound is designed to degrade the androgen receptor (AR) in prostate cancer. Another compound (ARV-471), designed to degrade the estrogen receptor, also entered clinical trials in Q3-2019.

[0011] Several BH3 mimetics, such as Bcl-xL / Bcl-2 dual inhibitors (DT2216 and XZ-739 based on the ABT-263 scaffold, Khan et al., Nat Med 2019 Dec;25(12):1938-1947; Zhang et al., Eur. J. of Med. Chem. 2020 Apr 15; 192: 112186), Bcl-xL inhibitors (XZ-424 based on the A-1155463 scaffold, Zhang et al., Chem. Commun. 2019 Dec 5; 55(98):14765-14768), Mcl-1 inhibitors (dMCL1-2 based on the A-1210477 scaffold, Papatzimas et al., J. Med. Chem. 2019 62(11):5522-5540), and a Bcl-2 / Mcl-1 dual inhibitor (Wang et al., J. Med. Chem. 2019 Sep 12;62(17):8152-8163) have been converted into PROTACs to date. Interestingly, because VHL and CRBN E3 ligases are minimally expressed in platelets, ABT-263-based Bcl-xL PROTACs can selectively induce Bcl-xL degradation in various cancer cells, but not in platelets, thus potentially resulting in dose-limiting platelet toxicity.

[0012] Therefore, BH3 mimetic-based degraders represent a very attractive approach for developing novel therapeutics in the field of oncology and immune and autoimmune diseases.In particular, there is a need for potent PROTACs that selectively degrade Bcl-xL protein.As described herein, the present disclosure meets this need. Summary of the Invention

[0013] The present disclosure provides, in part, potent and selective Bcl-xL PROTAC degraders of formula (A) as defined below. Based on their pro-apoptotic properties, these compounds may be of interest for the treatment of pathologies involving deregulation in apoptosis, such as cancer, autoimmune diseases and diseases of the immune system. These compounds may slow down, inhibit and / or reverse tumor growth in mammals and / or may be useful for treating human cancer patients. The present disclosure more specifically relates, in some embodiments, to pro-apoptotic agents capable of binding to and killing cancer cells. In some embodiments, the pro-apoptotic agent is a PROTAC compound that includes a linker that connects the Bcl-xL inhibitor to an E3 ubiquitin ligase recruitment ligand.

[0014] In a first embodiment of the present disclosure, the PROTAC compound of the present disclosure has formula (A): DL-DSM (A) [In the formula, DSM is a degradation signaling compound covalently attached to a linker L; L is a linker covalently attaching DSM to D; D is a group of formula (I) covalently attached to a linker L:

[0015] [ka] (In the formula, ·R 1 and R 2 are each independently hydrogen; hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl; trifluoromethyl; and straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C1 -C 6 is optionally substituted with an alkyl group; or R 1 and R 2 together with the carbon atom that carries them, C 3 -C 6 It forms a cycloalkylene group, ·R 3 is hydrogen; C 3 -C 6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0016] [ka] represents a group selected from the group consisting of ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 alkoxy groups); and the groups:

[0017] [ka] represents a group selected from the group consisting of or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·R c , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R fare linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0018] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0019] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 RG2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl, halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and RG2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0020] [ka] [In the formula, R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; R G5 is a C optionally substituted with a hydrogen atom or 1 to 3 halogen atoms 1 -C 6 represents an alkyl group, ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0021] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 basis, represents a group selected from the group consisting of ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 ;

[0022] [ka] represents a group selected from the group consisting of Cy is C 3-C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0023] [ka] represents a group selected from the group consisting of ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 represents a group selected from the group consisting of alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NRh R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 61 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 alkoxy groups); and the groups:

[0024] [ka] represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl, R 3 and R 8 One of the groups, if present, is covalently attached to the linker, provided that the valency of the atom is not exceeded by one or more of the substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts, or Formula (II)

[0025] [ka] (In the formula, n=0, 1 or 2, ----- represents a single bond or a double bond, A 4 and A 5 each independently represents a carbon or nitrogen atom; Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 1 is hydrogen; hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl; trifluoromethyl; and straight or branched chain C 1 -C 6alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; ·R 2 represents hydrogen or methyl; ·R 3 is hydrogen; straight or branched chain C 1 -C 4 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0026] [ka] represents a group selected from the group consisting of ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 alkoxy groups); and the groups:

[0027] [ka] represents a group selected from the group consisting of or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·R c , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8forming a heterocycloalkyl, Het 1 teeth,

[0028] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0029] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2, -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl, halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8or alternatively, G is linked to form a heterocycloalkyl;

[0030] [ka] [In the formula, R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; R G5 is a C optionally substituted with a hydrogen atom or 1 to 3 halogen atoms 1 -C 6 represents an alkyl group, ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0031] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from the group consisting of ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 ;

[0032] [ka] represents a group selected from the group consisting of Cy is C 3 -C 8 represents cycloalkyl, ·R 8is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0033] [ka] represents a group selected from the group consisting of ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 represents a group selected from the group consisting of alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, halogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' bare each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 alkoxy groups); and the groups:

[0034] [ka] represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R'a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B.4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; R 3 , R 8 and one of the G groups, if present, is covalently attached to the linker such that the valency of the atom is not exceeded by one or more of the substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0035] In a second embodiment of the present disclosure, the PROTAC compound of the present disclosure has formula (A): DL-DSM (A), [In the formula, DSM is a degradation signaling compound (e.g., an E3 ubiquitin ligase recruiting ligand, e.g., a CRBN ligand or a VHL ligand) covalently attached to a linker, L; L is a linker covalently attaching DSM to D; D is a group of formula (I) covalently attached to a linker L:

[0036] [ka] (In the formula, ·R 1 and R 2 are each independently hydrogen; hydroxyl or C1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl;Trifluoromethyl;Straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; or R 1 and R 2 together with the carbon atom that carries them, C 3 -C 6 It forms a cycloalkylene group, ·R 3 is hydrogen; C 3 -C 6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0037] [ka] represents a group selected from ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2-phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 (optionally substituted by an alkoxy group);

[0038] [ka] represents a group selected from or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·R c , R d , R e, R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0039] [ka] represents a group selected from Het 2 teeth,

[0040] [ka] represents a group selected from A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1)NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4-phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0041] [ka] [In the formula, R G4 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; halogen or -CN; ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0042] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 basis, Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0043] [ka] represents a group selected from Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R'c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0044] [ka] represents a group selected from ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, C 1 -C 6 represents a group selected from alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , C 3 -C 8Heterocycloalkylene-CH 2 -R 8 represents a group selected from ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2O-;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 (optionally substituted by an alkoxy group);

[0045] [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight-chain or branched-chain C 1 -C 6 Alkyl, hydroxyl, -NH 2、 optionally substituted with one or two groups selected from oxo or piperidinyl; R 3 and R 8One of the groups, if present, is covalently attached to the linker, provided that the valency of the atom is not exceeded by one or more of the substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts, or Formula (II)

[0046] [ka] (In the formula, n=0, 1 or 2, ----- represents a single bond or a double bond, A 4 and A 5 each independently represents a carbon or nitrogen atom; Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 1 is hydrogen; hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl;Trifluoromethyl;Straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; ·R 2 represents hydrogen or methyl; ·R 3 is hydrogen; straight or branched chain C 1 -C 4 Alkyl;-X 1 -NR a R b ;-X 1 -N+ R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0047] [ka] represents a group selected from ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O-;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6(optionally substituted by an alkoxy group);

[0048] [ka] represents a group selected from or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·R c , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0049] [ka] represents a group selected from Het 2 teeth,

[0050] [ka] represents a group selected from A1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0051] [ka] [In the formula, R G4 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; halogen or -CN; ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0052] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 basis, Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from ·R 7 is a linear or branched chain C 1 -C6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0053] [ka] represents a group selected from Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0054] [ka] represents a group selected from ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, C 1 -C 6 represents a group selected from alkoxy, ·R 10is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, halogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, C 1-C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O-;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 (optionally substituted by an alkoxy group);

[0055] [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2-,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight-chain or branched-chain C 1 -C 6 Alkyl, hydroxyl, -NH 2、 optionally substituted with one or two groups selected from oxo or piperidinyl; R 3 and R 8 One of the groups, if present, is covalently attached to the linker, provided that the valency of the atom is not exceeded by one or more of the substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0056] In a third embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the linker L is C 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6A straight or branched chain C optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy 1 -C 20 Alkylene;C 3 -C 10 Cycloalkylene; C 3 -C 8 Heterocycloalkylene; -C(O)-; -O-; -S-; -N(R 16 )-;-N(R 16 )-C(O)-;-C(O)-N(R 16 )-;-CH 2 -C(O)-N(R 16 )-;-N(R 16 )-C(O)-CH 2 -; polyoxyethylene (PEG) group; C 1 -C 8 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 arylene groups optionally substituted with one or two groups selected from the group consisting of alkoxy; and heteroarylene groups, wherein R 16 is hydrogen or C 1 -C 6 alkyl, and the remaining variables are as described in the first or second embodiment.

[0057] In a fourth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the linker L of formula (A) is 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 20 Alkylene;C 3 -C 10 Cycloalkylene; -C(O)-; -O-; -S-; -N(R 16)-;-N(R 16 )-C(O)-;-C(O)-N(R 16 )-;-CH 2 -C(O)-N(R 16 )-;-N(R 16 )-C(O)-CH 2 -; polyoxyethylene (PEG) group; C 1 -C 8 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 arylene groups optionally substituted with one or two groups selected from alkoxy; and heteroarylene groups, wherein R 16 is hydrogen or C 1 -C 6 alkyl, and the remaining variables are as described in the first or second embodiment.

[0058] In a fifth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the linker L of formula (A) comprises a 1,2,3-triazolene group formed by reacting an azide-containing precursor with an alkyne-containing precursor, and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0059] In a sixth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, -L- is a group of formula (i), (ii), (iii), (iv), (v), (vi) or (vii):

[0060] [ka] [In the formula, LK 1 is a bond, -NR 16 - or -C(O)-, LK 2 is a bond, -C(O)- or -N(R 16 )-C(O)-CH2 - * and LK 3 is -C(O)- or -N(R 16 )-C(O)-CH 2 - * and LK 4 is a bond or -C(O)-, LK 5 is a bond or -C(O)-, LK 6 is a bond, -C(O)-, -O-CH 2 -C(O)- * , or -N(R 16 )-C(O)-CH 2 - * and LK 7 is a bond or -NR 16 - and LK 8 is a bond, -R 22 -, -OR 22 -or-C(O)-R 22 - and Ring A is C 3 -C 8 Heterocycloalkylene, R 16 is H or methyl, R 17 is C 1 -C 20 Alkylene, C 3-10 Cycloalkylene, C 3-10 Cycloalkylene -CH 2 - ** , phenylene, -C 1 -C 20 Alkylene-OCH 2 CH 2 - ** , -C 1 -C 20 Alkylene-OCH 2 - ** , -CH 2 -(OCH 2 CH 2 ) p -OCH 2 -** or -(CH 2 CH 2 O) p -(C 1 -C 3 -alkylene)- ** where C 1 -C 20 The alkylene or the phenylene may have one or two R 17a and optionally substituted by ** LK 2 indicates the point of attachment to R 17a is, for each occurrence, independently, a straight-chain or branched-chain C 1 -C 6 alkyl or halogen, or two R 17a C, along with the carbon atom to which they are attached 3 -C 6 It forms a cycloalkyl, R 18 is C 1- C 20 Alkylene or -CH 2 CH 2 -(OCH 2 CH 2 ) p - ** where: ** LK 3 indicates the point of attachment to R 19 is C 1 -C 6 is alkylene, R 20 is C 3 -C 10 Cycloalkylene, phenylene, -S- or -N(R 16 )-and R 21 is C 1- C 20 Alkylene or -CH 2 -(OCH 2 CH 2 ) p - ** where: ** LK 6 indicates the point of attachment to R22 is C 1 -C 6 is alkylene, p is an integer from 1 to 7; d is an integer from 1 to 7;

[0061] [ka] is the binding to a Bcl-xL inhibitor compound,

[0062] [ka] is the binding to the DSM, the remaining variables are as described in the first, second, third or second embodiment.

[0063] In a seventh embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, the linker L of formula (A) is of formula (i), (ii), (iii), (iv), (v), or (vi):

[0064] [ka] [In the formula, LK 1 is a bond or -C(O)-, LK 2 is a bond, -C(O)- or -N(R 16 )-C(O)-CH 2 - * and LK 3 is -C(O)- or -N(R 16 )-C(O)-CH 2 - * and LK 4 is a bond or -C(O)-, LK 5 is a bond or -C(O)-, LK 6 is a bond, -O-CH2 -C(O)- * , or -N(R 16 )-C(O)-CH 2 - * and R 16 is H or methyl, R 17 is C 1 -C 20 Alkylene, C 3-10 Cycloalkylene, phenylene, -CH 2 -(OCH 2 CH 2 ) p -OCH 2 - where C 1 -C 15 Alkylene or phenylene is one or two R 17a and optionally substituted by R 17a is, for each occurrence, independently, a straight-chain or branched-chain C 1-6 alkyl or halogen, or two R 17a C, along with the carbon atom to which they are attached 3-6 It forms a cycloalkyl, R 18 is C 1-20 Alkylene or -CH 2 CH 2 -(OCH 2 CH 2 ) p - ** where: ** LK 3 indicates the point of attachment to R 19 is C 1-6 is alkylene, R 20 is C 3-10 Cycloalkylene, phenylene, -S- or -N(R 16 )-and R 21 is C 1-20 Alkylene or -CH 2 -(OCH 2 CH 2 ) p - **where: ** LK 6 indicates the point of attachment to p is an integer from 1 to 7; d is an integer from 1 to 7;

[0065] [ka] is the binding to a Bcl-xL inhibitor compound,

[0066] [ka] is the binding to the DSM, the remaining variables are as described in the first, second, third or fourth embodiment.

[0067] In an eighth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the linker L of formula (A) is

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka]

[0076] [ka]

[0077] [ka]

[0078] [ka] where:

[0079] [ka] is the binding to a Bcl-xL inhibitor compound,

[0080] [ka] is the binding to the DSM, The remaining variables are as described in the first, second, third or fourth embodiment. In some embodiments, the linker L of formula (A) is selected from (L1)-(L50).

[0081] In a ninth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D is a compound of formula (I):

[0082] [ka] [In the formula, ·R 1 and R 2 are each independently hydrogen; hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl; trifluoromethyl; and straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; or R 1 and R 2 together with the carbon atom that carries them, C 3 -C 6 It forms a cycloalkylene group, ·R 3 is hydrogen; C 3 -C 6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0083] [ka] represents a group selected from the group consisting of ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 alkoxy groups); and the groups:

[0084] [ka] represents a group selected from the group consisting of or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a, R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·R c , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0085] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0086] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NRG1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl, halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2-C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0087] [ka] [In the formula, R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; R G5 is a C optionally substituted with a hydrogen atom or 1 to 3 halogen atoms 1 -C6 represents an alkyl group, ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 represents a group selected from the group consisting of alkynyl; halogen; and -CN, ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0088] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from the group consisting of ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 ;

[0089] [ka] represents a group selected from the group consisting of Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0090] [ka] represents a group selected from the group consisting of ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 represents a group selected from the group consisting of alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 alkoxy groups); and the groups:

[0091] [ka] represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2-CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; R 3 and R 8 One of the groups, if present, is covalently attached to the linker such that the valency of the atom is not exceeded by one or more of the substituents attached thereto, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0092] In a tenth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D in formula (A) is a compound of formula (I):

[0093] [ka] [In the formula, ·R 1 and R 2 are each independently hydrogen; hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl;Trifluoromethyl;Straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; or R 1 and R 2 together with the carbon atom that carries them, C 3 -C 6 It forms a cycloalkylene group, ·R 3 is hydrogen; C 3 -C 6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0094] [ka] represents a group selected from ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O-;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 (optionally substituted by an alkoxy group);

[0095] [ka] represents a group selected from or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C8 forming a heterocycloalkyl, ·R c , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0096] [ka] represents a group selected from Het 2 teeth,

[0097] [ka] represents a group selected from A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2, -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0098] [ka] [In the formula, R G4 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; halogen or -CN; ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7,

[0099] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 basis, Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0100] [ka] represents a group selected from Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' aR' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b、 -X' 2 -NR' a R' b、 -NR' c -X' 2 -N 3 and

[0101] [ka] represents a group selected from ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, C 1 -C 6 represents a group selected from alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8Cycloalkylene -CH 2 -R 8 , C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 (optionally substituted by an alkoxy group);

[0102] [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight-chain or branched-chain C 1 -C 6 Alkyl, hydroxyl, -NH 2、optionally substituted with one or two groups selected from oxo or piperidinyl; R 3 and R 8 one of the groups, if present, is covalently attached to the linker such that the valency of the atom is not exceeded by one or more of the substituents attached thereto; the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0103] In an eleventh embodiment of the present disclosure, for the compound of formula (A) in the ninth or tenth embodiment, or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, R 1 is a linear or branched chain C 1 -C 6 is alkyl, R 2 is H, and the remainder of the variables are as described in the ninth or tenth embodiment.

[0104] In a twelfth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D is a compound of formula (II):

[0105] [ka] [In the formula, n=0, 1 or 2, ----- represents a single bond or a double bond, A 4 and A 5 each independently represents a carbon or nitrogen atom; Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 1 is hydrogen; hydroxyl or C 1 -C 6Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl; trifluoromethyl; and straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; ·R 2 represents hydrogen or methyl; ·R 3 is hydrogen; straight or branched chain C 1 -C 4 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0106] [ka] represents a group selected from the group consisting of ·R a and R b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O-;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 alkoxy groups); and the groups:

[0107] [ka] represents a group selected from the group consisting of or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·R c , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R etogether with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0108] [ka] represents a group selected from the group consisting of Het 2 teeth,

[0109] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O)2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl, halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0110] [ka] [In the formula, R G4 is hydrogen, C optionally substituted with 1 to 3 halogen atoms 1 -C 6 C substituted with alkyl, hydroxyl 1 -C 6 Alkyl, C 1 -C 6 C substituted with alkoxy groups 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; R G5 is a C optionally substituted with a hydrogen atom or 1 to 3 halogen atoms 1 -C 6 represents an alkyl group, ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; a group selected from the group consisting of halogen and -CN, ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0111] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 Groups, and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from the group consisting of ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 ;

[0112] [ka] represents a group selected from the group consisting of Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0113] [ka] represents a group selected from the group consisting of ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 represents a group selected from the group consisting of alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, halogen, C1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1-C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 alkoxy groups); and the groups:

[0114] [ka] represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO2 -CH 2 -, -NH-CO-, or -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; R 3 , R 8 and one of the G groups, if present, is covalently attached to the linker such that the valency of the atom is not exceeded by one or more substituents attached thereto, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0115] In a thirteenth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D in formula (A) is a compound of formula (II):

[0116] [ka] [In the formula, n=0, 1 or 2, ----- represents a single bond or a double bond, A 4 and A 5each independently represents a carbon or nitrogen atom; Z 1 represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 1 is hydrogen; hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 3 -C 6 Cycloalkyl;Trifluoromethyl;Straight or branched chain C 1 -C 6 alkylene-heterocycloalkyl, wherein the heterocycloalkyl group is a straight or branched chain C 1 -C 6 is optionally substituted with an alkyl group; ·R 2 represents hydrogen or methyl; ·R 3 is hydrogen; straight or branched chain C 1 -C 4 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -COOR c ;-X 1 -PO(OH) 2 ;-X 1 -SO 2 (OH);-X 1 -N 3 and

[0117] [ka] represents a group selected from ·R a and R bare each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 substituted by alkyl); straight or branched chain C optionally substituted by one or two hydroxyl groups; 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR d R e ;C 1 -C 6 Alkylene-N + R d R e R f ;C 1 -C 6 Alkylene-phenyl, where the phenyl is C 1 -C 6 (optionally substituted by an alkoxy group);

[0118] [ka] represents a group selected from or R a and R b together with the nitrogen atom carrying them, form ring B 1 It is formed, or R a , R b and R c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, ·Rc , R d , R e , R f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R d and R e together with the nitrogen atom carrying them, form ring B 2 It is formed, or R d , R e and R f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Het 1 teeth,

[0119] [ka] represents a group selected from Het 2 teeth,

[0120] [ka] represents a group selected from A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen, C optionally substituted with 1 to 3 halogen atoms, 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6Cycloalkyl, phenyl and -(CH 2 ) 1-4 -phenyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 or alternatively, G is linked to form a heterocycloalkyl;

[0121] [ka] [In the formula, R G4 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl and C 3 -C 6 cycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 Alkyl;C 2 -C 6 Alkenyl; C 2 -C 6 alkynyl; halogen or -CN; ·R 6 teeth, hydrogen, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -C 2 -C 6 Alkenyl, -X 2 -OR 7 ,

[0122] [ka] -X 2 -NSO 2 -R 7 , -C=C(R 9 )-Y 1 -OR 7 , C 3 -C 6 Cycloalkyl, C optionally substituted with a hydroxyl group 3 -C 6 Heterocycloalkyl, C 3 -C 6 Cycloalkylene-Y 2 -R 7 , C 3 -C 6 Heterocycloalkylene-Y 2 -R 7 basis, Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0123] [ka] represents a group selected from Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR'c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b , -X' 2 -NR' a R' b , -NR' c -X' 2 -N 3 and

[0124] [ka] represents a group selected from ·R 9 is a linear or branched chain C 1 -C 6 Alkyl, trifluoromethyl, hydroxyl, halogen, C 1 -C 6 represents a group selected from alkoxy, ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, halogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R8 , C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 is trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 4 represents an alkylene group, X 2 is trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 (optionally substituted by an alkoxy group);

[0125] [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R'd , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, Y 1 is a linear or branched chain C 1 -C 4 represents alkylene, Y 2 is a bond, -O-, -O-CH 2 -, -O-CO-, -O-SO 2 -, -CH 2 -, -CH 2 -O, -CH 2 -CO-, -CH 2 -SO 2 -, -C 2 H 5 -, -CO-, -CO-O-, -CO-CH 2 -,-CO-NH-CH 2 -, -SO 2 -, -SO 2 -CH 2 -, -NH-CO-, -NH-SO 2 - represents m=0, 1 or 2, ·B 1 , B 2 , B 3 and B. 4 are each independently 3 -C 8represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight-chain or branched-chain C 1 -C 6 Alkyl, hydroxyl, -NH 2、 optionally substituted with one or two groups selected from oxo or piperidinyl; R 3 and R 8 one of the groups, if present, is covalently attached to the linker such that the valency of the atom is not exceeded by one or more of the substituents attached thereto; the remaining variables are as described in the first, second, third, fourth or fifth embodiment.

[0126] In a fourteenth embodiment of the present disclosure, the compound of formula (A) of the embodiment, or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, is 4 and A 5 Both represent nitrogen atoms, and R 1 is a straight or branched chain C 1-6 is alkyl, R 2 is H, n is 1, ------- represents a single bond, and the remainder of the variables are as described in the twelfth or thirteenth embodiment.

[0127] In a fifteenth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D is a compound of formula (IA) or (IIA):

[0128] [ka] [In the formula, Z 1 represents a bond or -O-; ·R 3 is hydrogen; C 3 -C6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0129] [ka] represents a group selected from the group consisting of ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from the group consisting of ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, Het 2 teeth,

[0130] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OH, -C(O)OR G3 , -C(O)NRG1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl, -C(O)NR G5 S(O) 2 R G4 , halogen, -NO 2 and -CN, wherein - R G1 , R G2 , R G4 and R G5 each occurrence independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 -C 6 is selected from the group consisting of alkyl, - R G3is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 is alkyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 are linked to form a heterocycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 represents a group selected from the group consisting of alkyl; halogen and -CN, ·R 6 teeth, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -X 2 -OR 7 , and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from the group consisting of ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 ;

[0131] [ka] represents a group selected from the group consisting of Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0132] [ka] represents a group selected from the group consisting of ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i , -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH2 -R 8 represents a group selected from the group consisting of ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O- ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 alkoxy groups); and the groups:

[0133] [ka] represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' etogether with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, m=0, 1 or 2, p=1, 2, 3 or 4, B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl; the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0134] In a sixteenth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D is a compound of formula (IA) or (IIA):

[0135] [ka] [In the formula, Z 1 represents a bond or -O-; ·R 3is hydrogen; C 3 -C 6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0136] [ka] represents a group selected from ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, Het 2 teeth,

[0137] [ka] represents a group selected from A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OH, -C(O)OR G3, -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 -C 6 is selected from the group consisting of alkyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 is alkyl, or R G1 and R G2Each atom, together with the atom to which it is bonded, is C 3 -C 8 are linked to form a heterocycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 represents a group selected from alkyl; halogen or -CN, ·R 6 teeth, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -X 2 -OR 7 , and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 basis, ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0138] [ka] represents a group selected from Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N +R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0139] [ka] represents a group selected from ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R'e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 (optionally substituted by an alkoxy group);

[0140] [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, m=0, 1 or 2, B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight-chain or branched-chain C 1 -C 6 Alkyl, hydroxyl, -NH 2、 and optionally substituted with one or two groups selected from oxo, oxo, or piperidinyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0141] In a seventeenth embodiment of the present disclosure, R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0142] [ka] [Wherein, Cy is C 3 -C 8 represents cycloalkyl, The remaining variables represent groups selected from the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments.

[0143] In an eighteenth embodiment of the present disclosure, R7 teeth,

[0144] [ka] and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth or seventeenth embodiment.

[0145] In a nineteenth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, D is a compound of formula (IB), (IC-1), (IIB) or (IIC-1):

[0146] [ka] [In the formula, With respect to formula (IB) or (IC-1), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0147] [ka] represents a group selected from the group consisting of With respect to formula (IIB) or (IIC-1), Z 1 represents a bond, and R 3 represents hydrogen or Z 1 represents -O-, R 3 -X 1 -NR a R b - represents With respect to formula (IC-1), G is -C(O)OH and -C(O)NR G1 R G2 is selected from the group consisting of With respect to formula (IIC-1), G is -C(O)OH, -C(O)NR G1 R G2 , -C(O)R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl and -C(O)NR G5 S(O) 2 R G4 wherein R G1 , R G2 , R G4 and R G5 each occurrence independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 -C 6 is selected from the group consisting of alkyl, ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from the group consisting of ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 , or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0148] [ka] represents a group selected from the group consisting of ·R 8 is -NR' a R' b ;-O-X' 2 -NR' a R' b ; and -X' 2 -NR' a R' b represents a group selected from the group consisting of ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-NR' d R' e represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 and optionally substituted with one or two groups selected from the group consisting of alkyl, hydroxyl, and oxo. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0149] In a twentieth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, D in formula (A) is a compound of formula (IB), (IC), (IIB) or (IIC):

[0150] [ka]

[0151] [In the formula, With respect to formula (IB) or (IC), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b Rc ;-X 1 -OR c ;-X 1 -N 3 and

[0152] [ka] represents a group selected from With respect to formula (IIB) or (IIC), Z 1 represents a bond, and R 3 represents hydrogen or Z 1 represents -O-, R 3 -X 1 -NR a R b represents ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 , or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0153] [ka] represents a group selected from ·R8 is -NR' a R' b ;-O-X' 2 -NR' a R' b ; and -X' 2 -NR' a R' b represents a group selected from ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-NR' d R' e represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C1 -C 6 represents an alkyl group, B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 optionally substituted with one or two groups selected from alkyl, hydroxyl, and oxo; the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment. Includes.

[0154] In a twenty-first embodiment of the present disclosure, R 6 -X 2 -OR 7 R 7 is the following group:

[0155] [ka] and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0156] In a twenty-second embodiment of the present disclosure, R 6 is a linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7represents a group, R 7 teeth,

[0157] [ka] and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.

[0158] In a twenty-third embodiment of the present disclosure, a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, is 3 is selected from a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 4,4-difluoropiperidin-1-yl group; 3 -C 8 represents a heterocycloalkyl group and the remainder of the variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment.

[0159] In a twenty-fourth embodiment of the present disclosure, a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, is 3 represents a pyrrolidinyl or piperazinyl group, and the remainder of the variables are as described in the twenty-third embodiment.

[0160] In a twenty-fifth embodiment of the present disclosure, a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, is 3 represents a piperazinyl group, and the remainder of the variables are as described in the twenty-third embodiment.

[0161] In a twenty-sixth embodiment of the present disclosure, R 8 teeth,

[0162] [ka] [In the formula,

[0163] [ka] is the bond to the linker, the remaining variables represent a group selected from the group consisting of:

[0164] In a twenty-seventh embodiment of the present disclosure, R 8 teeth,

[0165] [ka] [In the formula,

[0166] [ka] is the bond to the linker, the remaining variables represent groups selected from the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment.

[0167] In a twenty-eighth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof: With respect to formula (IB) or (IC-1), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N 3 and

[0168] [ka] represents a group selected from the group consisting of With respect to formula (IIB) or (IIC-1), Z 1 represents a bond, and R 3 represents hydrogen, With respect to formula (IC-1), G is -C(O)OH and -C(O)N(CH 3 ) 2 is selected from the group consisting of With respect to formula (IIC-1), G is -C(O)NHS(O) 2 H, -C(O)NH 2 , -C(O)NHCH 3 , -C(O)NHC(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , -C(O)OH, and -CH 2 OH; ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 Or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0169] [ka] represents a group selected from the group consisting of ·R 8 is -NR' a R' b ; and -O-X' 2 -NR' a R' b represents a group selected from the group consisting of ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-NR' d R' e represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' eare each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 optionally substituted with one or two groups selected from the group consisting of alkyl, hydroxyl, and oxo; The remaining variables are as described in the nineteenth embodiment.

[0170] In a twenty-ninth embodiment of the present disclosure, for a compound of formula (IB), (IC), (IIB) or (IIC), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the variables are defined as follows: With respect to formula (IB) or (IC), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -N 3 and

[0171] [ka] represents a group selected from With respect to formula (IIB) or (IIC), Z 1 represents a bond, and R 3 represents hydrogen, ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 Or linear or branched chain C 1 -C 6Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0172] [ka] represents a group selected from ·R 8 is -NR' a R' b ; and -O-X' 2 -NR' a R' b represents a group selected from ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-NR' d R' e represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 optionally substituted with one or two groups selected from alkyl, hydroxyl, and oxo; The remaining variables are as described in the twentieth embodiment.

[0173] In a thirtieth embodiment of the present disclosure, a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, is provided comprising: 3 represents a pyrrolidinyl or piperazinyl group, and the remaining variables are as described in the twenty-eighth or twenty-ninth embodiment.

[0174] In a thirty-first embodiment of the present disclosure, a compound of formula (A), (IB), (IC), (IIB), or (IIC), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, is provided comprising: B 3 represents a piperazinyl group, and the remaining variables are as described in the twenty-eighth or twenty-ninth embodiment.

[0175] In a thirty-second embodiment of the present disclosure, R 8 teeth,

[0176] [ka] [In the formula,

[0177] [ka] is the bond to the linker, The remaining variables are as described in the twenty-eighth or twenty-ninth embodiment.

[0178] In a thirty-third embodiment of the present disclosure, R 8 teeth,

[0179] [ka] [In the formula,

[0180] [ka] is the bond to the linker, The remaining variables are as described in the twenty-eighth or twenty-ninth embodiment.

[0181] In a thirty-fourth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, D is attached to L any one of the following:

[0182] [Table 1-1]

[0183] [Table 1-2]

[0184] [Table 1-3]

[0185] [Table 1-4] [In the formula,

[0186] [ka] is the bond to the linker, The remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0187] In a thirty-fifth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, DL of formula (A) is:

[0188] [ka]

[0189] [ka]

[0190] [ka]

[0191] [ka]

[0192] [ka]

[0193]

change

[0194]

change

[0195]

change

[0196]

change

[0197]

change

[0198]

change

[0199]

change

[0200]

change

[0201]

change

[0202]

change

[0203]

change

[0204]

change

[0205]

change

[0206]

change

[0207]

change

[0208]

change

[0209]

change

[0210]

change

[0211]

change

[0212]

change

[0213]

change

[0214] [ka]

[0215] [ka] [In the formula,

[0216] [ka] is the binding to the DSM, The remaining variables are as described in the first embodiment.

[0217] In a thirty-sixth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the DSM of formula (A) is an E3 ligase recognition agent and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment.

[0218] In a thirty-seventh embodiment of the present disclosure, for a compound of Formula (A), or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, the DSM of Formula (A) is a VHL ligand, a thalidomide cereblon binding agent, or an inhibitor of apoptosis (IAP) E3 ligase, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment.

[0219] In a thirty-eighth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, the DSM of formula (A) is attached to L by any one of the following:

[0220] [Table 2-1]

[0221] [Table 2-2] [In the formula,

[0222] [ka] represents a bond to a linker (L), the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0223] In a thirty-ninth embodiment of the present disclosure, for a compound of formula (A), or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof, the DSM is attached to L by one of the following:

[0224] [ka] [In the formula,

[0225] [ka] represents a bond to a linker (L), the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, or thirty-fifth embodiment] or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0226] In a fortieth embodiment, the compound of the disclosure is any one of the compounds in Table 7, or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof.

[0227] The present disclosure also provides pharmaceutical compositions comprising a PROTAC compound described herein (e.g., a compound of the first to twenty-eighth embodiments described above) and a pharma- ceutically acceptable carrier.

[0228] The present disclosure also relates to a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g., a compound of any of the first to twenty-eight embodiments described above) or a pharmaceutical composition thereof.

[0229] In some embodiments, the cancer is a solid tumor or a hematological cancer.

[0230] In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer.

[0231] In some embodiments, the PROTAC compound is administered as a monotherapy.

[0232] In some embodiments, the PROTAC compound is administered as an adjunct to another therapeutic agent or to radiation therapy.

[0233] In some embodiments, the PROTAC compound is administered in an amount effective to sensitize tumor cells to one or more additional therapeutic agents and / or radiation therapy.

[0234] In some embodiments, the methods described above further comprise administering to a subject in need thereof at least one additional therapeutic agent.

[0235] In some embodiments, the additional therapeutic agent is a Bcl-2 inhibitor, a taxane, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor.

[0236] The disclosure also includes PROTAC compounds of formula (A) for use in the methods described above (e.g., methods for treating a subject having or suspected of having cancer). The disclosure also relates to the use of PROTAC compounds of formula (A) for the manufacture of a medicament for treating a subject having or suspected of having cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0237] The disclosed compositions and methods can be more readily understood by reference to the following detailed description.

[0238] Throughout this text, descriptions refer to compositions and methods of using the compositions. Where the disclosure describes or claims features or embodiments related to compositions, such features or embodiments are equally applicable to methods of using the compositions. Similarly, where the disclosure describes or claims features or embodiments related to methods of using the compositions, such features or embodiments are equally applicable to the compositions.

[0239] When a range of values ​​is expressed, the values ​​include embodiments using any specific value within that range. Moreover, reference to values ​​stated in ranges includes each and every value within that range. All ranges are inclusive of their endpoints and can be combined. When values ​​are expressed as approximations, by use of the antecedent "about," it is to be understood that the specific value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of "or" means "and / or," unless the specific context of its use dictates otherwise. All references cited herein are incorporated by reference for all purposes. In the event of a conflict between a reference and the specification, the specification shall control.

[0240] Unless the context of the description dictates otherwise, e.g., where a structure or fragment of a structure is depicted in the absence of a symbol indicating a particular point of attachment(s), it may be used alone or attached to other components of the compound, and such attachment may be in any orientation, e.g., a DSM (degradation signaling moiety) may be attached to a chemical moiety, e.g., a linker, at any suitable point of attachment. However, where indicated, the components of the PROTAC compounds described herein are attached in the orientation shown in the given formula.

[0241] It will be appreciated that certain features of the disclosed compositions and methods are, for clarity, described herein in the context of separate embodiments, and that these features may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are described in the context of a single embodiment may also be provided separately or in any subcombination for brevity.

[0242] As used throughout this application, PROTAC compounds may be identified using a naming convention in the general format of "DSM-linker-Bcl-xL inhibitor compound." By way of example only, if a compound is referred to as "DSM1a-L1-D1a," such compound comprises a DSM designated as DSM1a, a linker designated as L1, and a Bcl-xL inhibitor compound portion designated as D1a. Similar nomenclature may be used to identify components or portions of PROTAC compounds described herein.

[0243] Any formula given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms.Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number.Isotopes that can be incorporated into the compounds of the present disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as: 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, and 36 Cl. Thus, the present disclosure includes compounds incorporating any one or more of the above-mentioned isotopes, including, for example, radioisotopes, e.g., 3 H and 14 C, or non-radioactive isotopes, e.g. 2 H and 13 It should be understood that such isotope-labeled compounds include those in which C is present. 14 C), kinetic reaction experiments (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including, for example, drug or substrate tissue distribution assays, or in radiation treatment of patients. 18F or labeled compounds may be particularly desirable for PET or SPECT experiments. Isotopically labeled compounds can generally be prepared by conventional techniques known to those of skill in the art, e.g., by substituting an appropriate isotopically labeled reagent for a non-labeled reagent previously utilized.

[0244] definition Various terms relating to the described aspects are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein.

[0245] As used herein, the singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise. The terms "being of," "including," and "containing," such as "comprising," "having," and "a chemical formula of," are to be construed as open terms (i.e., meaning "including, but not limited to") unless expressly stated otherwise. Furthermore, whenever "comprising" or another open-ended term is used in an embodiment, it is to be understood that the same embodiment could be more narrowly claimed using the intermediate term "consisting essentially of" or the closed term "consisting of."

[0246] The term "alkyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. 1 -C 6The term "alkyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. 1 -C 6 A non-limiting example of an alkyl group is methyl (C 1 Alkyl), Ethyl (C 2 alkyl), 1-methylethyl (C 3 Alkyl), n-propyl (C 3 Alkyl), isopropyl (C 3 Alkyl), n-Butyl (C 4 Alkyl), Isobutyl (C 4 alkyl), sec-butyl (C 4 alkyl), tert-butyl (C 4 Alkyl), n-pentyl (C 5 Alkyl), isopentyl (C 5 Alkyl), neopentyl (C 5 Alkyl) and Hexyl (C 6 alkyl).

[0247] The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond. 2 -C 6 The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 6 carbon atoms which are attached to the remainder of the molecule by single bonds. 2 -C 6 Non-limiting examples of "alkenyl" groups include ethenyl (C 2 alkenyl), prop-1-enyl (C 3 alkenyl), but-1-enyl (C 4 alkenyl), pent-1-enyl (C 5 alkenyl), pent-4-enyl (C 5 alkenyl), penta-1,4-dienyl (C 5alkenyl), hex-1-enyl (C 6 alkenyl), hex-2-enyl (C 6 alkenyl), hex-3-enyl (C 6 alkenyl), hexa-1-,4-dienyl (C 6 alkenyl), hexa-1-,5-dienyl (C 6 alkenyl) and hexa-2-,4-dienyl (C 6 alkenyl). 2 -C 3 The term "alkenyl," as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having 2 to 3 carbon atoms which are attached to the remainder of the molecule by single bonds. 2 -C 3 Non-limiting examples of "alkenyl" groups include ethenyl (C 2 alkenyl) and prop-1-enyl (C 3 alkenyl).

[0248] The term "alkylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. 1 -C 6 The term "alkylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 6 carbon atoms. 1 -C 6 Non-limiting examples of alkylene groups include methylene (C 1 Alkylene), Ethylene (C 2 Alkylene), 1-methylethylene (C 3 Alkylene), n-propylene (C 3 Alkylene), isopropylene (C 3 Alkylene), n-butylene (C 4 Alkylene), Isobutylene (C 4 Alkylene), sec-butylene (C 4 alkylene), tert-butylene (C 4Alkylene), n-pentylene (C 5 Alkylene), isopentylene (C 5 alkylene), neopentylene (C 5 alkylene), and hexylene (C 6 alkylene).

[0249] The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond. 2 -C 6 The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 6 carbon atoms. 2 -C 6 Non-limiting examples of "alkenylene" groups include ethenylene (C 2 alkenylene), prop-1-enylene (C 3 alkenylene), buta-1-enylene (C 4 alkenylene), pent-1-enylene (C 5 alkenylene), pent-4-enylene (C 5 alkenylene), penta-1,4-dienylene (C 5 alkenylene), hex-1-enylene (C 6 alkenylene), hex-2-enylene (C 6 alkenylene), hex-3-enylene (C 6 alkenylene), hexa-1-,4-dienylene (C 6 alkenylene), hexa-1-,5-dienylene (C 6 alkenylene) and hexa-2-,4-dienylene (C 6 Alkenylene). 2 -C 6 The term "alkenylene," as used herein, refers to a divalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having 2 to 3 carbon atoms. 2 -C 3Non-limiting examples of "alkenylene" groups include ethenylene (C 2 alkenylene) and prop-1-enylene (C 3 alkenylene).

[0250] The term "aryl" as used herein, refers to a phenyl, naphthyl, biphenyl or indenyl group.

[0251] The term "cycloalkyl" as used herein refers to a monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members and can include fused, bridged, or spiro ring systems. Non-limiting examples of fused bicyclic or bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and adamantanyl. Monocyclic C 3 -C 8 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0252] The term "cycloalkylene" refers to a cycloalkyl, as defined herein, having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkyl. Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. Cycloalkylenes of the present disclosure include monocyclic, bicyclic, and tricyclic ring structures.

[0253] The term "haloalkyl" as used herein refers to a straight or branched alkyl chain substituted with one or more halogen groups in place of hydrogen along the hydrocarbon chain. Examples of halogen groups suitable for substitution in a haloalkyl group include fluorine, bromine, chlorine, and iodine. A haloalkyl group can include multiple halogen groups substituted for hydrogen in the alkyl chain, and the halogen groups can be attached to the same carbon or different carbons in the alkyl chain.

[0254] The term "heteroaryl," as used herein, refers to a monocyclic or bicyclic group consisting of 5 to 10 ring members, having at least one aromatic moiety and containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogen).

[0255] The term "heterocycloalkyl" refers to a heterocyclic alkyl group consisting of 3 to 10 ring members, including oxygen, sulfur, SO, SO 2 and nitrogen, and it is understood that the bicyclic group may be fused or spiro. 3 -C 8 Heterocycloalkyl refers to a heterocycloalkyl having from 3 to 8 ring carbon atoms. Heterocycloalkyl can have from 4 to 10 ring members.

[0256] The terms "heteroarylene" and "heterocycloalkylene" refer to divalent heteroaryl and heterocycloalkyl groups, and include heterocyclic groups having bicyclic and tricyclic ring structures.

[0257] As used herein, alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups include optionally substituted straight or branched chain (C 1 -C 6 ) alkyl, optionally substituted straight or branched chain (C 2 -C 6) alkenyl groups, optionally substituted straight or branched chain (C 2 -C 6 ) alkynyl radicals, optionally substituted straight or branched chain (C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 ) alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro, cyano, -C(O)-OR 0 ', -OC(O)-R 0 ', -C(O)-NR 0 'R 0 '', -NR 0 'R 0 '', -(C=NR 0 ')-OR 0 '', linear or branched chain (C 1 -C 6 ) optionally substituted with 1 to 4 groups selected from haloalkyl, trifluoromethoxy, or halogen; R 0 ' and R 0 '' each independently represents a hydrogen atom or an optionally substituted straight or branched chain (C 1 -C 6 ) alkyl group, linear or branched (C 1 -C 6 ) One or more carbon atoms of an alkyl group are optionally deuterated.

[0258] The term "linker," as used herein, refers to a chemical moiety of formula (A) that connects D to the DSM.

[0259] The term "polyoxyethylene," "polyethylene glycol," or "PEG," as used herein, refers to 2 CH 2 In certain embodiments, the polyethylene or PEG group refers to a linear, branched, or star-shaped configuration composed of -(OCH 2 CH 2 ) t *- [wherein t is 1 to 40 or 4 to 40, "-" represents an end toward the self-immolative spacer, * -" is the terminal group R' (where R' is OH, OCH 3 or OCH 2 CH 2 In another embodiment, the polyethylene or PEG group is -(CH 2 CH 2 O) t * - [wherein t is 1 to 40 or 4 to 40, "-" represents an end toward the self-immolative spacer, * -" is the terminal group R'' (where R'' is H, CH 3 or CH 2 CH 2 For example, the term "PEG12" as used herein means that t is 12.

[0260] The term "polyalkylene glycol" as used herein means (O(CH 2 ) m ) n In certain embodiments, the polyethylene or PEG group is a -(O(CH 2 ) m ) t * - (wherein m is 1 to 10, t is 1 to 40 or 4 to 40, and "-" indicates the end toward the self-immolative spacer, * -" is the terminal group R' (where R' is OH, OCH 3 or OCH 2 CH 2 In another embodiment, the polyethylene or PEG group is -((CH 2 ) m O) t * - [wherein m is 1 to 10, t is 1 to 40 or 4 to 40, and "-" represents an end toward the self-immolative spacer, * -" is the terminal group R'' (where R'' is H, CH3 or CH 2 CH 2 C(=O)OH).

[0261] The term "about" or "approximately," when used in the context of numerical values ​​and ranges, refers to a value or range that is close or proximate to the recited value or range, as would be apparent to one of ordinary skill in the art from the teachings contained herein, thereby allowing the embodiment to be performed as intended. In some embodiments, "about" means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of the numerical amount. In one embodiment, the term "about" refers to a range of values ​​that is 10% greater or less than the specified value. In another embodiment, the term "about" refers to a range of values ​​that is 5% greater or less than the specified value. In another embodiment, the term "about" refers to a range of values ​​that is 1% greater or less than the specified value.

[0262] The term "agent" is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological material, or a combination of two or more of these. The term "therapeutic agent" or "drug" refers to an agent capable of modulating a biological process and / or biological activity. Bcl-xL inhibitors and PROTAC compounds, including those described herein, are exemplary therapeutic agents.

[0263] The term "chemotherapeutic agent" or "anti-cancer agent" is used herein to refer to any agent effective in treating cancer (regardless of mechanism of action). Inhibition of metastasis or angiogenesis is often a property of chemotherapeutic agents. Chemotherapeutic agents include antibodies, biological molecules, and small molecules, including Bcl-xL inhibitors and DSM conjugates containing same, as described herein. Chemotherapeutic agents may be cytotoxic or cytostatic agents. The term "cytostatic agent" refers to an agent that inhibits or suppresses cell growth and / or proliferation of cells. The term "cytotoxic agent" refers to a substance that causes cell death, primarily by interfering with the expression activity and / or function of a cell.

[0264] The terms "PROTAC conjugate", "PROTAC compound", "PROTAC degrader", "DSM-drug conjugate", "DSM conjugate", "Bcl-degradation conjugate", "Bcl-xL degrading compound", "bifunctional Bcl-xL degrading compound", and "compound" are used interchangeably and refer to one or more therapeutic compounds (e.g., Bcl-xL inhibitors) that are covalently attached to a DSM, e.g., an E3 ubiquitin ligase recruitment ligand. In some embodiments, PROTAC compounds are defined by the general formula: DL-DSM (Formula (A)), where DSM=degradation signaling moiety, L=linker moiety, and D=drug moiety (e.g., Bcl-xL inhibitor drug moiety).

[0265] The terms "degradation signaling moiety" and "DSM" are used herein to refer to a degradation signaling compound, or moiety derived therefrom, that induces degradation of a targeted protein, e.g., Bcl-xL. DSMs of the present disclosure degrade a target protein by binding to or recruiting at least one degradative protein, which is typically associated with the proteasome, the ubiquitin-proteasome pathway, or lysosomal protein degradation. DSMs of the present disclosure include, but are not limited to, E3 ligase-recognizing or recruiting ligands.

[0266] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, alone or in combination with an E2 ubiquitin conjugating enzyme, causes the attachment of ubiquitin to lysines on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome.

[0267] The term "B-cell lymphoma-extra-large" or "Bcl-xL" as used herein refers to any naturally occurring form of human Bcl-xL, i.e., an anti-apoptotic member of the Bcl-2 protein family. The term encompasses full-length human Bcl-xL (e.g., UniProt Reference Sequence: Q07817-1; SEQ ID NO: 71), as well as any form of human Bcl-xL that may result from cellular processing. The term also encompasses functional variants or fragments of human Bcl-xL, including, but not limited to, splice variants, allelic variants, and isoforms that retain one or more biological functions of human Bcl-xL (i.e., variants and fragments are included unless the context indicates that the term is being used to refer only to the wild-type protein). Bcl-xL can be isolated from humans or can be produced by recombinant or synthetic methods.

[0268] The terms "inhibit" or "inhibition" or "inhibiting" as used herein means to decrease a biological activity or process by a measurable amount, which can include, but does not necessarily include, complete prevention or inhibition. In some embodiments, "inhibition" refers to decreasing the expression and / or activity of Bcl-xL and / or one or more upstream modulators or downstream targets thereof.

[0269] The term "Bcl-xL inhibitor", as used herein, refers to an agent capable of decreasing the expression and / or activity of Bcl-xL and / or one or more of its upstream modulators or downstream targets. Exemplary Bcl-xL modulators (including exemplary Bcl-xL inhibitors) are described in WO 2010 / 080503, WO 2010 / 080478, WO 2013 / 055897, WO 2013 / 055895, WO 2016 / 094509, WO 2016 / 094517, WO 2016 / 094505, Tao et al., ACS Medicinal Chemistry Letters (2014), 5(10), 1088-109, and Wang et al., ACS Medicinal Chemistry Letters (2020), 11(10), 1829-1836, each of which is incorporated herein by reference as exemplary Bcl-xL modulators, including exemplary Bcl-xL inhibitors that can include as a drug moiety a PROTAC compound described herein.

[0270] As used herein, "Bcl-xL inhibitor drug moiety," "Bcl-xL inhibitor moiety," and the like, refer to a component of a PROTAC compound described herein that provides a structure for a Bcl-xL inhibitor compound or a modified compound for binding to a DSM that retains essentially the same, similar, or enhanced biological function or activity compared to the original compound. In some embodiments, the Bcl-xL inhibitor drug moiety is component (D) of the compound of formula (A).

[0271] The term "cancer" as used herein refers to the presence of cells that possess characteristics typical of cancer cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and / or certain morphological characteristics. Often, cancer cells can be in the form of a tumor or mass, but such cells may be present alone in a subject or circulating in the bloodstream as independent cells, e.g., leukemia or lymphoma cells. The term "cancer" includes all types of cancer and cancer metastasis, including blood cancers, solid tumors, sarcomas, carcinomas, and other solid and non-solid tumor cancers. Blood cancers may include B-cell malignancies, cancers of the blood (leukemias), cancers of plasma cells (myelomas, e.g., multiple myeloma), or cancers of the lymph nodes (lymphomas). Exemplary B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. Lymphomas include Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc. Other hematological cancers include myelodysplastic syndrome (MDS). Solid tumors include carcinomas, such as adenocarcinomas, such as breast cancer, pancreatic cancer, prostate cancer, colon or rectal cancer, lung cancer, gastric cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, glioma, melanoma, etc. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0272] As used herein, the term "tumor" refers to any mass of tissue resulting from excessive cell growth or proliferation, either benign or malignant, including precancerous lesions. In some embodiments, the tumor is breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the tumor is gastric cancer.

[0273] The terms "tumor cell" and "cancer cell" may be used interchangeably herein and refer to individual cells or entire populations of cells derived from a tumor or cancer, including both non-tumorigenic cells and cancer stem cells. When the terms "tumor cell" and "cancer cell" refer only to those cells that lack the ability to reproduce and differentiate, they are modified with the term "non-tumorigenic" to distinguish these cells from cancer stem cells.

[0274] The terms "subject" and "patient" are used interchangeably herein to refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is a human.

[0275] The term "subject in need of treatment," as used herein, refers to a subject who would benefit biologically, medically, or in quality of life from treatment (e.g., treatment with any one or more of the exemplary compounds described herein).

[0276] As used herein, the terms "treat", "treating" or "treatment" refer to any improvement in any outcome of a disease, disorder or condition, e.g., increased survival time, decreased morbidity, and / or reduced side effects resulting from alternative therapeutic modalities. In some embodiments, treatment includes delaying or reversing a disease, disorder or condition (i.e., slowing or stopping or reducing the progression of a disease or at least one of its clinical symptoms). In some embodiments, treatment includes delaying, alleviating, or reversing at least one physical parameter of a disease, disorder, or condition, including those that may not be discernible by the patient. In some embodiments, treatment includes modulating a disease, disorder, or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In some embodiments, treatment includes administering a compound or composition as described to a subject, e.g., a patient, to obtain the benefits of the treatments listed herein. Treatment can cure, repair, alleviate, delay, prevent, relieve, alter, relieve, ameliorate, ameliorate, or affect a disease, disorder, or condition (e.g., cancer), a symptom of a disease, disorder, or condition (e.g., cancer), or a predisposition to a disease, disorder, or condition (e.g., cancer). In some embodiments, in addition to treating a subject having a disease, disorder, or condition, the compositions disclosed herein can also be provided to prophylactically prevent or reduce the likelihood of developing the disease, disorder, or condition.

[0277] As used herein, the terms "prevent" a disease, disorder, or condition, "preventing" a disease, disorder, or condition, or "prevention" of a disease, disorder, or condition refer to prophylactic treatment of a disease, disorder, or condition, or delaying the onset or progression of a disease, disorder, or condition.

[0278] As used herein, a "pharmaceutical composition" refers to a composition, e.g., a preparation of a compound or composition to which at least one other (and optionally more than one other) component, e.g., a pharma- ceutically acceptable carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient, is added, suitable for administration to a subject. The pharmaceutical compositions provided herein are in a form that allows for administration and subsequently results in the intended biological activity of the active ingredient(s) and / or achieves a therapeutic effect. The pharmaceutical compositions provided herein preferably do not contain any additional components that are unacceptably toxic to the subject to whom the formulation is administered.

[0279] As used herein, the terms "pharmaceutical acceptable carrier" and "physiologically acceptable carrier" can be used interchangeably and refer to a carrier or diluent that does not cause significant irritation to a subject and does not negate the biological activity and properties of the administered compound or composition and / or any additional therapeutic agent within the composition. A pharmaceutical acceptable carrier can enhance or stabilize a composition or can be used to facilitate preparation of the composition. Pharmaceutically acceptable carriers can include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. Carriers can be selected to minimize adverse side effects in the subject and / or to minimize degradation of the active ingredient(s). Adjuvants may also be included in any of these formulations.

[0280] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Formulations for parenteral administration can contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated napthalenes. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, ethylene-vinyl acetate copolymer particles, and surfactants including, for example, polysorbate 20.

[0281] The term "pharmaceutically acceptable salt" as used herein refers to a salt that does not cancel the biological activity and properties of the compound of the present disclosure and does not cause significant irritation to the subject to which it is administered.Examples of such salts include, but are not limited to: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, etc.; and (b) salts formed with anions of elements, such as chlorine, bromine, and iodine. See, e.g., Haynes et al., "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database," J. Pharmaceutical Sciences, vol. 94, no. 10 (2005) and Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, vol. 66, no.1 (1977), which are incorporated by reference herein.

[0282] In some embodiments, depending on their electronic charge, the PROTAC compounds, linkers, Bcl-xL inhibitors and linker-Bcl-xL inhibitors described herein may be coupled to a monovalent anionic counterion M 1 - Any suitable anionic counterion can be used. In certain embodiments, the monovalent anionic counterion is a pharma- ceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic counterion M 1 - can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, etc. In some embodiments, the monovalent anionic counterion M 1 - is trifluoroacetate or formate.

[0283] As used herein, the term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of a compound described herein, e.g., a PROTAC compound or composition described herein, that achieves a desired therapeutic outcome (i.e., reduction or inhibition of enzyme or protein activity, amelioration of symptoms, alleviation of a symptom or condition, delaying disease progression, reduction in tumor size, inhibition of tumor growth, prevention of metastasis).

[0284] In some embodiments, a therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically effective amount induces or causes side effects, but only those side effects that are tolerable by the attending clinician, taking into account the patient's condition. In some embodiments, a therapeutically effective amount is effective to detectably kill, reduce, and / or inhibit the growth or spread of cancer cells, the size or number of tumors, and / or other measures of the level, stage, progression, and / or severity of cancer. This term also applies to a dose that induces a specific response in target cells, such as a reduction, slowing, or inhibition of cell growth.

[0285] The therapeutically effective amount can be determined by administering a low dose initially and then gradually increasing the dose until the desired effect is achieved. The therapeutically effective amount can also vary depending on the intended use (in vitro or in vivo), or the subject and condition being treated, such as the subject's weight and age, the severity of the condition, the mode of administration (which can be easily determined by one of ordinary skill in the art), etc. The specific amount can vary depending, for example, on the specific pharmaceutical composition, the subject and the subject's age and existing health condition or risk to health condition, the subsequent administration regimen, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system to which it is delivered. In the case of cancer, a therapeutically effective amount of a PROTAC compound can reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or alleviate one or more symptoms.

[0286] As used herein, the term "prophylactically effective amount" or "prophylactically effective dose" refers to an amount of a compound disclosed herein, e.g., a PROTAC compound or composition described herein, effective at a dosage and for a period of time necessary to achieve a desired prophylactic result. Typically, a prophylactically effective amount is lower than a therapeutically effective amount, since a prophylactic dose is used in a subject prior to or at an early stage of disease. In some embodiments, a prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with cancer.

[0287] PROTAC compounds The PROTAC compounds disclosed herein include those that have anti-cancer activity. In particular, the PROTAC compounds include a degradation signaling moiety (DSM) conjugated (i.e., covalently attached by a linker) to a drug moiety (e.g., a Bcl-xL inhibitor), which has cytotoxic or cytostatic activity when not conjugated to a DSM. In some embodiments, when not conjugated to a DSM, the drug moiety is capable of decreasing the expression and / or activity of Bcl-xL and / or one or more of its upstream modulators or downstream targets. By targeting the expression and / or activity of Bcl-xL, in some embodiments, the PROTAC compounds disclosed herein can provide potent anti-cancer agents. Also, without being bound by theory, by conjugating the drug moiety to a DSM that binds to an E3 ubiquitin ligase, the PROTAC compounds can have improved activity, improved cytotoxic specificity, and / or reduced off-target killing compared to the drug moiety when administered alone.

[0288] Thus, in some embodiments, the components of the PROTAC compound are selected to (i) retain one or more therapeutic properties exhibited by the isolated DSM, (ii) maintain the specific binding properties of the DSM; (iii) enable delivery of the drug moiety, e.g., intracellular delivery, via stable binding to the DSM; (iv) maintain the stability of the PROTAC compound as an intact compound until transported or delivered to the target site; (v) enable the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage or other release mechanism within the cellular environment; (vi) exhibit anti-cancer treatment efficacy in vivo that is comparable to or exceeds that of the isolated DSM and drug moiety; (vii) minimize off-target killing by the drug moiety; and / or (viii) exhibit desirable pharmacokinetic and pharmacodynamic properties, suitability for formulation, and toxicological / immunological profile. Each of these properties can provide a PROTAC compound for therapeutic use (Ab et al. (2015) Mol Cancer Ther. 14:1605-13).

[0289] In certain aspects, provided herein are PROTAC compounds that include a degradation signaling moiety (DSM), a Bcl-xL inhibitor drug moiety (D), and a linker moiety (L) covalently linking the DSM to D.

[0290] In some embodiments, the PROTAC compounds of the present disclosure include Formula (A): DL-DSM(A), where DSM is a degradation signaling compound covalently attached to a linker L, L is a linker covalently attaching DSM to D, and D is a Bcl-xL inhibitor compound covalently attached to the linker. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0291] 1. Bcl-xL inhibitors In some embodiments, the Bcl-xL inhibitor compound (D) of formula (A) is represented by formula (I) or formula (II):

[0292] [ka] wherein the definitions of the variables shown in formulas (I) and (II) are described above (e.g., in the first or second embodiment). or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0293] In some embodiments, the Bcl-xL inhibitor compound (D) is 1 Is a straight or branched chain C 1 -C 6 is alkyl, R 2 is H, and the remaining variables are as described above for formula (I), or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0294] In some embodiments, the Bcl-xL inhibitor compound (D) is 4 and A 5 Both represent nitrogen atoms, and R 1 Is a straight or branched chain C 1-6 is alkyl, R 2 is H, n is 1, --- in formula (II) represents a single bond, and the remaining variables are as described above for formula (II), or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0295] In some embodiments, the Bcl-xL inhibitor compound (D) has formula (IA) or (IIA):

[0296] [ka]

[0297] [In the formula, Z 1 represents a bond or -O-; ·R 3 is hydrogen; C 3 -C 6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0298] [ka] represents a group selected from the group consisting of ¨R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from the group consisting of ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, Het 2 teeth,

[0299] [ka] represents a group selected from the group consisting of A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A2 is N, CH or C(R 5 ) and G is -C(O)OH, -C(O)OR G3 , -C(O)NR G1 R G2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl, -C(O)NR G5 S(O) 2 R G4 , halogen, -NO 2 and -CN, wherein - R G1 , R G2 , R G4 and R G5each occurrence independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 -C 6 is selected from the group consisting of alkyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 is alkyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C 8 are linked to form a heterocycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 represents a group selected from the group consisting of alkyl; halogen and -CN, ·R 6 teeth, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -X 2 -OR 7 , and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from the group consisting of ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 ;

[0300] [ka] represents a group selected from the group consisting of Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R' b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b ;-NR' c -X' 2 -N 3 and

[0301] [ka] represents a group selected from the group consisting of ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i , -CH=CH-C 1 -C 4 Alkylene-NR h R i, -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , and C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from the group consisting of ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R' e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 alkoxy groups); and the groups:

[0302] [ka] represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' fare each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, m=0, 1 or 2, p=1, 2, 3 or 4, B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2 , oxo and piperidinyl. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0303] In some embodiments, the Bcl-xL inhibitor compound (D) has formula (IA) or (IIA):

[0304] [ka] [In the formula, Z 1 represents a bond or -O-; ·R 3 is hydrogen; C 3 -C6 Cycloalkyl; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0305] [ka] represents a group selected from ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, Het 2 teeth,

[0306] [ka] represents a group selected from A 1 -NH-, -N(C 1 -C 3 alkyl), O, S or Se; A 2 is N, CH or C(R 5 ) and G is -C(O)OH, -C(O)OR G3 , -C(O)NR G1 RG2 , -C(O)R G2 , -NR G1 C(O)R G2 , -NR G1 C(O)NR G1 R G2 , -OC(O)NR G1 R G2 , -NR G1 C(O)OR G3 , -C(=NOR G1 )NR G1 R G2 , -NR G1 C(=NCN)NR G1 R G2 , -NR G1 S(O) 2 NR G1 R G2 , -S(O) 2 R G3 , -S(O) 2 NR G1 R G2 , -NR G1 S(O) 2 R G2 , -NR G1 C(=NR G2 )NR G1 R G2 , -C(=S)NR G1 R G2 , -C(=NR G1 )NR G1 R G2 , halogen, -NO 2 and -CN, wherein - R G1 and R G2 each occurrence independently represents hydrogen and C optionally substituted with 1 to 3 halogen atoms; 1 -C 6 is selected from the group consisting of alkyl, - R G3 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 is alkyl, or R G1 and R G2 Each atom, together with the atom to which it is bonded, is C 3 -C8 are linked to form a heterocycloalkyl; ·R 4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group, ·R 5 is C optionally substituted with 1 to 3 halogen atoms 1 -C 6 represents a group selected from alkyl; halogen or -CN, ·R 6 teeth, Linear or branched chain-C 1 -C 6 Alkylene-R 8 basis, -X 2 -OR 7 , and Linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 base represents a group selected from ·R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0307] [ka] represents a group selected from Cy is C 3 -C 8 represents cycloalkyl, ·R 8 is hydrogen; straight or branched chain C 1 -C 6 Alkyl, -NR' a R' b ;-NR' a -CO-OR' c ;-NR' a -CO-R' c ;-N + R' a R'b R' c ;-O-R' c ;-NH-X' 2 -N + R' a R' b R' c ;-O-X' 2 -NR' a R' b ;-X' 2 -NR' a R' b :-NR' c -X' 2 -N 3 and

[0308] [ka] represents a group selected from ·R 10 is hydrogen, fluorine, chlorine, bromine, -CF 3 and methyl, ·R 11 is hydrogen, C 1 -C 3 Alkylene-R 8 , -OC 1 -C 3 Alkylene-R 8 , -CO-NR h R i and -CH=CH-C 1 -C 4 Alkylene-NR h R i , -CH=CH-CHO, C 3 -C 8 Cycloalkylene -CH 2 -R 8 , C 3 -C 8 Heterocycloalkylene-CH 2 -R 8 represents a group selected from ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15each independently represents a hydrogen atom or a methyl group, or R 14 and R 15 together with the carbon atom carrying them form a cyclohexyl, ·R h and R i are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; heterocycloalkyl; -SO 2 -phenyl, wherein the phenyl is a straight or branched chain C 1 -C 6 1 or 2 hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-SO 2 OH;C 1 -C 6 Alkylene-SO 2 O - ;C 1 -C 6 Alkylene-COOH;C 1 -C 6 Alkylene-PO(OH) 2 ;C 1 -C 6 Alkylene-NR' d R'e ;C 1 -C 6 Alkylene-N + R' d R' e R' f ;C 1 -C 6 Alkylene-OC 1 -C 6 Alkylene-OH;C 1 -C 6 Alkylene-phenyl, where the phenyl is hydroxyl or C 1 -C 6 (optionally substituted by an alkoxy group);

[0309] [ka] represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, or R' a , R' b and R' c are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, R' c , R' d , R' e , R' f are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, or R' d and R' e together with the nitrogen atom carrying them, form ring B 4 It is formed, or R' d , R' e and R' f are linked together with the nitrogen atom carrying them to form bridged C 3 -C 8 forming a heterocycloalkyl, m=0, 1 or 2, B 3 and B. 4 are each independently 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; (iii) can be selected from fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 Alkyl, hydroxyl, -NH 2、 and optionally substituted with one or two groups selected from oxo and piperidinyl. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0310] In some embodiments, with respect to formula (I), (II), (IA), or (IIA), R 7 is a linear or branched chain C 1 -C 6 Alkyl group; (C 3 -C 6 ) Cycloalkylene-R 8 or

[0311] [ka] represents a group selected from Cy is C 3 -C 8 It represents cycloalkyl.

[0312] In some embodiments, with respect to formula (I), (II), (IA), or (IIA), R 7 teeth,

[0313] [ka] represents a group selected from

[0314] In some embodiments, the Bcl-xL inhibitor compound (D) has formula (IB), (IC-1), (IIB) or (IIC-1):

[0315] [ka] [In the formula, With respect to formula (IB) or (IC-1), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0316] [ka] represents a group selected from the group consisting of With respect to formula (IIB) or (IIC-1), Z 1 represents a bond, and R 3 represents hydrogen or Z 1 represents -O-, R 3 -X 1 -NR a R b represents With respect to formula (IC-1), G is -C(O)OH and -C(O)NR G1 R G2 is selected from the group consisting of With respect to formula (IIC-1), G is -C(O)OH, -C(O)NR G1 R G2 , -C(O)R G2 , optionally substituted with a hydroxyl group -C 1 -C 6 Alkyl and -C(O)NR G5 S(O) 2 R G4wherein R G1 , R G2 , R G4 and R G5 each occurrence independently represents C optionally substituted with hydrogen and 1 to 3 halogen atoms; 1 -C 6 is selected from the group consisting of alkyl, ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from the group consisting of ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 , or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0317] [ka] represents a group selected from the group consisting of ·R 8 is -NR' a R' b ;-O-X' 2 -NR' a R' b ; and -X' 2 -NR' a R' b represents a group selected from the group consisting of ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-NR' d R' e represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, B 3 is C 3 -C 8represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 and optionally substituted with one or two groups selected from the group consisting of alkyl, hydroxyl, and oxo. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0318] In some embodiments, the Bcl-xL inhibitor compound (D) has formula (IB), (IC), (IIB) or (IIC):

[0319] [ka] [In the formula, With respect to formula (IB) or (IC), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N + R a R b R c ;-X 1 -OR c ;-X 1 -N 3 and

[0320] [ka] With respect to formula (IIB) or (IIC), Z 1 represents a bond, and R 3 represents hydrogen or Z 1 represents -O-, R 3 -X 1 -NR a R b represents ·R a and R b are each independently hydrogen; a straight or branched chain C optionally substituted with one or two hydroxyl groups; 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-SO 2 O - represents a group selected from ·R c is hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 , or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0321] [ka] represents a group selected from ·R 8 is -NR' a R' b ;-O-X' 2 -NR' a R' b ; and -X' 2 -NR' a R' b represents a group selected from ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-NR' d R' e represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 optionally substituted with one or two groups selected from alkyl, hydroxyl, and oxo; or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt thereof.

[0322] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), R 6 -X 2 -OR 7 R 7 is the following group:

[0323] [ka] Represents.

[0324] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), R 6 is a linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, R 7 teeth

[0325] [ka] represents a group selected from

[0326] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), B 3 is selected from a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 4,4-difluoropiperidin-1-yl group; 3 -C 8 represents a heterocycloalkyl group.

[0327] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), B 3 represents a pyrrolidinyl group or a piperazinyl group.

[0328] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), B 3 represents a piperazinyl group.

[0329] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), R 8 teeth,

[0330] [ka] [In the formula,

[0331] [ka] represents a group selected from the group consisting of:

[0332] In some embodiments, with respect to formula (I), (II), (IA), (IIA), (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), R 8 teeth,

[0333] [ka] [In the formula,

[0334] [ka] represents a group selected from:

[0335] In some embodiments, R8 teeth,

[0336] [ka] [In the formula,

[0337] [ka] represents a group selected from:

[0338] In some embodiments, the Bcl-xL inhibitor compound (D) is represented by formula (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), With respect to formula (IB) or (IC-1), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -NR a R b ;-X 1 -N 3 and

[0339] [ka] represents a group selected from the group consisting of With respect to formula (IIB) or (IIC-1), Z 1 represents a bond, and R 3 represents hydrogen, With respect to formula (IC-1), G is -C(O)OH and -C(O)N(CH 3 ) 2 is selected from the group consisting of With respect to formula (IIC-1), G is -C(O)NHS(O) 2 H, -C(O)NH 2 , -C(O)NHCH 3 , -C(O)NHC(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , -C(O)OH, and -CH 2 OH; ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 Or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0340] [ka] represents a group selected from the group consisting of ·R 8 is -NR' a R' b ; and -O-X' 2 -NR' a R' b represents a group selected from the group consisting of ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy 1 -C 6 represents an alkylene group, ·X' 2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' bare each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl; and C 1 -C 6 Alkylene-NR' d R' e represents a group selected from the group consisting of or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 and optionally substituted with one or two groups selected from the group consisting of alkyl, hydroxyl, and oxo. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0341] In some embodiments, the Bcl-xL inhibitor compound (D) is represented by formula (IB), (IIB), (IC), (IC-1), (IIC) or (IIC-1), With respect to formula (IB) or (IC), R 3 is hydrogen; straight or branched chain C 1 -C 6 Alkyl;-X 1 -N 3 and

[0342] [ka] represents a group selected from With respect to formula (IIB) or (IIC), Z 1 represents a bond, and R 3 represents hydrogen, ·R 6 -C 1 -C 6 Alkylene-R 8 group, -X 2 -OR 7 Or linear or branched chain C 1 -C 6 Heteroarylene optionally substituted with an alkyl group -R 7 represents a group, ·R 7 teeth,

[0343] [ka] represents a group selected from ·R 8 is -NR' a R' b ; and -O-X' 2 -NR' a R' b represents a group selected from ·R 10 represents fluorine, ·R 12 and R 13 each independently represents a hydrogen atom or a methyl group; ·R 14 and R 15 each independently represents a hydrogen atom or a methyl group; X 1 and X 2 are each independently trifluoromethyl, hydroxyl, halogen, C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 6 represents an alkylene group, ·X'2 is a linear or branched chain C 1 -C 6 represents alkylene, R' a and R' b are each independently hydrogen; one or two hydroxyl or C 1 -C 6 Linear or branched chain C optionally substituted with alkoxy groups 1 -C 6 Alkyl;C 1 -C 6 Alkylene-NR' d R' e represents a group selected from or R' a and R' b together with the nitrogen atom carrying them, form ring B 3 It is formed, R' d , R' e are each independently hydrogen or a straight or branched chain C 1 -C 6 represents an alkyl group, ·B 3 is C 3 -C 8 represents a heterocycloalkyl group, which (i) can be a monocyclic or bicyclic group, including fused, bridged or spiro ring systems; (ii) can contain, in addition to the nitrogen atom, one or two heteroatoms independently selected from oxygen and nitrogen; (iii) can be any of fluorine, bromine, chlorine, straight or branched chain C 1 -C 6 and optionally substituted with one or two groups selected from alkyl, hydroxyl, and oxo. or any one of its enantiomers, diastereoisomers, and / or pharma- ceutically acceptable salts.

[0344] In some embodiments, the Bcl-xL inhibitor compound (D) comprises Bcl-xL inhibitors known in the art, such as ABT-737 and ABT-263.

[0345] In some embodiments, D represents a Bcl-xL inhibitor covalently attached to a linker L, wherein the Bcl-xL inhibitor is selected from the compounds of Table 1, or enantiomers, diastereomers and / or pharma-ceutically acceptable salts thereof.

[0346] [Table 3-1]

[0347] [Table 3-2]

[0348] [Table 3-3]

[0349] [Table 3-4]

[0350] In some embodiments, D is selected from the formulas in Table 2:

[0351] [ka] represents a bond to a linker (L)], or an enantiomer, diastereomer, and / or a pharma- ceutically acceptable salt thereof.

[0352] [Table 4-1]

[0353] [Table 4-2]

[0354] [Table 4-3]

[0355] [Table 4-4]

[0356] 2. Linker In some embodiments, a bifunctional linker compound can be used to covalently link a degradation signaling compound to a Bcl-xL inhibitor drug compound to form a PROTAC compound of the present disclosure, comprising a degradation signaling moiety (DSM) and a Bcl-xL inhibitor drug moiety (D). The bifunctional linker compound has a reactive group at one end that can react with a Bcl-xL inhibitor compound and another reactive group at the other end that can react with a degradation signaling compound. In some embodiments, the bifunctional linker compound reacts with a drug moiety (e.g., a Bcl-xL inhibitor) under appropriate conditions. The product of the reaction, the drug-linker compound, is then reacted with a degradation signaling compound under conditions to form a PROTAC compound of the present disclosure. Alternatively, the linker compound can first react with a degradation signaling compound to form a linker-DSM compound, which can then be reacted with a drug to obtain a PROTAC compound of the present disclosure.

[0357] In some embodiments, when the Bcl-xL inhibitor compound is linked to the linker compound by a reactive azide or alkyne group, the resulting triazole group is considered to be part of L. In some embodiments, the Bcl-xL inhibitor compound is -NR' c -X' 2 -N 3 or

[0358] [ka] In the case where the compound contains a triazole group, this compound can react with an alkyne or azide group of the linker compound to form a triazole group, which is considered to be part of the linker moiety L.

[0359] In some embodiments, the linker (L) is 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy 1 -C 20 Alkylene;C 3 -C 10 Cycloalkylene; C 3 -C 8 Heterocycloalkylene; -C(O)-; -O-; -S-; -N(R 16 )-;-N(R 16 )-C(O)-;-C(O)-N(R 16 )-;-CH 2 -C(O)-N(R 16 )-;-N(R 16 )-C(O)-CH 2 -; polyoxyethylene (PEG) group; C 1 -C 8 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 arylene groups optionally substituted with one or two groups selected from the group consisting of alkoxy; and heteroarylene groups, wherein R 16 is hydrogen or C 1 -C 6 Represents alkyl.

[0360] In some embodiments, the linker (L) is 1 -C 8 Alkyl, C 3 -C 8 Cycloalkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 A straight or branched chain C optionally substituted with one or two groups selected from alkoxy 1 -C 20 Alkylene;C3 -C 10 Cyclo-alkylene; -C(O)-; -O-; -S-; -N(R 16 )-;-N(R 16 )-C(O)-;-C(O)-N(R 16 )-;-CH 2 -C(O)-N(R 16 )-;-N(R 16 )-C(O)-CH 2 -; polyoxyethylene (PEG) group; C 1 -C 8 Alkyl, trifluoromethyl, hydroxyl, halogen, and C 1 -C 6 arylene groups optionally substituted with one or two groups selected from alkoxy; and heteroarylene groups, wherein R 16 is hydrogen or C 1 -C 6 Represents alkyl.

[0361] In some embodiments, the linker (L) comprises a 1,2,3-triazolene group formed by reacting an azide-containing precursor with an alkyne-containing precursor.

[0362] In some embodiments, the linker (L) has the formula (i):

[0363] [ka] [In the formula, LK 1 is a bond, -NR 16 - or -C(O)-, LK 2 is a bond, -C(O)- or -N(R 16 )-C(O)-CH 2 - * and R 16 is H or methyl, R 17 is C 1 -C 20 Alkylene, C 3-10 Cycloalkylene, C 3-10 Cycloalkylene -CH 2 - **, phenylene, -C 1 -C 20 Alkylene-OCH 2 CH 2 - ** , -C 1 -C 20 Alkylene-OCH 2 - ** , -CH 2 -(OCH 2 CH 2 ) p -OCH 2 - ** or -(CH 2 CH 2 O) p -(C 1 -C 3 -alkylene)- ** where C 1 -C 20 The alkylene or the phenylene may have one or two R 17a and optionally substituted by ** LK 2 indicates the point of attachment to R 17a is, for each occurrence, independently, a straight-chain or branched-chain C 1 -C 6 alkyl or halogen, or two R 17a C, along with the carbon atom to which they are attached 3 -C 6 forming a cycloalkyl, p being an integer from 1 to 7;

[0364] [ka] is the binding to a Bcl-xL inhibitor compound,

[0365] [ka] is the connection to the DSM].

[0366] In some embodiments, the linker (L) has the formula (i):

[0367] [ka] [In the formula, LK 1 is a bond or -C(O)-, and LK 2 is a bond, -C(O)- or -N(R 16 )-C(O)-CH 2 - * and R 16 is H or methyl, R 17 is C 1 -C 20 Alkylene, C 3-10 Cycloalkylene, phenylene, -CH 2 -(OCH 2 CH 2 ) p -OCH 2 - where C 1 -C 15 Alkylene or phenylene is one or two R 17a where p is an integer from 1 to 7, and R 17a is, for each occurrence, independently, a straight-chain or branched-chain C 1-6 alkyl or halogen, or two R 17a C, along with the carbon atom to which they are attached 3-6 Forming a cycloalkyl, where:

[0368] [ka] is the binding to a Bcl-xL inhibitor compound,

[0369] [ka] is the connection to the DSM].

[0370] In some embodiments, the linker (L) has formula (ii):

[0371] [ka] [In the formula, d is an integer of 1 to 7,

[0372] [ka] is the binding to a Bcl-xL inhibitor compound,

[0373] [ka] is the connection to the DSM].

[0374] In some embodiments, the linker (L) has formula (iii):

[0375] [ka] [In the formula, LK 3 is -C(O)- or -N(R 16 )-C(O)-CH 2 - * and R 16 is H or methyl, R 18 is C 1-20 Alkylene or -CH 2 CH 2 -(OCH 2 CH 2 ) p - ** where: ** LK 3 p is an integer from 1 to 7;

[0376] [ka] is the binding to a Bcl-xL inhibitor compound,

[0377] [ka] is the connection to the DSM].

[0378] In some embodiments, the linker (L) has formula (iv):

[0379] [ka] [In the formula, LK 4 is a bond or -C(O)-, and R 19 is C 1-6 alkylene, where

[0380] [ka] is the binding to a Bcl-xL inhibitor compound,

[0381] [ka] is the connection to the DSM].

[0382] In some embodiments, the linker (L) has the formula (v):

[0383] [ka] [In the formula, LK 5 is a bond or -C(O)-, and R 20 is C 3-10 Cycloalkylene, phenylene, -S- or -N(R 16 )- and R 16 is H or methyl, where

[0384] [ka] is the binding to a Bcl-xL inhibitor compound,

[0385] [ka] is the connection to the DSM].

[0386] In some embodiments, the linker (L) has formula (ii):

[0387] [ka] [In the formula, LK 6 is a bond, -C(O)-, -O-CH 2 -C(O)- * , or -N(R 16 )-C(O)-CH 2 - * and R 16 is H or methyl, R 21 is C 1-20 Alkylene or -CH 2 -(OCH 2 CH 2 ) p - ** where: ** LK 6 represents the point of attachment to, and p is an integer from 1 to 7, where

[0388] [ka] is the binding to a Bcl-xL inhibitor compound,

[0389] [ka] is a bond to DSM. 6 is a bond, -O-CH 2 -C(O)- * , or -N(R 16 )-C(O)-CH 2 - * It is.

[0390] In some embodiments, the linker (L) has formula (vii):

[0391] [ka] [In the formula, LK 7 is a bond or -NR 16 - and LK 8 is a bond, -R22 -, -OR 22 -or-C(O)-R 22 -, and ring A is C 3 -C 8 Heterocycloalkylene, R 16 is H or methyl, R 22 is C 1 -C 6 is alkylene,

[0392] [ka] is the binding to a Bcl-xL inhibitor compound,

[0393] [ka] is the connection to the DSM].

[0394] In some embodiments, L is a formula selected from formulas (L1) to (L109) in Table 3:

[0395] [ka] represents binding to a Bcl-xL inhibitor compound (D);

[0396] [ka] represents binding to degradation signaling compound (DSM)].

[0397] [Table 5-1]

[0398] [Table 5-2]

[0399] [Table 5-3]

[0400] [Table 5-4]

[0401] [Table 5-5]

[0402] [Table 5-6]

[0403] [Table 5-7]

[0404] [Table 5-8]

[0405] In some embodiments, DL of formula (A) is selected from the formulas in Table 4:

[0406] [ka] represents binding to a degradation signaling compound (DSM)] or an enantiomer, diastereoisomer, and / or pharma- ceutically acceptable salt thereof.

[0407] [Table 6-1]

[0408] [Table 6-2]

[0409] [Table 6-3]

[0410]

Table 6-4

[0411]

Table 6-5

[0412]

Table 6-6

[0413]

Table 6-7

[0414]

Table 6-8

[0415]

Table 6-9

[0416]

Table 6-10

[0417]

Table 6-11

[0418]

Table 6-12

[0419]

Table 6-13

[0420]

Table 6-14

[0421]

Table 6-15

[0422]

Table 6-16

[0423]

Table 6-17

[0424]

Table 6-18

[0425]

Table 6-19

[0426]

Table 6-20

[0427]

Table 6-21

[0428]

Table 6-22

[0429]

Table 6-23

[0430] [Table 6-24]

[0431] [Table 6-25]

[0432] [Table 6-26]

[0433] [Table 6-27]

[0434] [Table 6-28]

[0435] 3. Degradation signaling moiety Degradation signaling compounds and moieties (DSMs) of the present disclosure include compounds and moieties thereof that induce degradation of a targeted Bcl protein (e.g., Bcl-xL). DSMs degrade Bcl by binding to or recruiting at least one degradative protein, which is usually associated with the proteasome, the ubiquitin-proteasome pathway, or lysosomal protein degradation. DSMs of the present disclosure include, but are not limited to, E3 ubiquitin ligase recognition agents. In some embodiments, the targeted E3 ubiquitin ligase or component of an E3 ubiquitin ligase complex is MDM2, cIAPI, VHL protein, CBRN, or SCF. β-TRCP It is.

[0436] An E3 ligase recognition agent is any compound that effectively binds to an E3 ubiquitin ligase or an E3 ubiquitin ligase complex. In some embodiments, the E3 ligase recognition agent is an E3 ubiquitin ligase ligand, such as a VHL ligand, a thalidomide cereblon binding agent, or an inhibitor of apoptosis (IAP) E3 ligase. As used herein, "thalidomide cereblon binding agent" refers to thalidomide or a thalidomide derivative (e.g., pomalidomide or a modified version of pomalidomide) that binds to cereblon. Exemplary E3 ligase recognition agents are described in WO 2021 / 007307, WO 2020 / 163823, U.S. Patent Application Publication No. 2019 / 0127359, WO 2019 / 144117, WO 2018 / 200981, WO 2016 / 149668, WO 2016 / 105518, WO 2017 / 184995, WO 2017 / 007612, WO 2015 / 160845, Girardini, M. et al., “Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs”, Bioorganic & Medicinal Chemistry 27 (2019), each of which is incorporated by reference herein. 2466-79, Zhang, X. et al., “Discovery of IAP-recruiting BDL-X L PROTACs as potent degraders across multiple cancer cell lines”, European Journal of Medicinal Chemistry 199 (2020) 112397 and Chang, Yung-Chieh et al., “An Updated Review of Smac Mimetics, LCL161, Birinapant, and GDC-0162 in Cancer Treatment”, Applied Sciences, 2021, 11, 335.

[0437] In some embodiments, DSM refers to a degradation signaling compound covalently attached to a linker, where the degradation signaling compound (DSM compound) is selected from the compounds in Table 5, or enantiomers, diastereomers, and / or pharma- ceutically acceptable salts thereof.

[0438] [Table 7-1]

[0439] [Table 7-2]

[0440] In some embodiments, the DSM of formula (A) is selected from the group consisting of the formulas in Table 6:

[0441] [ka] represents a bond to a linker (L)] or its enantiomers, diastereomers, and / or pharma- ceutically acceptable salts.

[0442] [Table 8-1]

[0443] [Table 8-2]

[0444] In some embodiments, the DSM is DSM1a

[0445] [ka] or an enantiomer, diastereomer, and / or pharma- ceutically acceptable salt thereof, wherein

[0446] [ka] represents a bond to a linker (L).

[0447] 4. Bifunctional Bcl-xL degrader compounds In some embodiments, the Bcl-xL decomposer compound is represented by formula (A) as described above (e.g., a compound described in any one of the first to twenty-eight embodiments). In some embodiments, the Bcl-xL decomposer compound is a compound in Table 7 or an enantiomer, diastereoisomer and / or pharma-ceutically acceptable salt thereof.

[0448] [Table 9-1]

[0449] [Table 9-2]

[0450] [Table 9-3]

[0451] [Table 9-4]

[0452] [Table 9-5]

[0453] [Table 9-6]

[0454] [Table 9-7]

[0455]

Table 9-8

[0456]

Table 9-9

[0457]

Table 9-10

[0458]

Table 9-11

[0459]

Table 9-12

[0460]

Table 9-13

[0461]

Table 9-14

[0462]

Table 9-15

[0463]

Table 9-16

[0464]

Table 9-17

[0465]

Table 9-18

[0466]

Table 9-19

[0467]

Table 9-20

[0468]

Table 9-21

[0469]

Table 9-22

[0470]

Table 9-23

[0471]

Table 9-24

[0472]

Table 9-25

[0473]

Table 9-26

[0474]

Table 9-27

[0475]

Table 9-28

[0476]

Table 9-29

[0477]

Table 9-30

[0478]

Table 9-31

[0479]

Table 9-32

[0480]

Table 9-33

[0481]

Table 9-34

[0482]

Table 9-35

[0483]

Table 9-36

[0484]

Table 9-37

[0485]

Table 9-38

[0486]

Table 9-39

[0487]

Table 9-40

[0488]

Table 9-41

[0489]

Table 9-42

[0490]

Table 9-43

[0491]

Table 9-44

[0492]

Table 9-45

[0493]

Table 9-46

[0494]

Table 9-47

[0495]

Table 9-48

[0496]

Table 9-49

[0497]

Table 9-50

[0498]

Table 9-51

[0499]

Table 9-52

[0500]

Table 9-53

[0501]

Table 9-54

[0502]

Table 9-55

[0503]

Table 9-56

[0504]

Table 9-57

[0505]

Table 9-58

[0506]

Table 9-59

[0507]

Table 9-60

[0508]

Table 9-61

[0509]

Table 9-62

[0510]

Table 9-63

[0511]

Table 9-64

[0512]

Table 9-65

[0513]

Table 9-66

[0514]

Table 9-67

[0515]

Table 9-68

[0516] [Table 9-69]

[0517] [Table 9-70]

[0518] [Table 9-71]

[0519] [Table 9-72]

[0520] [Table 9-73]

[0521] [Table 9-74]

[0522] Pharmaceutical Compositions and Methods of Treatment Therapeutic uses of the disclosed compounds and compositions are further provided herein. An exemplary embodiment is a compound, composition, or pharmaceutical composition (e.g., any of the exemplary compounds, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject having or suspected of having cancer (e.g., Bcl-xL-mediated cancer). Another exemplary embodiment is the use of a compound, composition, or pharmaceutical composition (e.g., any of the exemplary compounds, compositions, or pharmaceutical compositions disclosed herein) in treating a subject having or suspected of having cancer (e.g., Bcl-xL-mediated cancer). Another exemplary embodiment is the use of a compound, composition, or pharmaceutical composition (e.g., any of the exemplary compounds, compositions, or pharmaceutical compositions disclosed herein) in a method of manufacturing a medicament for treating a subject having or suspected of having cancer (e.g., Bcl-xL-mediated cancer).

[0523] The therapeutic compositions used in carrying out the aforementioned methods can be formulated into pharmaceutical compositions comprising a pharma- ceutically acceptable carrier suitable for the desired delivery method. An exemplary embodiment is a pharmaceutical composition comprising a compound of the present disclosure and a pharma- ceutically acceptable carrier, e.g., suitable for a selected means of administration, e.g., intravenous administration. The pharmaceutical composition may also include one or more additional inactive and / or therapeutic agents suitable for treating or preventing, for example, cancer (e.g., standard of care agents, etc.). The pharmaceutical composition may also include one or more carrier, excipient, and / or stabilizer components, etc. Methods for formulating such pharmaceutical compositions and suitable formulations are known in the art (see, e.g., "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA).

[0524] Suitable carriers include any material that, when combined with the therapeutic composition, retains the antitumor function of the therapeutic composition and is generally non-reactive to the patient's immune system. Pharmaceutically acceptable carriers include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents and absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, mesylate, and the like, and combinations thereof. In many cases, isotonicity agents, such as sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride, are included in the composition. Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compounds of the present disclosure.

[0525] The pharmaceutical compositions of the present disclosure can be administered in a variety of ways known in the art. The route and / or mode of administration can vary depending on the desired outcome. In some embodiments, the therapeutic formulation is solubilized and administered via any route capable of delivering the therapeutic composition to the cancer site. Potentially effective routes of administration include, but are not limited to, parenteral (e.g., intravenous, subcutaneous), intraperitoneal, intramuscular, intratumoral, intradermal, intraorgan, orthotopic, and the like. In some embodiments, administration is intravenous, subcutaneous, intraperitoneal, or intramuscular. The pharmaceutically acceptable carrier should be appropriate for the route of administration, e.g., intravenous or subcutaneous administration (e.g., by injection or infusion). Depending on the route of administration, the active compound(s), i.e., the compound and / or any additional therapeutic agent, can be coated in a material to protect the compound(s) from the action of acids and other natural conditions that may inactivate the compound(s). Administration can be either systemic or local.

[0526] The therapeutic compositions disclosed herein can be sterile, stable, and in a variety of forms under the conditions of manufacture and storage. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application. In some embodiments, the disclosed compounds can be incorporated into pharmaceutical compositions suitable for parenteral administration. Injection solutions can be comprised of either liquid or lyophilized dosage forms in flint or amber vials, ampoules, or pre-filled syringes, or other known delivery or storage devices. In some embodiments, one or more compounds or pharmaceutical compositions are supplied as dry, sterilized, lyophilized powders or water-free concentrates in hermetically sealed containers, which can be reconstituted (e.g., with water or saline) to the appropriate concentration for administration to a subject.

[0527] Generally, a therapeutically effective amount or an effective amount of the disclosed compositions, e.g., the disclosed compounds, are utilized in the pharmaceutical compositions of the present disclosure.Compositions, e.g., those that include the compounds disclosed herein, can be formulated into pharmaceutically acceptable dosage forms by conventional methods known in the art.The dosage and administration protocol for treating cancer using the aforementioned methods varies with the method and the target cancer, and generally depends on several other factors recognized in the art.

[0528] Dosage regimens for compositions disclosed herein, e.g., compositions comprising a compound, alone or in combination with at least one additional inactive and / or active therapeutic agent, can be adjusted to obtain the optimum desired response (e.g., therapeutic response). For example, a single bolus of one or both agents may be administered at once, or several divided doses may be administered over a predetermined period of time, or the dose of one or both agents may be proportionally increased or decreased as indicated by the exigencies of the therapeutic situation. In some embodiments, treatment involves a single bolus or repeated administration of a compound preparation via an acceptable route of administration. In some embodiments, the compound is administered to the patient daily, weekly, monthly, or for any period of time. For any particular subject, the specific dosage regimen can also be adjusted over time according to the individual need and the professional judgment of the treating clinician. Parenteral compositions can be formulated into unit dosage forms for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited to the subjects to be treated as unitary dosages, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0529] Dosage values ​​for compositions containing the compounds disclosed herein and / or any additional therapeutic agent(s) can be selected based on the unique characteristics of the active compound(s) and the particular therapeutic effect to be achieved. A physician or veterinarian can start the dose of the compound utilized in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. In general, the effective dose of the compositions of the present disclosure for the treatment of cancer can vary depending on many different factors, including the means of administration, the target site, the physiological condition of the patient, whether the patient is human or animal, other medications administered, and whether the treatment is prophylactic or therapeutic. The selected dose level can also depend on various pharmacokinetic factors, including the activity of the particular composition of the present disclosure utilized, or its esters, salts, or amides, the route of administration, the time of administration, the excretion rate of the particular compound utilized, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular composition utilized, the age, sex, weight, condition, general health and previous medical history of the patient undergoing treatment, and other factors. Treatment dosages can be titrated to optimize safety and efficacy.

[0530] The toxicity and therapeutic efficacy of the compounds provided herein can be determined by standard pharmaceutical procedures in cell cultures or animal models. For example, LD50, ED50, EC50, and IC50 can be determined, and the dose ratio between toxic and therapeutic effects (LD50 / ED50) can be calculated as the therapeutic index. Data obtained from in vitro and in vivo assays can be used to estimate or formulate a range of doses for use in humans. For example, the compositions and methods disclosed herein can be initially evaluated in xenogeneic cancer models (e.g., NCI-H929 multiple myeloma mouse model).

[0531] In some embodiments, the compound disclosed herein or a composition comprising the compound is administered once. In other embodiments, the compound or a composition comprising the compound is administered multiple times. The interval between single doses can be, for example, one day, one week, one month, or one year. The interval can also be irregular based on measuring the blood concentration of the drug (e.g., compound) administered to the patient so as to maintain a relatively consistent plasma concentration of the drug. The dosage and frequency of administration of the compound or a composition comprising the compound can also vary depending on whether the treatment is preventive or therapeutic. In preventive applications, relatively low doses may be administered at relatively infrequent intervals for a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, relatively high doses are required at relatively short intervals, sometimes until the progression of the disease is reduced or terminated, preferably until the patient shows partial or complete recovery of one or more symptoms of the disease. The patient may then be applied to a lower, e.g., prophylactic, regimen.

[0532] In some embodiments, the compounds of the present disclosure may be administered in an amount effective to sensitize tumor cells to one or more additional therapeutic agents and / or radiation therapy.

[0533] In some embodiments, the compounds of the present disclosure may be administered as a monotherapy, while in other embodiments, the compounds may be administered as an adjunct to another therapeutic agent or radiation therapy. For example, in some embodiments, the methods of the present disclosure include further administration (in addition to at least one PROTAC compound disclosed herein) of at least one additional therapeutic agent, such as a Bcl-2 inhibitor, a taxane, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor, to a subject in need thereof.

[0534] The above therapeutic measures can be combined with any one of a wide variety of additional surgical, chemotherapy, or radiation therapy regimens. In some embodiments, the compounds or compositions disclosed herein are co-formulated and / or co-administered with one or more additional therapeutic agents for the particular condition being treated, such as one or more chemotherapeutic agents, one or more standard of care agents.

[0535] Kits for use in the therapeutic and / or diagnostic applications described herein are also provided. Such kits may include carriers, packages, or containers compartmentalized to accommodate one or more containers, e.g., vials, tubes, etc., each of the container(s) containing one of the separate elements used in the methods disclosed herein. Labels may be present on or with the container(s) to indicate that the compound or composition in the kit is used for a particular therapeutic or non-therapeutic application, e.g., prognostic, preventive, diagnostic, or testing application. Labels may also indicate instructions for either in vivo or in vitro use, such as those described herein. Instructions and / or other information may also be included in insert(s) or label(s) that are included with or on the kit. Labels may be on or associated with the container. Labels may be on the container if letters, numbers, or other characters forming the label are molded or etched into the container itself. The label can be associated with the container, e.g., if present in a container or carrier that also holds the container, e.g., as a package insert. The label can indicate that the compound or composition in the kit is used for diagnosing or treating a condition, e.g., cancer, as described herein.

[0536] In some embodiments, the kit comprises the compound or a composition comprising the compound. In some embodiments, the kit further comprises one or more additional components, including, but not limited to, instructions; other reagents, such as therapeutic agents (e.g., standard of care drugs); devices, containers, or other materials for preparing the compound for administration; pharmaceutically acceptable carriers; and devices, containers, or other materials for administering the compound to a subject. The instructions can include guidance for therapeutic use, including, for example, a suggested dose and / or mode of administration to a patient having or suspected of having cancer. In some embodiments, the kit comprises the compound and instructions for use of the compound in the treatment, prevention, and / or diagnosis of cancer.

[0537] Elevated expression of Bcl-xL is known to correlate with resistance to radiation therapy and chemotherapy. Compounds of the present disclosure that may not be sufficiently effective to treat cancer as monotherapy may provide therapeutic benefit by administration in combination with other therapeutic agents (including non-targeted and targeted therapeutic agents) or radiation therapy (including radioligand therapy). Without wishing to be bound by theory, it is believed that the linked drug conjugates described herein may sensitize tumor cells to treatment with other therapeutic agents (including standard of care chemotherapeutic agents to which tumor cells may have developed resistance) and / or radiation therapy. In some embodiments, the compounds described herein are administered to a subject with cancer in an amount effective to sensitize tumor cells. As used herein, the term "sensitize" means that treatment with the compound increases the potency or effectiveness of treatment with other therapeutic agents and / or radiation therapy on tumor cells.

[0538] Disclosed herein are methods of using the compositions described herein in treating a subject against a disorder, such as cancer. The compounds and compositions of the present disclosure may be administered alone or in combination with at least one additional inactive and / or active agent, such as at least one additional therapeutic agent, and may be administered in any pharma- ceutically acceptable formulation, dose, and administration regimen. The efficacy of treatment may be evaluated against toxicity and efficacy indicators and adjusted accordingly. Measures of efficacy include, but are not limited to, cytostatic and / or cytotoxic effects observed in vitro or in vivo, reduction in tumor volume, tumor growth inhibition, and / or prolonged survival.

[0539] In certain aspects, the disclosure features a method of eradicating, inhibiting or modulating the growth of cancer cells or tissues by disrupting the expression and / or activity of Bcl-xL and / or one or more of its upstream modulators or downstream targets. The method can be used in any subject in which disruption of Bcl-xL expression and / or activity provides a therapeutic benefit. Subjects that may benefit from disruption of Bcl-xL expression and / or activity include, but are not limited to, subjects having or at risk of having cancer, e.g., tumor or hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0540] Exemplary methods include contacting cells with an effective amount, i.e., an amount sufficient to kill the cells, of a compound or composition described herein. The method can be used with cells in culture, e.g., in vitro, in vivo, ex vivo, or in situ. For example, cells (e.g., cells collected by biopsy of a tumor or metastatic lesion; cells from an established cancer cell line; or recombinant cells) can be cultured in vitro in culture medium, and the contacting step can be effected by adding the compound or composition to the culture medium. Alternatively, the compound or composition can be administered to a subject by any suitable route of administration (e.g., intravenously, subcutaneously, or by direct contact with tumor tissue) to have an in vivo effect.

[0541] The in vivo efficacy of the therapeutic compositions disclosed herein can be evaluated in suitable animal models. For example, xenogeneic cancer models can be used in which cancer grafts or passaged xenograft tissues are introduced into immune-compromised animals, such as nude or SCID mice (Klein et al. (1997) Nature Med. 3:402-8). Efficacy can be predicted using assays that measure inhibition of tumor formation, tumor regression, or metastasis, etc.

[0542] In vivo assays that evaluate the promotion of tumor death by mechanisms such as apoptosis can also be used. In some embodiments, xenografts from tumor-bearing mice treated with a therapeutic composition can be examined for the presence of apoptotic foci and compared to mice bearing untreated control xenografts. The extent to which apoptotic foci are found in the tumors of treated mice provides an indication of the therapeutic efficacy of the composition.

[0543] Further provided herein are methods of treating disorders, such as cancer. The compositions described herein can be administered to a non-human mammal or a human subject for therapeutic purposes. The method of treatment includes administering to a subject having or suspected of having cancer a therapeutically effective amount of a composition comprising a Bcl-xL inhibitor.

[0544] An exemplary embodiment is a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a composition disclosed herein. In some embodiments, the cancer is a solid tumor or a hematological cancer. In some embodiments, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer. In some embodiments, the cancer is lymphoma or gastric cancer.

[0545] An exemplary embodiment is a method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of a PROTAC compound, composition, or pharmaceutical composition (e.g., any of the exemplary compounds, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, administration of the compound, composition, or pharmaceutical composition reduces or inhibits tumor growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% when compared to growth in the absence of treatment.

[0546] In certain aspects, the present disclosure further provides a method of reducing or slowing the expansion of a cancer cell population, comprising administering a therapeutically effective amount of a PROTAC compound or a composition comprising a PROTAC compound.

[0547] Additionally, compounds or compositions of the disclosure may be administered to mammals other than humans for veterinary purposes or as animal models of human disease. Regarding the latter, such animal models can be useful for evaluating the therapeutic efficacy of the disclosed compounds (e.g., testing doses and time courses of administration).

[0548] Combination therapy In some embodiments, the disclosure provides methods of treatment in which a DSM-drug conjugate disclosed herein is administered in combination with one or more (e.g., one or two) additional therapeutic agents. Exemplary combination partners are disclosed herein.

[0549] In certain embodiments, the combinations described herein include a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck&Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). In some embodiments, the PD-1 inhibitor is PDR001. PDR001 is also known as Spartalizumab.

[0550] In certain embodiments, the combinations described herein include a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro).

[0551] In certain embodiments, the combinations described herein include a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MBG453 (Novartis), TSR-022 (Tesaro), LY-3321367 (Eli Lily), Sym23 (Symphogen), BGB-A425 (Beigene), INCAGN-2390 (Agenus), BMS-986258 (BMS), RO-7121661 (Roche), or LY-3415244 (Eli Lilly).

[0552] In certain embodiments, the combinations described herein include a PDL1 inhibitor. In one embodiment, the PDL1 inhibitor is selected from FAZ053 (Novartis), atezolizumab (Genentech), durvalumab (Astra Zeneca), or avelumab (Pfizer).

[0553] In certain embodiments, the combinations described herein include a GITR agonist. In some embodiments, the GITR agonist is selected from GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte / Agenus), AMG228 (Amgen) or INBRX-110 (Inhibrx).

[0554] In some embodiments, the combinations described herein include an IAP inhibitor. In some embodiments, the IAP inhibitor includes LCL161 or a compound disclosed in International Application Publication No. WO 2008 / 016893.

[0555] In one embodiment, the combination includes an mTOR inhibitor, such as RAD001 (also known as everolimus).

[0556] In one embodiment, the combination includes an HDAC inhibitor, such as LBH589. LBH589 is also known as panobinostat.

[0557] In one embodiment, the combination includes an IL-17 inhibitor, such as CJM112.

[0558] In certain embodiments, the combinations described herein include an estrogen receptor (ER) antagonist. In some embodiments, the estrogen receptor antagonist is used in combination with a PD-1 inhibitor, a CDK4 / 6 inhibitor, or both. In some embodiments, the combination is used to treat ER-positive (ER+) cancer or breast cancer (e.g., ER+ breast cancer).

[0559] In some embodiments, the estrogen receptor antagonist is a selective estrogen receptor degrader (SERD). A SERD is an estrogen receptor antagonist that binds to the receptor, e.g., resulting in degradation or downregulation of the receptor (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology 9(7): 465-479). ER is a hormone-activated transcription factor that is important for the development, progression, and physiological function of, for example, the human reproductive system. ER is activated, for example, by the hormone estrogen (17 beta estradiol). ER expression and signaling are associated with cancer (e.g., breast cancer), e.g., ER-positive (ER+) breast cancer. In some embodiments, the SERD is selected from LSZ102, fulvestrant, brilanestrant, or elacestrant.

[0560] In some embodiments, the SERD comprises a compound disclosed in International Application Publication No. WO 2014 / 130310, the entirety of which is hereby incorporated by reference herein.

[0561] In some embodiments, the SERD comprises LSZ102. LSZ102 has the chemical name: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid. In some embodiments, the SERD comprises fulvestrant (CAS Registry Number: 129453-61-8), or a compound disclosed in International Application Publication WO 2001 / 051056, which is hereby incorporated by reference in its entirety. In some embodiments, the SERD comprises elacestrant (CAS Registry Number: 722533-56-4), or a compound disclosed in U.S. Pat. No. 7,612,114, which is hereby incorporated by reference in its entirety. Elacestrant is also known as RAD1901, ER-306323, or (6R)-6-{2-[ethyl({4-[2-(ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol. Elacestrant is an orally bioavailable, non-steroidal combined selective estrogen receptor modulator (SERM) and SERD. Elacestrant is also disclosed, for example, in Garner F et al., (2015) Anticancer Drugs 26(9):948-56. In some embodiments, the SERD is brillanestran (CAS Registry Number: 1365888-06-7), or a compound disclosed in International Application Publication WO 2015 / 136017, the entirety of which is incorporated by reference.

[0562] In some embodiments, the SERD is selected from RU58668, GW7604, AZD9496, bazedoxifene, pipendoxifene, arzoxifene, OP-1074, or acolbifene, e.g., as disclosed in McDonell et al. (2015) Journal of Medicinal Chemistry 58(12) 4883-4887.

[0563] Other exemplary estrogen receptor antagonists are disclosed, for example, in WO 2011 / 156518, WO 2011 / 159769, WO 2012 / 037410, WO 2012 / 037411, and U.S. Patent Application Publication No. 2012 / 0071535, all of which are hereby incorporated by reference in their entireties.

[0564] In certain embodiments, the combinations described herein include inhibitors of cyclin-dependent kinase 4 or 6 (CDK4 / 6). In some embodiments, the CDK4 / 6 inhibitor is used in combination with a PD-1 inhibitor, an estrogen receptor (ER) antagonist, or both. In some embodiments, the combination is used to treat ER-positive (ER+) cancer or breast cancer (e.g., ER+ breast cancer). In some embodiments, the CDK4 / 6 inhibitor is selected from ribociclib, abemaciclib (Eli Lilly), or palbociclib.

[0565] In some embodiments, the CDK4 / 6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3) or a compound disclosed in U.S. Pat. Nos. 8,415,355 and 8,685,980, which are incorporated by reference in their entireties.

[0566] In some embodiments, CDK4 / 6 inhibitors include compounds disclosed in International Application Publication No. WO 2010 / 020675 and U.S. Pat. Nos. 8,415,355 and 8,685,980, which are incorporated by reference in their entireties.

[0567] In some embodiments, the CDK4 / 6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3). Ribociclib is also known as LEE011, KISQALI®, or 7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0568] In some embodiments, the CDK4 / 6 inhibitor comprises abemaciclib (CAS Registry Number: 1231929-97-7). Abemaciclib is also known as LY835219 or N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine. Abemaciclib is a selective CDK inhibitor for CDK4 and CDK6, and is disclosed, for example, in Torres-Guzman R et al. (2017) Oncotarget 10.18632 / oncotarget.17778.

[0569] In some embodiments, the CDK4 / 6 inhibitor comprises palbociclib (CAS Registry Number: 571190-30-2). Palbociclib is also known as PD-0332991, IBRANCE®, or 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib inhibits CDK4 with an IC50 of 11 nM and CDK6 with an IC50 of 16 nM, as disclosed, for example, in Finn et al. (2009) Breast Cancer Research 11(5):R77.

[0570] In certain embodiments, the combinations described herein include an inhibitor of chemokine (CXC motif) receptor 2 (CXCR2). In some embodiments, the CXCR2 inhibitor is selected from 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide, danilixin, reparixin, or navarixin.

[0571] In some embodiments, the CSF-1 / 1R binding agent is selected from an inhibitor of macrophage colony stimulating factor (M-CSF), such as a monoclonal antibody or Fab to M-CSF (e.g., MCS110), a CSF-1R tyrosine kinase inhibitor (e.g., 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide or BLZ945), a receptor tyrosine kinase inhibitor (RTK) (e.g., pexidartinib), or an antibody targeting CSF-1R (e.g., emactuzumab or FPA008). In some embodiments, the CSF-1 / 1R inhibitor is BLZ945. In some embodiments, the CSF-1 / 1R binding agent is MCS110. In other embodiments, the CSF-1 / 1R binding agent is pexidartinib.

[0572] In certain embodiments, the combinations described herein include a c-MET inhibitor. c-MET, a receptor tyrosine kinase that is overexpressed or mutated in many tumor cell types, plays an important role in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. Inhibition of c-MET can induce cell death in tumor cells that overexpress c-MET protein or express constitutively activated c-MET protein. In some embodiments, the c-MET inhibitor is selected from capmatinib (INC280), JNJ-3887605, AMG337, LY2801653, MSC2156119J, crizotinib, tivantinib, or golvatinib.

[0573] In certain embodiments, the combinations described herein include a transforming growth factor beta (also known as TGF-β TGFβ, TGFb, or TGF-beta, and are used interchangeably herein) inhibitor. In some embodiments, the TGF-β inhibitor is selected from fresolimumab or XOMA 089.

[0574] In certain embodiments, the combinations described herein include an adenosine A2a receptor (A2aR) antagonist (e.g., an inhibitor of the A2aR pathway, e.g., an adenosine inhibitor, e.g., an inhibitor of A2aR or CD-73). In some embodiments, the A2aR antagonist is used in combination with a PD-1 inhibitor and one or more (e.g., 2, 3, 4, 5, or all) CXCR2 inhibitors, CSF-1 / 1R binders, LAG-3 inhibitors, GITR agonists, c-MET inhibitors, or IDO inhibitors. In some embodiments, the combination is used to treat pancreatic cancer, colorectal cancer, gastric cancer, or melanoma (e.g., refractory melanoma). In some embodiments, the A2aR antagonist is selected from PBF509 (NIR178) (Palobiofarma / Novartis), CPI444 / V81444 (Corvus / Genentech), AZD4635 / HTL-1071 (AstraZeneca / Heptares), Vipadenant (Redox / Juno), GBV-2034 (Globavir), AB928 (Arcus Biosciences), Theophylline, Istradefylline (Kyowa Hakko Kogyo), Tozadenant / SYN-115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST-4206 (Leadiant Biosciences), or Preladenant / SCH420814 (Merck / Schering). Without wishing to be bound by theory, in some embodiments, inhibition of A2aR is believed to result in the upregulation of IL-1b.

[0575] In certain embodiments, the combinations described herein include inhibitors of indoleamine 2,3-dioxygenase (IDO) and / or tryptophan 2,3-dioxygenase (TDO). In some embodiments, the IDO inhibitor is used in combination with a PD-1 inhibitor and one or more (e.g., two, three, four, or all) of a TGF-β inhibitor, an A2aR antagonist, a CSF-1 / 1R binder, a c-MET inhibitor, or a GITR agonist. In some embodiments, the combination is used to treat pancreatic cancer, colorectal cancer, gastric cancer, or melanoma (e.g., refractory melanoma). In some embodiments, the IDO inhibitor is selected from (4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as epacadostat or INCB24360), indoximod (NLG8189), (1-methyl-D-tryptophan), α-cyclohexyl-5H-imidazo[5,1-a]isoindole-5-ethanol (also known as NLG919), indoximod, BMS-986205 (formerly F001287).

[0576] In certain embodiments, the combinations described herein include inhibitors of galectins, e.g., galectin-1 or galectin-3. In some embodiments, the combinations include a galectin-1 inhibitor and a galectin-3 inhibitor. In some embodiments, the combinations include a bispecific inhibitor (e.g., a bispecific antibody molecule) that targets both galectin-1 and galectin-3. In some embodiments, the galectin inhibitor is used in combination with one or more therapeutic agents described herein. In some embodiments, the galectin inhibitor is selected from an anti-galectin antibody molecule, GR-MD-02 (Galectin Therapeutics), Galectin-3C (Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck).

[0577] In some embodiments, the combinations described herein include inhibitors of the MAP kinase pathway, including ERK inhibitors, MEK inhibitors and RAF inhibitors.

[0578] In some embodiments, the combinations described herein include a MEK inhibitor. In some embodiments, the MEK inhibitor is selected from trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or G02443714.

[0579] In some embodiments, the MEK inhibitor is trametinib, also known as JTP-74057, TMT212, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide, or mekinist (CAS number 871700-17-3).

[0580] In some embodiments, the MEK inhibitor comprises selumetinib, which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide. Selumetinib is also known as AZD6244 or ARRY 142886, which is described, for example, in PCT Publication WO2003077914.

[0581] In some embodiments, the MEK inhibitor comprises AS703026, BIX 02189 or BIX 02188.

[0582] In some embodiments, the MEK inhibitor comprises 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352), e.g., as described in PCT Publication WO2000035436.

[0583] In some embodiments, the MEK inhibitor comprises N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901), e.g., as described in PCT Publication WO2002006213.

[0584] In some embodiments, the MEK inhibitor comprises 2'-amino-3'-methoxyflavone (also known as PD98059), available from Biaffin GmbH & Co., KG, Germany.

[0585] In some embodiments, the MEK inhibitor comprises 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126), as described, for example, in US Pat. No. 2,779,780.

[0586] In some embodiments, the MEK inhibitor comprises XL-518 (also known as GDC-0973), having CAS No. 1029872-29-4 and available from ACC Corp.

[0587] In some embodiments, the MEK inhibitor comprises G-38963. In some embodiments, the MEK inhibitor comprises G02443714 (also known as AS703206).

[0588] Additional examples of MEK inhibitors are disclosed in WO 2013 / 019906, WO 03 / 077914, WO 2005 / 121142, WO 2007 / 04415, WO 2008 / 024725, and WO 2009 / 085983, the contents of which are incorporated herein by reference. Further examples of MEK inhibitors include, but are not limited to, 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126 and described in U.S. Pat. No. 2,779,780); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] (also known as E6201 and described in PCT Publication WO 2003076424); vemurafenib (PLX-4032, CAS 918504-65-1;(R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555-63-5);Pimasertib (AS-703026, CAS 1204531-26-9); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD8330); and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH 4987655 or Ro 4987655).

[0589] In some embodiments, the combinations described herein include a RAF inhibitor.

[0590] RAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®, PLX-4032, CAS 918504-65-1), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexavar®).

[0591] In some embodiments, the RAF inhibitor is Dabrafenib.

[0592] In some embodiments, the RAF inhibitor is LXH254.

[0593] In some embodiments, the combinations described herein include an ERK inhibitor.

[0594] ERK inhibitors include, but are not limited to, LTT462, ulixertinib (BVD-523), LY3214996, GDC-0994, KO-947, and MK-8353.

[0595] In some embodiments, the ERK inhibitor is LTT462, which is 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide, a compound of the following structure:

[0596] [ka] It is.

[0597] The preparation of LTT462 is described in PCT Patent Application Publication WO 2015 / 066188. LTT462 is an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1 / 2).

[0598] In some embodiments, the combinations described herein include a taxane, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor.

[0599] In some embodiments, the combinations described herein comprise at least two inhibitors independently selected from a MEK inhibitor, an ERK inhibitor, and a RAF inhibitor.

[0600] In some embodiments, the combinations described herein include an antimitotic drug.

[0601] In some embodiments, the combinations described herein include a taxane.

[0602] Taxanes include, but are not limited to, docetaxel, paclitaxel, or cabazitaxel. In some embodiments, the taxane is docetaxel.

[0603] In some embodiments, the combinations described herein include a topoisomerase inhibitor.

[0604] Topoisomerase inhibitors include, but are not limited to, topotecan, irinotecan, camptothecin, diflomotecan, lamellarin D, ellipticine, etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, aurintricarboxylic acid, and HU-331.

[0605] In one embodiment, the combination described herein includes an interleukin-1 beta (IL-1β) inhibitor. In some embodiments, the IL-1β inhibitor is selected from canakinumab, gevokizumab, anakinra, or rilonacept.

[0606] In certain embodiments, the combinations described herein comprise an IL-15 / IL-15Ra complex. In some embodiments, the IL-15 / IL-15Ra complex is selected from NIZ985 (Novartis), ATL-803 (Altor), or CYP0150 (Cytune).

[0607] In certain embodiments, the combinations described herein include a double minute 2 homolog (MDM2) inhibitor. The human homolog of MDM2 is also known as HDM2. In some embodiments, the MDM2 inhibitors described herein are also known as HDM2 inhibitors. In some embodiments, the MDM2 inhibitors are selected from HDM201 or CGM097.

[0608] In one embodiment, MDM2 inhibitors include (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (also known as CGM097) or compounds disclosed in PCT Publication WO 2011 / 076786 for treating a disorder, e.g., a disorder described herein. In one embodiment, a therapeutic agent disclosed herein is used in combination with CGM097.

[0609] In some embodiments, the combinations described herein include a hypomethylating agent (HMA). In some embodiments, the HMA is selected from decitabine or azacitidine.

[0610] In certain embodiments, the combinations described herein include an inhibitor that acts on any pro-survival protein of the Bcl2 family. In certain embodiments, the combinations described herein include a Bcl-2 inhibitor. In some embodiments, the Bcl-2 inhibitor is venetoclax.

[0611] [ka]

[0612] In one embodiment, the Bcl-2 inhibitor is selected from compounds described in WO 2013 / 110890 and WO 2015 / 011400. In some embodiments, the Bcl-2 inhibitor comprises navitoclax (ABT-263), ABT-737, BP1002, SPC2996, APG-1252, obatoclax mesylate (GX15-070MS), PNT2258, Zn-d5, BGB-11417, or oblimersen (G3139). In some embodiments, the Bcl-2 inhibitor is N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide, compound A1:

[0613] [ka] It is.

[0614] In some embodiments, the Bcl-2 inhibitor is (S)-5-(5-chloro-2-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide), compound A2:

[0615] [ka] It is.

[0616] In one embodiment, the DSM-drug conjugates or combinations disclosed herein are suitable for the treatment of cancer in vivo. For example, the combinations can be used to inhibit the growth of cancer tumors. The combinations can also be used in conjunction with one or more of the following to treat the disorders herein: standard of care treatments (e.g., for cancer or infectious disorders), vaccines (e.g., therapeutic cancer vaccines), cell therapy, hormonal therapy (e.g., with antiestrogens or antiandrogens), radiation therapy, surgery, or any other therapeutic agent or modality. For example, to achieve antigen-specific immune enhancement, the combinations can be administered together with the antigen of interest. The combinations disclosed herein can be administered sequentially or simultaneously. EXAMPLES

[0617] The following examples provide exemplary embodiments of the present disclosure.A person skilled in the art will recognize many modifications and variations that can be made without changing the spirit or scope of the present disclosure.Such modifications and variations are encompassed within the scope of the present disclosure.The examples provided do not limit the present disclosure in any way.

[0618] The exemplary compounds were synthesized using the exemplary methods described in this Example. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

[0619] Column chromatography: Flash chromatography was performed on a CombiFlash® Rf (Teledyne ISCO) using pre-packed silica gel cartridges (Macherey-Nagel Chromabond® Flash). Thin layer chromatography was performed using 5×10 cm plates coated with Merck Type 60 F254 silica gel.

[0620] Microwave heating: Microwave heating was performed in a CEM Discover® instrument or using an Anton Paar Monowave Microwave Reactor.

[0621] NMR:DMSO-d 6 or CDCl 3 as a solvent, 1 H-NMR measurements were performed on a 400 MHz Bruker® Avance or 500 MHz Avance Neo spectrometer. 1 H NMR data shows residual peaks of the solvent (DMSO-d 6 2.50 ppm and CDCl 3 The splitting patterns are designated as follows: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), brs (bold singlet), dd (doublet of doublet), td (triplet of doublet), dt (doublet of triplet), ddd (doublet of doublet of doublet).

[0622] IR: IR measurements were performed on a Bruker® Tensor27 equipped with an ATR Golden Gate® device (SPECAC).

[0623] Mass spectrometry: High resolution MS measurements (HRMS) were performed on an LTQ OrbiTrap® Velos Pro mass spectrometer (ThermoFisher Scientific). Samples were analyzed by CH 3 CN / H 2 The samples were dissolved in O (2 / 1: v / v) and introduced into the source by injection of 2 μL at a flow rate of 0.1 mL / min. ESI ionization parameters were as follows: mobile ion capillary at 3.5 kV and 350° C. All spectra were acquired in positive ion mode with a resolving power of 30000 or 60000 using a lock mass.

[0624] A portion of the high resolution mass spectra were acquired in positive ion mode using an Agilent® 6545 quadrupole time-of-flight mass spectrometer equipped with a Dual AJS electrospray ion source. A 0.5 μl injection was directed to the mass spectrometer using an Agilent® 1290 Infinity II HPLC system at a flow rate of 1.5 ml / min (5 mM ammonium formate in water and acetonitrile gradient program). Jet Stream parameters: drying gas (N 2 ) flow and temperature: 10.0 l / min and 300 °C, respectively; nebulizer gas (N 2 ) Pressure: 40 psi; Capillary voltage: 2500 V; Sheath gas flow and temperature: 300 °C and 10.0 l / min; QTOFMS parameters: Fragmenter voltage: 100 V; Skimmer potential: 65 V; OCT 1 RF Vpp: 750 V. Full scan mass spectra were acquired over the m / z range of 105-1700 with an acquisition rate of 995.6 ms / spectrum and processed by Agilent MassHunter B.04.00 software.

[0625] UPLC®-MS: UPLC-MS data was acquired using an instrument with the following parameters (Table 8):

[0626] [Table 10]

[0627] Preparative HPLC (preparative HPLC): Preparative HPLC ("Prep HPLC") data was obtained using an instrument with the parameters in Table 9, or using an instrument with the parameters in Table 10:

[0628] [Table 11]

[0629] [Table 12]

[0630] Three preparative HPLC methods were used: 1) TFA method: Solvent: A = water + 0.05% TFA, B = acetonitrile + 0.05% TFA, gradient of 5-100% B, 15-30 CV 2)NH 4 HCO 3 Method: Solvent: A = water + 0.02M NH 4 HCO 3 , B = acetonitrile / water 80 / 20 + 0.02M NH 4 HCO 3 , 5-100% B gradient, 15-30 CV 3) Neutral method: Solvent: A = water, B = acetonitrile, gradient of 5-100% B, 15-30 CV

[0631] Certain compounds of the present disclosure were purified using 5-25 mM NH 4 HCO 3 118 mL / min with UV diode array detection (210-400 nm) using water and MeCN or IPA, or 0.1% TFA in water and MeCN. -1 The purification was performed on a Teledyne EZ system equipped with a Gemini-NX® 10 μM C18, 250 mm×50 mm ID column operated at a flow rate of 1000 s.

[0632] All fractions containing the pure compound were combined and directly freeze-dried to yield the compound as an amorphous powder.

[0633] Chemical Naming: IUPAC preferred names were generated using the "Structure to Name" (s2n) feature of ChemAxon within MarvinSketch or JChem for Excel (JChem versions 16.6.13-18.22.3), or by the chemical naming functionality provided by Biovia® Draw 4.2.

[0634] Abbreviations: The following abbreviations are used in the examples below. Boc 2 O Di-tert-butyl dicarbonate DCM Dichloromethane DEA N,N-Diethylamine DIAD Diisopropyl azodicarboxylate DIPEA or DIEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethyl sulfoxide DTAD Di-tert-butyl azodicarboxylate EDC * HCl N-Ethyl, N'-Dimethylamino-propylcarbodiimide, Hydrochloride EEDQ Ethyl 2-ethoxy-2H-quinoline-1-carboxylate EtOAc Ethyl acetate Fmoc Fluorenylmethyloxycarbonyl h time HATU [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU [Benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium; Hexafluorophosphate HFxPyr Hydrogen Fluoride Pyridine HOAt 1-Hydroxy-7-azabenzotriazole HOBt 1-Hydroxy-benzotriazole IPA Isopropanol La(OiPr) 3 Lanthanum(III) isopropoxide min MeCN Acetonitrile MgSO 4 Magnesium sulfate MTBE Methyl tert-butyl ether Na 2 SO4 Sodium sulfate NH 4 Cl Ammonium chloride NMP N-Methylpyrrolidone Pd(Ataphos) 2 Cl 2 Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd / C Palladium(0) supported on carbon Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0) PTFE Polytetrafluoroethylene RT room temperature SOCl 2 Thionyl chloride TBAF Tetra-n-butylammonium fluoride TBAI Tetrabutylammonium iodide TEA N,N-Diethylethanamine TFA Trifluoroacetic acid THF Tetrahydrofuran THTPA Tris(3-hydroxypropyltriazolyl-methyl)amine TSTU [Dimethylamino-(2,5-dioxopyrrolidin-1-yl)oxy-methylene]-dimethyl-ammonium; Tetrafluoroborate VHL von Hippel-Lindau protein XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0635] A. Synthesis and Characterization of Bcl-xL Payload Compounds Exemplary Bcl-xL payloads were synthesized using the exemplary methods described in this Example.

[0636] Mitsunobu's General Procedure To a mixture of 1.0-1.5 equivalents of aliphatic alcohol, 1 equivalent of carbamate / phenol, and 1-2 equivalents of triphenylphosphine in THF or toluene (5 mL / mmol) was added 1-3 equivalents of di-tert-butyl azodicarboxylate / diisopropyl azodicarboxylate in one portion. The mixture was stirred at room temperature or 50° C. for carbamates and at room temperature for phenols, if necessary. After reaching an appropriate conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash column chromatography.

[0637] General procedure for deprotection with HFIP The substrate in 1,1,1,3,3,3-hexafluoropropan-2-ol (10 mL / mmol) was kept in a pressure bottle at 100-120° C. After reaching adequate conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash column chromatography.

[0638] Buchwald's General Procedure II 1 equivalent of thiazolamine, 1.2 to 1.5 equivalents of (Z)-N-(6-chloro-4-methyl-pyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-imine, and 3 equivalents of Cs in 1,4-dioxane (5 mL / mmol). 2 CO 3 , 0.1 equivalent of Pd 2 (dba) 3 A mixture of 0.2 equivalents of Xantphos and 3 equivalents of DIPEA was kept at reflux. After reaching a suitable conversion, the volatiles were removed under reduced pressure and the crude intermediate was purified via flash column chromatography.

[0639] General procedure for deprotection and hydrolysis A mixture of 1 equivalent of substrate and 100 equivalents of HF×Pyr in MeCN (15 mL / mmol) was stirred at 60° C. After adequate conversion was reached, the volatiles were removed under reduced pressure and the residue was suspended in a 1:1 mixture of 1,4-dioxane-water (30 mL / mmol) and 150 equivalents of LiOH×H 2O and stirred at 60 °C. After reaching a suitable conversion, the volatiles were removed under reduced pressure and the crude product was purified by elution with DCM and MeOH (1.2% NH 3 The product was purified via flash column chromatography using hexanes (containing hexane).

[0640] Preparation 1: 3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propan-1-ol

[0641] [ka] Step A: [(pent-4-yn-1-yloxy)methyl]benzene To an oven-dried flask was added 4-pentyn-1-ol (11.1 mL, 119 mmol, 1 equiv) in THF (100 mL) and the solution was cooled to 0° C. Sodium hydride (60% dispersion; 7.13 g, 1.5 equiv) was added portionwise and the mixture was stirred at 0° C. for 30 min before benzyl bromide (15.6 mL, 131 mmol, 1.1 equiv) was added dropwise. The mixture was warmed to ambient temperature and stirred for 16 h, then cooled to 0° C., quenched with saturated aqueous ammonium chloride (30 mL) and diluted with water (30 mL). The mixture was extracted with ethyl acetate (2×150 mL) and the combined organic extracts were washed successively with dilute aqueous ammonium hydroxide (150 mL) and brine (100 mL), dried (magnesium sulfate) and concentrated in vacuo. Purification by automated flash column chromatography (CombiFlash Rf, 330 g RediSep™ silica cartridge) eluting with a gradient of ethyl acetate in isoheptane gave the desired product (19.5 g, 94%). 1 H NMR (400 MHz, chloroform-d) δ 7.37 - 7.32 (m, 4H), 7.31 - 7.27 (m, 1H), 4.52 (s, 2H), 3.58 (t, J = 6.1 Hz, 2H), 2.32 (td, J = 7.1, 2.6 Hz, 2H), 1.95 (t, J = 2.7 Hz, 1H), 1.83 (tt, J = 7.1, 6.2 Hz, 2H); LC / MS (C12 H 14 O) 175 [M+H] + .

[0642] Step B: [(hex-4-yn-1-yloxy)methyl]benzene To an oven-dried flask was added the product from Step A (19.5 g, 112 mmol, 1 equiv) and tetrahydrofuran (200 mL) and the solution was cooled to -78°C. n-Butyllithium (2M solution in hexanes, 66.9 mL, 135 mmol, 1.2 equiv) was added dropwise over 30 min and the reaction was stirred for 1 h, then iodomethane (10.5 mL, 168 mmol, 1.5 equiv) was added dropwise and the mixture was warmed to 0°C over 1 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (40 mL), diluted with water (40 mL), extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were washed successively with 2M aqueous sodium thiosulfate solution (200 mL) and brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo. Purification by automated flash column chromatography (CombiFlash Rf, 330 g RediSep™ silica cartridge) eluting with a gradient of 0-10% ethyl acetate in isoheptane gave the desired product (19.2 g, 91%). 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.23 (m, 5H), 4.46 (s, 2H), 3.48 (t, J = 6.3 Hz, 2H), 2.23 - 2.14 (m, 2H), 1.72 (s, 3H), 1.70 - 1.65 (m, 2H); LC / MS (C 13 H 16 O) 189 [M+H] + .

[0643] Step C: 4-[3-(benzyloxy)propyl]-3,6-dichloro-5-methylpyridazine A solution of 3,6-dichloro-1,2,4,5-tetrazine (5 g, 33.1 mmol, 1 equiv) and the product from step B (7.48 g, 39.8 mmol, 1.2 equiv) in tetrahydrofuran (30 mL) was heated at 160° C. for 19 h in a sealed flask. The reaction was cooled to ambient temperature and then concentrated in vacuo. Purification by automated flash column chromatography (CombiFlash Rf, 220 g RediSep™ silica cartridge) eluting with a gradient of 0-30% ethyl acetate in isoheptane gave the desired product (7.32 g, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 7.45 - 7.18 (m, 5H), 4.48 (s, 2H), 3.53 (t, J = 5.9 Hz, 2H), 2.96 - 2.83 (m, 2H), 2.42 (s, 3H), 1.88 - 1.69 (m, 2H); LC / MS (C 15 H 16 Cl 2 N 2 O) 311 [M+H] + .

[0644] Step D: 3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propan-1-ol To a cooled solution of the product from step C (7.32 g, 23.5 mmol, 1 equiv) in dichloromethane (100 mL) was added dropwise a boron trichloride solution (1 M in dichloromethane; 58.8 mL, 58.8 mmol, 2.5 equiv) and the mixture was stirred at ambient temperature for 1 h. The reaction was quenched by the addition of methanol and concentrated in vacuo. The residue was partitioned between dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (150 mL) and the organic phase was washed with brine (150 mL), dried (magnesium sulfate) and concentrated in vacuo. Purification by automated flash column chromatography (CombiFlash Rf, 80 g RediSep™ silica cartridge) eluting with a gradient of 0-80% ethyl acetate in isoheptane gave the desired product (4.19 g, 81%). 1 H NMR (400 MHz, DMSO-d 6) δ 4.67 (t, J = 5.1 Hz, 1H), 3.49 (td, J = 6.0, 5.1 Hz, 2H), 2.91 - 2.80 (m, 2H), 2.43 (s, 3H), 1.72 - 1.59 (m, 2H); LC / MS (C 8 H 10 Cl 2 N 2 O) 221 [M+H] + .

[0645] Preparation 2: Methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate

[0646] [ka] Step A: Methyl 6-[bis(tert-butoxycarbonyl)amino]-3-bromo-pyridine-2-carboxylate Methyl 6-amino-3-bromo-pyridine-2-carboxylate (25.0 g, 108.2 mmol) and DMAP (1.3 g, 0.1 equiv.) in DCM (541 mL) were added at 0° C. to Boc 2 O (59.0 g, 2.5 equiv.) was added and the reaction mixture was stirred for 2.5 h. 3 After addition of a saturated solution of and extraction with DCM, the combined organic phases were dried and concentrated to give the desired product (45.0 g, 72.3%). 17 H 23 BrN 2 O 6 Na) 453 [M+Na] + .

[0647] Step B: Methyl 3-bromo-6-(tert-butoxycarbonylamino)pyridine-2-carboxylate To the product from Step A (42.7 g, 74.34 mmol) in DCM (370 mL) was added TFA (17.1 mL, 3 eq) at 0° C. and the reaction mixture was stirred for 18 h. 3After washing with a saturated solution of and brine, the combined organic phase was dried, concentrated and purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (28.3 g, 115.2%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 10.29 (s, 1H), 8.11 (d, 1H), 7.88 (d, 1H), 3.87 (s, 3H), 1.46 (s, 9H) 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 165.6, 153.1, 151.8 / 148.3, 143.5, 116.3, 109.2, 53.2, 28.4. LC / MS (C 12 H 15 BrN 2 O 4 Na) 353 [M+Na] + .

[0648] Step C: Methyl 3-bromo-6-[tert-butoxycarbonyl-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propyl]amino]pyridine-2-carboxylate The product of Step B (748 mg, 2.2 mmol), the product of Preparation 1 (500 mg, 1 equiv.) and PPh 3 (593 mg, 1 equiv.) was mixed in toluene (10 mL), followed by addition of DTAD (520 mg, 1 equiv.) and stirring for 30 min at 50° C. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) afforded the desired product (1.1 g, 91%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.13 (d, 1H), 7.78 (d, 1H), 3.91 (t, 2H), 3.89 (s, 3H), 2.79 (m, 2H), 2.38 (s, 3H), 1.82 (m, 2H), 1.46 (s, 9H); 13 C NMR (100 MHz, DMSO-d 6) δ ppm 165.3, 157.6, 156.6, 153.2, 152.9, 147.2, 143.1, 142.2, 139.7, 122.6, 111.8, 82.2, 53.3, 46.4, 28.1, 27.7, 26.5, 16.3; HRMS-ESI (m / z): [M+Na] + C 20 H 23 BrCl 2 N 4 NaO 4 Calculated value: 555.0177 Measured value: 555.0172.

[0649] Step D: Methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate The product from step C (17.5 g, 32.7 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (330 mL) was stirred for 18 h at 110° C. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) afforded the desired product (9.9 g, 70%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.63 (d, 1H), 7.22 (t, 1H), 6.57 (d, 1H), 3.83 (s, 3H), 3.30 (m, 2H), 2.83 (m, 2H), 2.37 (s, 3H), 1.74 (m, 2H) 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 166.5, 141.5, 112.6, 52.9, 40.9, 28.0, 27.0, 16.4.

[0650] Preparation 3: tert-Butyl-diphenyl-[2-[[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]oxy]ethoxy]silane

[0651] [ka] Step A: 3-Bromo-5,7-dimethyladamantane-1-carboxylic acid After stirring iron (6.7 g, 120 mmol) in bromine (30.7 mL, 600 mmol, 5 equiv.) at 0° C. for 1 h, 3,5-dimethyladamantane-1-carboxylic acid (25 g, 1 equiv.) was added and the reaction mixture was stirred at room temperature for 2 days. After adding EtOAc, the reaction mixture was carefully treated with a saturated solution of sodium thiosulfate at 0° C. and stirred for 15 min. After filtering through a pad of Celite and rinsing with EtOAc, the organic phase was separated, washed with a saturated solution of sodium thiosulfate and brine, dried and concentrated to give the desired product (34.28 g, 74.6%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 12.33 (br s, 1H), 2.21 (s, 2H), 1.96 / 1.91 (d+d, 4H), 1.50 / 1.43 (d+d, 4H), 1.21 / 1.14 (dm+dm, 2H), 0.86 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 176.8, 66.8, 54.0, 48.7, 48.5, 45.7, 43.3, 35.5, 29.4; HRMS-ESI (m / z): [MH]- C 13 H 18 Bro 2 Calculated value: 285.0496; Measured value: 285.0498.

[0652] Step B: 3-Bromo-5,7-dimethyl-1-adamantyl-methanol To the product from Step A (34.3 g, 119 mmol) in THF (77.6 mL) was added BH 3A 1M solution of -THF in THF (358 mL, 3 eq.) was slowly added and the reaction mixture was stirred for 18 h. Methanol was added and stirred for 30 min, after which it was purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (16.19 g, 49.6%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 4.51 (t, 1H), 3.05 (d, 2H), 1.91 (s, 2H), 1.91 (s, 4H), 1.19 / 1.09 (d+d, 2H), 1.19 / 1.05 (d+d, 4H), 0.85 (s, 6H) 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 70.4, 68.9, 54.9, 49.8, 49.3, 43.8, 41.4, 35.7, 29.7; HRMS-ESI (m / z): [M-Br]- C 13 H 21 Calculated O: 193.1598 Measured: 193.1589.

[0653] Step C: 1-[(3-bromo-5,7-dimethyl-1-adamantyl)methyl]pyrazole To the product from step B (16.19 g, 59.26 mmol) and 1H-pyrazole (4.841 g, 1.2 equiv.) in toluene (178 mL) was added cyanomethylenetributylphosphorane (18.64 mL, 1.2 equiv.) in one portion and the reaction mixture was stirred for 2 h at 90° C. Purification by column chromatography (silica gel, heptane and MTBE as eluents) afforded the desired product (17.88 g, 93%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.63 (d, 1H), 7.43 (d, 1H), 6.23 (t, 1H), 3.90 (s, 2H), 1.92-1.02 (m, 12H), 0.83 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6) δ ppm 139.0, 131.8, 105.2, 67.7, 61.4, 54.4 / 48.8 / 44.6, 50.4, 35.7, 29.6; HRMS-ESI (m / z): [M]+ C 16 H 23 BrN 2 Calculated value: 322.1045 Measured value: 322.1014.

[0654] Step D: 5-Methyl-1-[(3-bromo-5,7-dimethyl-1-adamantyl)methyl]pyrazole To a solution of the product from step C (17.88 g, 55.3 mmol) in THF (277 mL) at -78°C was added butyllithium (2.5 M in THF, 66 mL, 3 equiv.) and after 1 h iodomethane (17.2 mL, 5 equiv.). After 10 min, the reaction mixture was diluted with NH 4 Quenched with a saturated solution of Cl, extracted with EtOAc, the combined organic layers were dried and concentrated to give the desired product (18.7 g, 100%) which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.31 (d, 1H), 6.00 (d, 1H), 3.79 (s, 2H), 2.23 (s, 3H), 2.01 (s, 2H), 1.89 / 1.85 (d+d, 4H), 1.23 / 1.15 (d+d, 4H), 1.16 / 1.05 (d+d, 2H), 0.83 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 139.2, 138.0, 105.2, 67.8, 57.8, 54.4, 50.6, 48.8, 44.8, 41.5, 35.7, 29.6, 11.8; HRMS-ESI (m / z): [M+H]+ C 17 H 26 BrN 2 Calculated value: 337.1279 Measured value: 337.1289.

[0655] Step E: 2-[[3,5-dimethyl-7-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]oxy]ethanol A mixture of the product from step D (18.7 g, 55.3 mmol), ethylene glycol (123 mL, 40 equiv.) and DIPEA (48.2 mL, 5 equiv.) was stirred for 6 h at 120° C. After diluting the reaction mixture with water and extracting with EtOAc, the combined organic layers were dried and concentrated to give the desired product (18.5 g, 105%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.29 (d, 1H), 5.99 (d, 1H), 4.45 (t, 1H), 3.78 (s, 2H), 3.39 (q, 2H), 3.32 (t, 2H), 2.23 (s, 3H), 1.34 (s, 2H), 1.27 / 1.21 (d+d, 4H), 1.13 / 1.07 (d+d, 4H), 1.04 / 0.97 (d+d, 2H), 0.84 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 139.0, 137.8, 105.1, 74.0, 62.1, 61.5, 58.5, 50.1, 47.0, 46.1, 43.3, 39.7, 33.5, 30.2, 11.9; HRMS-ESI (m / z): [M+H]+ C 19 H 31 N 2 O 2 Calculated value: 319.2386 Measured value: 319.2387.

[0656] Step F: tert-Butyl-diphenyl-[2-[[3,5-dimethyl-7-[(5-methylpyrazol-1-yl)methyl]-1-adamantyl]oxy]ethoxy]silane To a mixture of the product from step E (17.6 g, 55.3 mmol) and imidazole (5.65 g, 1.5 equiv.) in DCM (150 ml) was added tert-butyl-chloro-diphenyl-silane (18.6 g, 1.2 equiv.) and the reaction mixture was stirred for 1 h. Purification by column chromatography (silica gel, heptane and MTBE as eluents) afforded the desired product (27.0 g, 87.8%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.72-7.34 (m, 10H), 7.29 (d, 1H), 5.99 (br s, 1H), 3.78 (s, 2H), 3.67 (t, 2H), 3.44 (t, 2H), 2.21 (s, 3H), 1.33 (s, 2H), 1.26 / 1.18 (d+d, 4H), 1.12 / 1.06 (d+d, 4H), 1.03 / 0.96 (d+d, 2H), 0.98 (s, 9H), 0.82 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 139.0, 137.8, 105.1, 74.2, 64.4, 61.7, 58.5, 50.0, 46.9, 46.0, 43.4, 39.6, 33.5, 30.1, 27.1, 19.3, 11.9; HRMS-ESI (m / z): [M+H] + C 35 H 49 N 2 O 2 Calculated Si: 557.3563 Measured: 557.3564.

[0657] Step G: tert-Butyl-diphenyl-[2-[[3-[(4-iodo-5-methyl-pyrazol-1-yl)methyl]-5,7-dimethyl-1-adamantyl]oxy]ethoxy]silane To a solution of the product from step F (27.0 g, 48.56 mmol) in DMF (243 mL) was added N-iodosuccinimide (13.6 g, 1.25 equiv.) and the reaction mixture was stirred for 2 h. After dilution with water, the mixture was extracted with DCM. The combined organic layers were washed with a saturated solution of sodium thiosulfate and brine, dried and concentrated to give the desired product (30.1 g, 90%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.68-7.37 (m, 10H), 7.45 (s, 1H), 3.89 (s, 2H), 3.67 (t, 2H), 3.44 (t, 2H), 2.23 (s, 3H), 1.30 (s, 2H), 1.26 / 1.17 (d+d, 4H), 1.12 / 1.05 (d+d, 4H), 1.00 / 0.96 (d+d, 2H), 0.98 (s, 9H), 0.82 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 142.5, 140.8, 133.7, 64.4, 61.7, 60.3, 59.9, 49.9, 46.8, 45.9, 43.2, 39.7, 33.5, 30.1, 27.1, 19.3, 12.2; HRMS-ESI (m / z): [M+H] + C 35 H 48 IN 2 O 2 Calculated Si: 683.2530 Measured: 683.2533.

[0658] Step H: tert-Butyl-diphenyl-[2-[[3,5-dimethyl-7-[[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]-1-adamantyl]oxy]ethoxy]silane To the product from step G (17.5 g, 25.6 mmol) in THF (128 mL) at 0° C. was added chloro(isopropyl)magnesium-LiCl (1.3 M in THF, 24 mL, 1.2 equiv.), stirred for 40 min, treated with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15.7 mL, 3 equiv.) and the reaction mixture was stirred for 10 min. Saturated NH 4 After dilution with Cl solution and extraction with EtOAc, the combined organic phases were concentrated and purified by column chromatography (silica gel, heptane and MTBE as eluents) to give the desired product (15.2 g, 86.9%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.65 (dm, 4H), 7.47 (s, 1H), 7.45 (tm, 2H), 7.40 (tm, 4H), 3.80 (s, 2H), 3.66 (t, 2 H), 3.44 (t, 2H), 2.35 (s, 3H), 1.35-0.94 (m, 12H), 1.24 (s, 12H), 0.97 (s, 9H), 0.83 (s, 6H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 146.9, 144.3, 135.6, 130.2, 128.2, 104.7, 83.0, 74.2, 64.4, 61.7, 58.4, 30.1, 27.1, 25.2, 19.3, 12.0; HRMS-ESI (m / z): [M+H] + C 41 H 60 BN 2 O 4 Calculated Si: 683.4415 Measured: 683.4423.

[0659] Preparation 4: (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(methylamino)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate

[0660] [ka] Step A: 3-Bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylic acid To the product of Preparation 2 (23.3 g, 53.7 mmol) in 1,4-dioxane (215 mL) and water (54 mL) was added LiOHxH 2 O (13.5 g, 6 equiv.) was added and the mixture was stirred for 1 h at 60° C. The reaction was quenched by addition of 1 M aqueous HCl and the product was filtered off to give the desired product (21.7 g, 96%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 13.30 (s, 1H), 7.60 (d, 1H), 7.14 (t, 1H), 6.53 (d, 1H), 3.32 (m, 2H), 2.84 (m, 2H), 2.77 (s, 3H), 1.74 (m, 2H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 167.5, 157.6, 157.4, 156.8, 149.4, 142.7, 141.4, 139.8, 112.0, 101.1, 40.9, 28.1, 27.1, 16.5; HRMS-ESI (m / z): [M+H] + C 14 H 14 BrCl 2 N 4 O 2 Calculated value: 418.9677, Measured value: 418.9681.

[0661] Step B: (4-Methoxyphenyl)methyl 3-bromo-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate To the product of step A (11.2 g, 26.6 mmol), (4-methoxyphenyl)methanol (6.6 mL, 2 equiv.), triphenylphosphine (13.9 g, 2 equiv.) in toluene (266 mL) and THF (20 ml), DIAD (10.5 mL, 2 equiv.) was added dropwise and the reaction was maintained at 50° C. for 1 h. The crude product was purified by flash chromatography on silica gel using heptane and EtOAc as eluents to give the desired product (10.4 g, 72.5%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.62 (d, 1H), 7.37 (dn, 2H), 7.21 (t, 1H), 6.91 (dm, 2H), 6.56 (d, 1H), 5.25 (s, 2H), 3.74 (s, 3H), 3.30 (q, 2H), 2.81 (m, 2H), 2.33 (s, 3H), 1.73 (m, 2H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 165.9, 159.7, 157.6, 157.5, 156.8, 148.0, 142.7, 141.5, 139.7, 130.6, 127.8, 114.3, 112.6, 101.6, 67.0, 55.6, 40.9, 28.0, 27.1, 16.4; HRMS-ESI (m / z): [M+H] + C 22 H 22 BrCl 2 N 4 O 3 Calculated value: 539.0252, Measured value: 539.0246.

[0662] Step C: (4-Methoxyphenyl)methyl 3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-[3-(3,6-dichloro-5-methyl-pyridazin-4-yl)propylamino]pyridine-2-carboxylate Product of Step B (27.0 g, 50.0 mmol), Preparation 3 (37.5 g, 1.1 equiv.), Cs 2 CO 3 (48.9g, 3 equivalents), Pd(AtaPhos) 2 Cl 2 (2.21 g, 0.1 equiv.) of 1,4-dioxane (300 mL) and H 2 The mixture in O (50 mL) was maintained at 80° C. for 6 h. After cooling and quenching by addition of saturated aqueous NaCl, the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated to give the desired product (54.0 g, 106%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.68-7.35 (m, 10H), 7.31 (d, 1H), 7.27 (s, 1H), 7.11 (dm, 2H), 6.98 (t, 1H), 6.83 (dm, 2H), 6.62 (d, 1H), 4.99 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 3.65 (t, 2H), 3.44 (t, 2H), 3.34 (q, 2H), 2.84 (m, 2H), 2.34 (s, 3H), 2.01 (s, 3H), 1.77 (m, 2H), 1.38-0.89 (m, 12H), 0.97 (s, 9H), 0.82 (s, 6H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 140.4, 137.6, 130.1, 114.2, 110.3, 66.3, 64.4, 61.7, 59.0, 55.5, 40.9, 30.1, 28.1, 27.3, 27.1, 16.4, 10.8; HRMS-ESI (m / z): [M+H] + C 57H 69 Cl 2 N 6 O 5 Calculated Si: 1015.4476, Measured: 1015.4474.

[0663] Step D: (4-Methoxyphenyl)methyl 3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)pyridine-2-carboxylate The product of step C (26.0 g, 25.6 mmol), Cs 2 CO 3 (9.87 g, 2 equiv.), DIPEA (8.9 mL, 2 equiv.) and Pd(Ataphos). 2 Cl 2 A mixture of (1.1 g, 0.1 equiv.) in 1,4-dioxane (128 mL) was stirred in a 200 ml pressure bottle at 110° C. for 18 h. After dilution with water, the mixture was extracted with EtOAc. The combined organic layers were dried and concentrated to give the desired product (24.8 g, 98.9%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.84 (d, 1H), 7.67 (d, 1H), 7.65 (d, 4H), 7.44 (t, 2H), 7.41 (s, 1H), 7.40 (t, 4H), 7.15 (d, 2H), 6.87 (d, 2H), 5.07 (s, 2H), 3.96 (t, 2H), 3.83 (s, 2H), 3.71 (s, 3H), 3.66 (t, 2H), 3.45 (t, 2H), 2.86 (t, 2H), 2.29 (s, 3H), 2.08 (s, 3H), 1.97 (qn, 2H), 1.38 (s, 2H), 1.25 / 1.18 (d+d, 4H), 1.18 / 1.12 (d+d, 4H), 1.01 / 0.93 (d+d, 2H), 0.97 (s, 9H), 0.82 (s, 6H); 13C NMR (125 MHz, DMSO-d 6 ) δ ppm 166.8, 159.7, 156.3, 153.6, 150.8, 147.7, 140.1, 137.6, 137.3, 136.0, 135.6, 133.8, 130.2, 130.2, 129.1, 128.2, 127.7, 123.0, 120.4, 115.6, 114.3, 74.2, 66.8, 64.4, 61.7, 59.3, 55.6, 49.9, 46.8, 46.0, 46.0, 43.3, 39.7, 33.6, 30.1, 27.1, 24.6, 21.0, 19.3, 15.5, 10.8; HRMS-ESI (m / z): [M+H] + C 57 H 68 ClN 6 O 5 Calculated Si: 979.4709, Measured: 979.4710.

[0664] Step E: (4-Methoxyphenyl)methyl 6-(3-chloro-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl)-3-[1-[[3-(2-hydroxyethoxy)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step D (3.40 g, 3.47 mmol) in THF (34.7 mL) was added a 1M solution of TBAF in THF (3.82 mL, 1.1 equiv) at 0° C. and the mixture was stirred at room temperature for 90 min. NH 4 After quenching with a saturated solution of Cl, the product was purified by flash chromatography on a silica gel column using DCM and MeOH as eluents to give the desired product (1.80 g, 70%). 1 H NMR (500 MHz, DMSO-d 6) δ ppm 7.85 (d, 1H), 7.70 (d, 1H), 7.39 (s, 1H), 7.18 (d, 2H), 6.9 (d, 2H), 5.10 (s, 2H), 4.45 (t, 1H), 3.96 (t, 2H), 3.84 (s, 2H), 3.74 (s, 3H), 3.40 (q, 2H), 3.33 (t, 2H), 2.86 (t, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 1.98 (qn, 2H), 1.39 (s, 2H), 1.27 / 1.21 (d+d, 4H), 1.18 / 1.12 (d+d, 4H), 1.03 / 0.94 (d+d, 2H), 0.84 (s, 6H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 166.8, 159.7, 156.3, 153.6, 150.8, 147.8, 140.2, 137.6, 137.3, 136.0, 130.2, 129.1, 127.7, 123.0, 120.4, 115.6, 114.3, 74.0, 66.8, 62.2, 61.5, 59.0, 55.6, 50.0, 46.9, 46.0, 46.0, 43.3, 39.7, 33.5, 30.1, 24.6, 21.0, 15.5, 10.9. HRMS-ESI (m / z): [M+H] + C 41 H 50 ClN 6 O 5 Calculated value: 741.3531, Measured value: 741.3530.

[0665] Step F: (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3-(2-hydroxyethoxy)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate Step E product (4.70 g, 6.30 mmol), 1,3-benzothiazol-2-amine (1.90 g, 2 equiv.), DIPEA (3.30 mL, 3 equiv.), Pd 2 (dba) 3 A mixture of XantPhos (580 mg, 0.1 equiv.) and XantPhos (730 mg, 0.2 equiv.) in cyclohexanol (38 mL) was maintained at 130° C. for 2 h. The product was then purified by column chromatography (silica gel, heptane, EtOAc and MeOH as eluents) to give the desired product (3.83 g, 71%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.95 (d, 1H), 7.81 (br d, 1H), 7.69 (d, 1H), 7.49 (br s, 1H), 7.39 (s, 1H), 7.35 (m, 1H), 7.19 (m, 2H), 7.16 (m, 1H), 6.91 (m, 2H), 5.10 (s, 2H), 4.46 (t, 1H), 3.99 (m, 2H), 3.85 (s, 2H), 3.75 (s, 3H), 3.40 (m, 2H), 3.34 (t, 2H), 2.85 (t, 2H), 2.32 (s, 3H), 2.11 (s, 3H), 1.99 (m, 2H), 1.45-0.90 (m, 12H), 0.84 (s, 6H); HRMS-ESI (m / z): [M+H] + C 48 H 55 N 8 O 5 Calculated S: 855.4016, Measured: 855.4011.

[0666] Step G: (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(p-tolylsulfonyloxy)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step F (3.83 g, 4.48 mmol) and triethylamine (1.87 mL, 3 equiv.) in DCM (45 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (2.19 g, 1.5 equiv.) at 0° C. and the mixture was stirred at room temperature for 2 h. The crude product was purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (2.50 g, 55%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.95 (d, 1H), 7.81 (br s, 1H), 7.76 (m, 2H), 7.45 (br s, 1H), 7.45 (m, 2H), 7.40 (s, 1H), 7.35 (m, 1H), 7.18 (m, 2H), 7.17 (m, 1H), 6.97 (d, 1H), 6.90 (m, 2H), 5.10 (s, 2H), 4.05 (m, 2H), 4.00 (m, 2H), 3.82 (s, 2H), 3.74 (s, 3H), 3.47 (m, 2H), 2.85 (m, 2H), 2.40 (s, 3H), 2.32 (s, HRMS-ESI (m / z): [M+H] + C 55 H 61 N 8 O 7 S 2 Calculated value: 1009.4105, Measured value: 1009.4102.

[0667] Step H: (4-Methoxyphenyl)methyl 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-[2-(methylamino)ethoxy]-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step G (2.00 g, 1.98 mmol) in MeCN (9.9 mL) was added a 2 M solution of methanamine in THF (9.9 mL, 10 equiv.) and the mixture was stirred in a sealed bottle at 50° C. for 18 h. The crude product was purified by column chromatography (silica gel, using heptane, EtOAc and MeOH as eluents) and preparative HPLC (Interchim method) (C18, 5 mM NH 4 HCO 3 Purification by aqueous solution, MeCN) afforded the desired product (922 mg, 54%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.94 (d, 1H), 7.81 (dm, 1H), 7.68 (d, 1H), 7.50 (brd, 1H), 7.39 (s, 1H), 7.35 (m, 1H), 7.19 (m, 2H), 7.16 (m, 1H), 6.94 (m, 2H), 5.10 (s, 2H), 3.99 (m, 2H), 3.85 (s, 2H), 3.75 (s, 3H), 3.37 (t, 2H), 2.85 (t, 2H), 2.51 (t, 2H), 2.32 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H), 1.98 (m, 2H), 1.44-0.90 (m, 12H), 0.84 (s, 6H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 140.0, 137.7, 130.2, 126.4, 122.3, 122.0, 118.9, 116.9, 114.3, 60.7, 59.4, 59.0, 55.6, 52.2, 45.4, 36.5, 30.1, 24.3, 21.7, 12.6, 10.9; HRMS-ESI (m / z): [M+H] + C 49 H 58 N 9 O 4 Calculated S: 868.4332, Measured: 868.4329.

[0668] Preparation 5: 6-[3-(1,3-benzothiazol-2-ylamino)-4-methyl-6,7-dihydro-5H-pyrido[2,3-c]pyridazin-8-yl]-3-[1-[[3,5-dimethyl-7-(2-piperazin-1-ylethoxy)-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylic acid

[0669] [ka] The product of Preparation 4, Step G (570 mg, 0.61 mmol) and piperazine (440 mg, 8.4 equiv.) were stirred in MeCN (10.0 mL) at 50° C. for 18 h, followed by addition of 10% aqueous KOH (2.0 mL) and stirring at 50° C. for 4 h. The crude product was purified by column chromatography (silica gel, using heptane, EtOAc and MeOH as eluents) and preparative HPLC (Interchim method) (C18, 5 mM NH 4 HCO 3 Purification by aqueous solution, MeCN) afforded the desired product (247 mg, 51%). 1 H NMR (500 MHz, dmso-d6) δ ppm 7.80 (brd, 1H), 7.61 (d, 1H), 7.50 (brs, 1H), 7.50 (s, 1H), 7.46 (d, 1H), 7.34 (m, 1H), 7.16 (m, 1H), 3.96 (m, 2H), 3.85 (s, 2H), 3.49 (t, 2H), 2.95 (m, 4H), 2.85 (t, 2H), 2.73 (m, 4H), 2.71 (t, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.41-1.03 (m, 12H), 0.88 (s, 6H); 13 C NMR (125 MHz, DMSO-D6) δ ppm 138.8, 138.3, 126.4, 122.3, 122.0, 115.6, 59.0, 57.3, 57.0, 49.6, 45.6, 43.2, 30.1, 24.5, 21.7, 12.5, 11.5; HRMS-ESI (m / z): [M+H]+ C44 H 55 N 10 O 3 Calculated S: 803.4179, Measured: 803.4177.

[0670] Preparation 6: (Z)-N-(6-chloro-4-methyl-pyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-imine

[0671] [ka] Step A: N-(6-chloro-4-methyl-pyridazin-3-yl)-1,3-benzothiazol-2-amine 6-Chloro-4-methyl-pyridazin-3-amine (34.0 g, 236 mmol), 2-chloro-1,3-benzothiazole (44.1 g, 1.1 equiv.), diisopropylethylamine (123 mL, 3 equiv.), Cs 2 CO 3 (137g, 3 equivalents), Pd 2 (dba) 3 (2.0 g, 0.025 eq.) and XantPhos (6.8 g, 0.05 eq.) were stirred in DMF (1 L) at 75° C. for 4 h, after which the reaction mixture was diluted with water and the crude product was filtered off. 2 After trituration in O (3:2), the desired product (68.4 g, 104%) was obtained. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 11.96 (br s, 1H), 7.86 (d, 1H), 7.65 (s, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.21 (t, 1H), 2.37 (s, 3H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 130.3, 129.5, 126.6, 122.8, 122.3, 17.2; HRMS-ESI (m / z): [M+H] + C 12 H 10 ClN 4Calculated S: 277.0315, Measured: 277.0305.

[0672] Step B: (Z)-N-(6-chloro-4-methyl-pyridazin-3-yl)-3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-imine To the product of step A (68.4 g, 247 mmol) and diisopropylethylamine (129 mL, 3 equiv.) in DCM (1 L) was added 2-(chloromethoxy)ethyl-trimethyl-silane (48.1 mL, 1.1 equiv.) at 0° C. and the mixture was stirred at room temperature for 15 min. The reaction was quenched by addition of water and the product was purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (42.1 g, 42%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.85 (dm, 1H), 7.72 (q, 1H), 7.53 (dm, 1H), 7.47 (m, 1H), 7.29 (m, 1H), 5.89 (s, 2H), 3.70 (m, 2H), 2.39 (d, 3H), 0.90 (m, 2H), -0.12 (s, 9H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 159.5, 158.5, 150.0, 138.1, 137.4, 129.5, 127.4, 125.5, 123.8, 123.2, 112.4, 73.0, 66.8, 17.7, 17.1, -1.0; HRMS-ESI (m / z): [M+H] + C 18 H 24 ClN 4 OSSi calculated value: 407.1129, measured value: 407.1120.

[0673] Preparation 7: (4-Methoxyphenyl)methyl 6-[5-azidopentyl-[5-methyl-6-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]pyridazin-3-yl]amino]-3-[1-[[3-[2-(dimethylamino)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate

[0674] [ka] Step A: Methyl 3-bromo-6-[tert-butoxycarbonyl(5-chloropentyl)amino]pyridine-2-carboxylate The product of Preparation 2, Step B (4.48 g, 13.5 mmol), 1-chloro-5-iodo-pentane (1.89 mL, 1 equiv.) and Cs 2 CO 3 (13.2 g, 3 equiv.) was stirred in acetone (68 mL) for 18 h, after which the reaction was quenched by addition of water and extracted with EtOAc. After concentration of the organic phase, the crude product was purified by column chromatography (silica gel, using heptane, EtOAc as eluent) to give 4.89 g (83%) of the desired product. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.13 (d, 1H), 7.73 (d, 1H), 3.89 (s, 3H), 3.82 (t, 2H), 3.61 (t, 2H), 1.71 (m, 2H), 1.57 (m, 2H), 1.47 (s, 9H), 1.36 (m, 2H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 143.1, 123.1, 53.4, 46.3, 45.7, 31.8, 28.2, 27.6, 23.8; HRMS (ESI) [M+H] + C 17 H 25 BrClN 2 O 4 Calculated value: 435.0686, Measured value = 435.0682.

[0675] Step B: Methyl 3-bromo-6-(5-chloropentylamino)pyridine-2-carboxylate To the product of Step A (4.0 g, 9.2 mmol) in DCM (46 mL) was added TFA (4.3 mL, 6 equiv.) and the reaction mixture was stirred at 40° C. for 1 h. 3 After addition of a saturated solution of and extraction with DCM, the combined organic phases were dried and concentrated to give the desired product (3.0 g, 97%). LC / MS(C 12 H 17 BrClN 2 O 2 )335[M+H] + .

[0676] Step C: (4-Methoxyphenyl)methyl 3-bromo-6-(5-chloropentylamino)pyridine-2-carboxylate Product of Step B (2.86 g, 8.5 mmol), (4-methoxyphenyl)methanol (1.27 mL, 1.2 equiv), La(OiPr) 3 After stirring (270 mg, 0.1 equiv.), 2-(2-hydroxyethoxy)ethanol (0.080 mL, 0.1 equiv.) and 5A molecular sieves (2.86 g) in hexanes (17 mL) at 65° C. for 48 h, the desired product (2.23 g, 59%) was isolated by column chromatography (silica gel, using heptane, EtOAc as eluent). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.59 (d, 1H), 7.39 (dm, 2H), 7.07 (t, 1H), 6.95 (dm, 2H), 6.53 (d, 1H), 5.25 (s, 2H), 3.75 (s, 3H), 3.61 (t, 2H), 3.16 (q, 2H), 1.71 (m, 2H), 1.51 (m, 2H), 1.41 (m, 2H); 13 C NMR (125 MHz, DMSO-d 6) δ ppm 166.0, 159.8, 157.6, 148.1, 141.3, 130.6, 127.9, 114.3, 112.4, 101.2, 67.0, 55.6, 45.8, 40.9, 32.2, 28.3, 24.3; HRMS (ESI) [M+H] + C 19 H 23 BrClN 2 O 3 Calculated value: 441.0581, Measured value = 441.0577.

[0677] Step D: (4-Methoxyphenyl)methyl 3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-(5-chloropentylamino)pyridine-2-carboxylate Product of Step C (2.00 g, 4.53 mmol), Preparation 3 (4.02 g, 1.3 equiv.), Cs 2 CO 3 (4.43 g, 3 equiv.) and Pd(AtaPhos) 2 Cl 2 (200 mg, 0.1 equiv.) of 1,4-dioxane (27 mL) and H 2 The mixture in O (4.5 mL) was stirred at 80° C. for 1.5 h. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) afforded the desired product (4.0 g, 96%). 1 H NMR (500 MHz, DMSO-d 6) δ ppm 7.69-7.35 (m, 10H), 7.28 (d, 1H), 7.25 (s, 1H), 7.11 (dm, 2H), 6.86 (dm, 2H), 6.59 (d, 1H), 4.99 (s, 2H), 3.79 (s, 2H), 3.71 (s, 3H), 3.66 (t, 2H), 3.62 (t, 2H), 3.44 (t, 2H), 3.21 (q, 2H), 2.01 (s, 3H), 1.74 (m, 2H), 1.54 (m, 2H), 1.45 (m, 2H), 1.38-1.06 (m, 12H), 0.97 (s, 9H), 0.82 (s, 6H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 140.2, 137.6, 130.1, 114.2, 109.9, 66.3, 64.4, 61.7, 59.0, 55.5, 45.9, 41.0, 32.3, 30.1, 28.6, 27.1, 24.4, 10.8; HRMS (ESI) [M+H] + C 54 H 70 ClN 4 O 5 Calculated Si: 917.4804, measured 917.4803.

[0678] Step E: (4-Methoxyphenyl)methyl 3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]-6-[5-chloropentyl-[5-methyl-6-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]pyridazin-3-yl]amino]pyridine-2-carboxylate The product of Step D (3.23 g, 3.52 mmol), the product of Preparation 6 (2.15 g, 5.28 mmol, 1.5 equiv.), diisopropylethylamine (1.84 mL, 3 equiv.), Pd 2 (dba) 3A mixture of XantPhos (322 mg, 0.1 equiv.) and XantPhos (407 mg, 0.2 equiv.) in 1,4-dioxane (17 mL) was stirred for 3 h at 120° C. After quenching with brine and extraction with EtOAc, the organic phase was dried, concentrated and purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (3.81 g, 84%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.78 (d, 1H), 7.68-7.35 (m, 10H), 7.58 (d, 1H), 7.54 (s, 1H), 7.47 (d, 1H), 7.45 (t, 1H), 7.37 (s, 1H), 7.25 (t, 1H), 7.17 (d, 1H), 7.15 (dm, 2H), 6.85 (dm, 2H), 5.87 (s, 2H), 5.07 (s, 2H), 4.18 (t, 2H), 3.83 (s, 2H), 3.72 (t, 2H), 3.70 (s, 3H), 3.66 (t, 2H), 3.58 (t, 2H), 3.45 (t, 2H), 2.31 (s, 3H), 2.08 (s, 3H), 1.73 (m, 2H), 1.70 (m, 2H), 1.43 (m, 2H), 1.39-0.91 (m, 12H), 0.96 (s, 9H), 0.91 (t, 2H), 0.83 (s, 6H), -0.11 (s, 9H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 141.3, 137.6, 130.0, 127.2, 124.1, 123.4, 123.1, 114.4, 114.2, 112.0, 72.9, 66.7, 66.6, 64.4, 61.7, 59.0, 55.5, 48.2, 45.8, 32.2, 30.1, 27.3, 27.1, 24.1, 17.8, 17.3, 10.9, 0.9; HRMS (ESI) [M+H] + C 72 H 92 ClN 8 O 6 SSi 2Calculated value: 1287.6088, measured value: 1287.6084.

[0679] Step F: (4-Methoxyphenyl)methyl 6-[5-azidopentyl-[5-methyl-6-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]pyridazin-3-yl]amino]-3-[1-[[3-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate A mixture of the product of step E (3.80 g, 3 mmol) and sodium azide (2.30 g, 12 equiv.) in 1-methylpyrrolidin-2-one (30 mL) was stirred for 18 h at 80° C. After quenching with brine and extraction with EtOAc, the organic phase was dried, concentrated and purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (3.4 g, 89%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.78 (dm, 1H), 7.68-7.36 (m, 10H), 7.58 (d, 1H), 7.54 (s, 1H), 7.47 (dm, 1H), 7.45 (m, 1H), 7.37 (s, 1H), 7.25 (m, 1H), 7.17 (d, 1H), 7.15 (m, 2H), 6.85 (m, 2H), 5.87 (s, 2H), 5.07 (s, 2H), 4.18 (t, 2H), 3.84 (s, 2H), 3.72 (t, 2H), 3.70 (s, 3H), 3.66 (t, 2H), 3.45 (t, 2H), 3.27 (t, 2H), 2.31 (s, 3H), 2.08 (s, 3H), 1.70 (m, 2H), 1.54 (m, 2H), 1.41-0.91 (m, 12H), 1.37 (m, 2H), 0.96 (s, 9H), 0.91 (t, 2H), 0.83 (s, 6H), -0.11 (s, 9H).

[0680] Step G: (4-Methoxyphenyl)methyl 6-[5-azidopentyl-[5-methyl-6-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]pyridazin-3-yl]amino]-3-[1-[[3-(2-hydroxyethoxy)-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step F (3.40 g, 2.62 mmol) in THF (27 mL) was added a 1 M solution of TBAF in THF (2.89 mL, 1.1 equiv) at 0° C. and stirred for 2 h. After quenching with brine and extraction with EtOAc, the organic phase was purified by column chromatography (silica gel, heptane and EtOAc as eluents) to give the desired product (2.34 g, 84%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.79 (dm, 1H), 7.62 (d, 1H), 7.55 (s, 1H), 7.47 (dm, 1H), 7.43 (m, 1H), 7.37 (s, 1H), 7.25 (m, 1H), 7.20 (d, 1H), 7.18 (m, 2H), 6.88 (m, 2H), 5.87 (s, 2H), 5.09 (s, 2H), 4.45 (t, 1H), 4.18 (t, 2H), 3.84 (s, 2H), 3.72 (s, 3H), 3.72 (t, 2H), 3.40 (m, 2H), 3.34 (t, 2H), 3.27 (t, 2H), 2.31 (s, 3H), 2.10 (s, 3H), 1.70 (m, 2H), 1.55 (m, 2H), 1.44-0.90 (m, 12H), 1.37 (m, 2H), 0.92 (t, 2H), 0.84 (s, 6H), -0.11 (s, 9H); HRMS (ESI) [M+H] + C 56 H 74 N 11 O 6 Calculated SSi: 1056.5314, measured 1056.5322.

[0681] Step H: (4-Methoxyphenyl)methyl 6-[5-azidopentyl-[5-methyl-6-[(Z)-[3-(2-trimethylsilylethoxymethyl)-1,3-benzothiazol-2-ylidene]amino]pyridazin-3-yl]amino]-3-[1-[[3-[2-(dimethylamino)ethoxy]-5,7-dimethyl-1-adamantyl]methyl]-5-methyl-pyrazol-4-yl]pyridine-2-carboxylate To the product of step G (2.34 g, 2.2 mmol) and triethylamine (1.24 mL, 4 equiv.) in DCM (22 mL) was added p-tolylsulfonyl 4-methylbenzenesulfonate (1.44 g, 2 equiv.). After stirring for 15 min, the volatiles were removed under reduced pressure and the residue was treated with MeCN (11 mL) and a 2 M solution of dimethylamine in THF (11 mL, 10 equiv.) and stirred at 40° C. for 5 h. NH 4 After quenching with a saturated solution of Cl and extraction with EtOAc, the organic phase was dried, concentrated and purified by preparative HPLC (Interchim method) (C18, 5 mM NH 4 HCO 3 Purification by aqueous solution, IPA) afforded the desired product (1.1 g, 45%). 1 H NMR (500 MHz, DMSO-d 6) δ ppm 7.79 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.47 (d, 1H), 7.43 (td, 1H), 7.37 (s, 1H), 7.25 (td, 1H), 7.19 (d, 1H), 7.18 (dm, 2H), 6.88 (dm, 2H), 5.87 (s, 2H), 5.09 (s, 2H), 4.16 (t, 2H), 3.85 (s, 2H), 3.72 (s, 3H), 3.72 (t, 2H), 3.39 (t, 2H), 3.27 (t, 2H), 2.32 (s, 3H), 2.29 (t, 2H), 2.11 (s, 6H), 2.10 (s, 3H), 1.70 (m, 2H), 1.55 (m, 2H), 1.42-0.91 (m, 12H), 1.38 (m, 2H), 0.92 (t, 2H), 0.86 (s, 6H), -0.11 (s, 9H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 141.3, 137.7, 129.9, 127.2, 124.1, 123.4, 123.1, 114.4, 114.2, 112.0, 72.9, 66.7, 66.5, 59.8, 59.0, 58.6, 55.5, 51.0, 48.2, 46.1, 30.1, 28.4, 27.6, 23.9, 17.8, 17.3, 10.9, -0.9; HRMS (ESI) [M+H] + C 58 H 79 N 12 O 5 Calculated SSi: 1083.5786, measured 1083.5784.

[0682] Preparation 8: 2-[[6-(1,3-benzothiazol-2-ylamino)-5-methyl-pyridazin-3-yl]-pent-4-ynyl-amino]-5-[3-[2-fluoro-4-[3-(methylamino)prop-1-ynyl]phenoxy]propyl]thiazole-4-carboxylic acid

[0683] [ka] Step A: Methyl 2-(tert-butoxycarbonylamino)-5-iodo-thiazole-4-carboxylate To 50.00 g (193.55 mmol) of methyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate in 600 mL of dry MeCN was added 52.25 g (232.30 mmol) of N-iodosuccinimide, and the resulting mixture was stirred for 18 h. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with Na 2 S 2 O 3 Extraction with a 1M solution of and brine, drying, concentration and purification by flash chromatography (silica gel, using heptane as eluent) afforded the desired product (60 g, 80%). 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 12.03 / 11.06 (br s,1H), 3.78 (s, 3H), 1.47 (s, 9H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 153.8, 82.5, 77.7, 52.3, 28.3; HRMS-ESI (m / z): [M+H] + C 10 H 14 IN 2 O 4 Calculated S: 384.9713; Measured 384.9708.

[0684] Step B: Methyl 2-(tert-butoxycarbonylamino)-5-(3-hydroxyprop-1-ynyl)thiazole-4-carboxylate 9.6 g (25 mmol) of the product from Step A, 2.91 mL (2 equiv.) of prop-2-yn-1-ol, 50 mL (14.27 equiv.) of diisopropylamine, Pd(PPh 3 ) 2 Cl 2A mixture of (549 mg, 0.05 equiv.) and CuI (238 mg, 0.05 equiv.) in THF (125 mL) was stirred at 60° C. until no further conversion was observed. The product was purified by flash chromatography using heptane and EtOAc as eluents to give 7.30 g (93%) of the desired product. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 12.10 (br s, 1H), 5.45 (t, 1H), 4.36 (d, 2H), 3.79 (s, 3H), 1.48 (s, 9H); 13 C NMR (100 MHz, DMSO-d 6 ) δ ppm 12.1 (br s, 1H), 5.45 (t, 1H), 4.36 (d, 2H), 3.79 (s, 3H), 1.48 (s, 9H); HRMS-ESI (m / z): [M+H] + C 13 H 17 N 2 O 5 Calculated S: 313.0852, measured 313.0866.

[0685] Step C: Methyl 2-(tert-butoxycarbonylamino)-5-(3-hydroxypropyl)thiazole-4-carboxylate A mixture of 44.75 g (143.3 mmol) of the product from step B and Pd / C (7.62 g, 0.05 equiv.) in 340 mL of ethanol was subjected to 4 bar H 2 The mixture was stirred under H for 18 h. After filtration through a pad of Celite, the mixture was treated with Pd / C (7.62 g, 0.05 equiv.) and diluted with 4 bar of H 2 Stirred under gas for 18 h. The product was purified by flash chromatography column using heptane and EtOAc as eluents to give 31.9 g (70.4%) of the desired product. 1 H NMR (500 MHz, DMSO-d 6): δ ppm 11.61 (br s, 1H), 4.54 (t, 1H), 3.76 (s, 3H), 3.43 (m, 2H), 3.09 (t, 2H), 1.74 (m, 2H), 1.46 (s, 9H); 13 C NMR (125 MHz, DMSO-d 6 ) δ ppm 162.8, 143.1, 135.4, 60.3, 51.9, 34.5, 28.3, 23.4; HRMS-ESI (m / z): [M+H] + C 13 H 21 N 2 O 5 Calculated S: 317.1165, measured 317.1164.

[0686] Step D: Methyl 2-(tert-butoxycarbonylamino)-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate 3.40 g (14 mmol) of 2-fluoro-4-iodo-phenol, 5.00 g (16 mmol, 1.1 eq) of the product from step C and PPh 3 To a mixture of (4.10 g, 1.1 equiv.) in 71 mL of toluene was added DIAD (3.10 mL, 3.20 g, 1.1 equiv.). After stirring at 50° C. for 30 min, the reaction mixture was directly poured onto a preconditioned silica gel column, which was then purified by flash chromatography using heptane and EtOAc as eluents. The crude product was crystallized from MeOH to give 4.64 g (66%) of the desired product. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 11.64 (br s, 1H), 7.59 (dd, 1H), 7.45 (dd, 1H), 6.98 (t, 1H), 4.06 (t, 2H), 3.73 (s, 3H), 3.22 (t, 2H), 2.06 (m, 2H), 1.46 (s, 9H); 13 C NMR (125 MHz, DMSO-d 6) δ ppm 134.0, 124.9, 117.6, 68.2, 51.9, 30.5, 28.3, 23.2; HRMS-ESI (m / z): [M+H] + C 19 H 23 N 2 O 5 Calculated FSI: 537.0350; measured 537.0348.

[0687] Step E: Methyl 2-[tert-butoxycarbonyl(5-trimethylsilylpent-4-ynyl)amino]-5-[3-(2-fluoro-4-iodo-phenoxy)propyl]thiazole-4-carboxylate The product of step D (5.36 g, 10 mmol, 1 equiv.) and 5-trimethylsilylpent-4-yn-1-ol (3.12 g, 20 mmol, 2 equiv.) were dissolved in toluene (50 mL) with PPh 3 (5.24 g, 2 eq.), followed by addition of DIAD (3.9 mL, 2 eq.) and stirring at 50° C. for 30 min. Purification by column chromatography (silica gel, heptane and EtOAc as eluents) afforded the desired product (6.0 g, 89%). MS-ESI (m / z): 675 [M+H] + .

[0688] Step F: Methyl 5-[3-(2-fluoro-4-iodo-phenoxy)propyl]-2-(5-trimethylsilylpent-4-ynylamino)thiazole-4-carboxylate The product of Step E (6.00 g, 8.9 mmol) was stirred in hexafluoroisopropan...

Claims

1. Compound of formula (A): DL-DSM (A), [In the formula, DSM is a degradation signaling compound covalently attached to a linker L; L is a linker covalently attaching the DSM to D; D is a group of formula (I) covalently attached to a linker L: 【Chemical 1】 (In the formula, ・R １ and R ２ are each independently hydrogen; hydroxyl or C １ -C ６ Arco Straight or branched chain C optionally substituted with an oxy group １ -C ６ Alkyl; C ３ - C ６ cycloalkyl; trifluoromethyl; and straight or branched chain C １ -C ６ Alkire represents a group selected from the group consisting of cycloalkyl-heterocycloalkyl, The alkyl group may be a straight or branched C １ -C ６ optionally substituted with alkyl groups And, or R １ and R ２ together with the carbon atom that carries them, ３ -C ６ Cycloalkane forming a cyclohexene group, ・R ３ is hydrogen; C ３ -C ６ Cycloalkyl; straight or branched chain C １ -C ６ Alkyl;- X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 2】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Chemistry 3】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ It forms or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ - C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ It forms or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ - C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemistry 4】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemistry 5】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Hide -C optionally substituted with a hydroxyl group １ -C ６ Alkyl, halogen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogen atoms, C optionally substituted by a fluorine atom １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C １ -C ６ C substituted with an alkoxy group １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, Phenyl and -(CH ２ ) １－４ -phenyl, -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, Phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemistry 6】 [In the formula, R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ -C ６ C substituted by alkyl, hydroxyl １ -C ６ Alkyl, C １ -C ６ a C substituted with an alkoxy group １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl] Selected, R Ｇ５ is a C optionally substituted with a hydrogen atom or 1 to 3 halogen atoms １ -C ６ represents an alkyl group, ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen; and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ basis, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Chemistry 7】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a linear or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemistry 8】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ ;-X’ ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Chemistry 9】 represents a group selected from the group consisting of ・R ９ is a linear or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH= CH-CHO, C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterogeneity Chloroalkylene-CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a linear or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched chain C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 10】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a linear or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: R ３ and R ８ One of the groups, if present, is covalently attached to the linker and is an atom of the (The valency of the group may not exceed one or more substituents attached thereto.) or any one of its enantiomers, diastereomers, isomers, and / or pharmaceutically acceptable salts thereof, or Formula (II) 【Chemistry 11】 (In the formula, n=0, 1 or 2, represents a single bond or a double bond, ・A ４ and A ５ each independently represents a carbon or nitrogen atom, ・Z １ represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or Branched Chain C １ -C ６ represents alkyl, ・R １ is hydrogen; hydroxyl or C １ -C ６ Optionally substituted with alkoxy groups Linear or branched chain C １ -C ６ Alkyl; C ３ -C ６ Cycloalkyl; trifluoromethyl and straight or branched chain C １ -C ６ From the group consisting of alkylene-heterocycloalkyl wherein the heterocycloalkyl group is a straight or branched chain C １ -C ６ optionally substituted with alkyl groups; ・R ２ represents hydrogen or methyl, ・R ３ is hydrogen; straight or branched chain C １ -C ４ Alkyl; -X １ -NR ａ R ｂ ;-X １ - N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ; -X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 12】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Chemistry 13】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ Forming the law of nature, or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemistry 14】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemistry 15】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Hide -C optionally substituted with a hydroxyl group １ -C ６ Alkyl, halogen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogen atoms, C optionally substituted by a fluorine atom １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C １ -C ６ C substituted with an alkoxy group １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, Phenyl and -(CH ２ ) １－４ -phenyl, -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, Phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ２ Each atom, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemistry 16】 [In the formula, R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ -C ６ C substituted by alkyl, hydroxyl １ -C ６ Alkyl, C １ -C ６ a C substituted with an alkoxy group １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl] and R Ｇ５ is optionally represented by a hydrogen atom or 1 to 3 halogen atoms. C substituted by １ -C ６ represents an alkyl group, ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen; and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ basis, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Chemistry 17】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemistry 18】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ 、-X’ ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemistry 19】 represents a group selected from the group consisting of ・R ９ is a straight or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, halogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Archi Ren-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ４ represents an alkylene group, ・X ２ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 20】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. Retard C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. Retard C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a straight or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: Here, R ３ , R ８ and one of the G groups, if present, is covalently attached to the linker and the valency of an atom is not exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereomers, isomers, and / or pharmaceutically acceptable salts thereof] or any one of its enantiomers, diastereoisomers, and / or pharmaceutically Acceptable salts.

2. D is covalently bonded to a linker L, Formula (I): 【Chemical 21】 [In the formula, ・R １ and R ２ are each independently hydrogen; hydroxyl or C １ -C ６ Arco Straight or branched chain C optionally substituted with an oxy group １ -C ６ Alkyl; C ３ - C ６ cycloalkyl; trifluoromethyl; and straight or branched chain C １ -C ６ Alkire represents a group selected from the group consisting of cycloalkyl-heterocycloalkyl, The alkyl group may be a straight or branched C １ -C ６ optionally substituted with alkyl groups And, or R １ and R ２ together with the carbon atom that carries them, ３ -C ６ Cycloa It forms an alkylene group, ・R ３ is hydrogen; C ３ -C ６ Cycloalkyl; straight or branched chain C １ -C ６ Alkyl;- X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemical 22】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Chemical 23】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ Forming the law of nature, or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemistry 24】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemistry 25】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Halo Gen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogens, C optionally substituted by atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -Fe is selected from the group consisting of: -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemical 26】 [In the formula, R Ｇ４ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl selected from the group consisting of selected from the group consisting of ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen; and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ basis, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 ​ -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemical Formula 28】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ ;-X’ ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Chemical 29】 represents a group selected from the group consisting of ・R ９ is a straight or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH= CH-CHO, C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterogeneity Chloroalkylene-CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 30】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Forming the law of nature, or R' ｄ , R' ｅ and R' ｆ together with the nitrogen atoms that carry them, C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a straight or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: Here, R ３ and R ８ One of the groups, if present, is covalently attached to the linker , the valency of an atom is not exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereomers, isomers, and / or pharmaceutically acceptable salts thereof, or Formula (II) 【Chemical 31】 [In the formula, n=0, 1 or 2, represents a single bond or a double bond, ・A ４ and A ５ each independently represents a carbon or nitrogen atom, ・Z １ represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or Branched Chain C １ -C ６ represents alkyl, ・R １ is hydrogen; hydroxyl or C １ -C ６ Optionally substituted with alkoxy groups Linear or branched chain C １ -C ６ Alkyl; C ３ -C ６ Cycloalkyl; trifluoromethyl and straight or branched chain C １ -C ６ From the group consisting of alkylene-heterocycloalkyl wherein the heterocycloalkyl group is a straight or branched chain C １ -C ６ optionally substituted with alkyl groups; ・R ２ represents hydrogen or methyl ・R ３ is hydrogen; straight or branched chain C １ -C ４ Alkyl; -X １ -NR ａ R ｂ ;-X １ - N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ; -X １ -SO ２ (OH); -X １ -N ３ and 【Chemical 32】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Chemical 33】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ It forms or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ - C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemical 34】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemical 35】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Halo Gen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogens, C optionally substituted by atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -Fe is selected from the group consisting of: -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemical 36】 [In the formula, R Ｇ４ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl selected from the group consisting of selected from the group consisting of ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen; and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ base, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Chemical 37】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a linear or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemical 38】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl, ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ 、-X’ ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemical 39】 represents a group selected from the group consisting of ・R ９ is a linear or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, halogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Archi Ren-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ４ represents an alkylene group, ・X ２ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ６ represents an alkylene group, ・X' ２ is a linear or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched chain C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 40】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a linear or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: R ３ and R ８ One of the groups, if present, is covalently attached to the linker and is an atom The valency of an atom is not to be exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereomers, 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof. any one enantiomer, diastereoisomer, and / or pharmaceutically acceptable salt.

3. The linker L is (1) C １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, trifluoromethyl, hydroxyl, halogen, and C １ -C ６ A straight or branched chain C optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy １ -C ２０ Alkylene; C ３ -C １０ Cycloalkylene; C ３ -C ８ Heterocycloalkylene; —C(O)—; —O—; —S—; —N(R １６ ) -; -N(R １６ )-C(O)-;-C(O)-N(R １６ )-;-CH ２ -C(O)-N(R １６ ) -; -N(R １６ )—C(O)—CH ２ -; polyoxyethylene (PEG) group; C １ -C ８ Alkyl, trifluoromethyl, hydroxyl, halogen, and C １ -C ６ arylene groups optionally substituted with one or two groups selected from the group consisting of alkoxy; and heteroarylene groups, wherein R １６ is hydrogen or C １ -C ６ represents alkyl, or (2) C １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, trifluoromethyl, hydroxyl, halogen, and C １ -C ６ A straight or branched chain C optionally substituted with one or two groups selected from the group consisting of alkoxy １ -C ２０ Alkylene; C ３ -C １０ Cycloalkylene; —C(O)—; —O—; —S—; —N(R １６ ) -; -N(R １６ )-C(O)-;-C(O)-N(R １６ )-;-CH ２ -C(O)-N(R １６ ) -; -N(R １６ )—C(O)—CH ２ -; polyoxyethylene (PEG) group; C １ -C ８ Alkyl, trifluoromethyl, hydroxyl, halogen, and C １ -C ６ arylene groups optionally substituted with one or two groups selected from the group consisting of alkoxy; and heteroarylene groups, wherein R １６ is hydrogen or C １ -C ６ 3. A compound according to claim 1 or 2, wherein said compound represents alkyl.

4. The linker L is (1) comprises a 1,2,3-triazolene group formed by reacting an azide-containing precursor with an alkyne-containing precursor; (2) Formula (i), (ii), (iii), (iv), (v), (vi) or (vii i): 【Chemistry 41】 [In the formula, LK １ is a bond, -NR １６ - or -C(O)-, LK ２ is a bond, —C(O)— or —N(R １６ )—C(O)—CH ２ - ＊ and LK ３ is —C(O)— or —N(R １６ )—C(O)—CH ２ - ＊ and LK ４ is a bond or —C(O)—, LK ５ is a bond or —C(O)—, LK ６ represents a bond, —C(O)—, —O—CH ２ -C(O)- ＊ , or -N(R １６ ) —C(O)—CH ２ - ＊ and LK ７ is a bond or -NR １６ - and LK ８ is a bond, -R ２２ -, -O-R ２２ -or-C(O)-R ２２ - and Ring A is C ３ -C ８ is heterocycloalkylene, R １６ is H or methyl, R １７ is C １ -C ２０ Alkylene, C ３－１０ Cycloalkylene, C ３－１０ Shik Trialkylene-CH ２ - ＊＊ , phenylene, -C １ -C ２０ Alkylene -OCH ２ CH ２ - ＊＊ 、-C １ -C ２０ アルキレン-OCH ２ - ＊＊ 、-CH ２ -(OCH ２ CH ２ ) ｐ -OCH ２ - ＊＊ or -(CH ２ CH ２ O) ｐ -(C １ -C ３ -alkylene)- ＊＊ Yes wherein said C １ -C ２０ The alkylene or the phenylene may be one or two R １７ ａ and optionally substituted by ＊＊ LK ２ indicates the point of attachment to R １７ａ is, for each occurrence, independently a straight or branched chain C １ -C ６ alkyl or halogen, or two R １７ａ and the carbon atoms to which they are bonded. Both, C ３ -C ６ forming a cycloalkyl, R １８ is C １ -C ２０ Alkylene or —CH ２ CH ２ -(OCH ２ CH ２ ) ｐ - ＊ ＊ where: ＊＊ LK ３ indicates the point of attachment to R １９ is C １ -C ６ is alkylene, R ２０ is C ３ -C １０ Cycloalkylene, phenylene, -S- or -N(R １６ ) - and R ２１ is C １－ C ２０ Alkylene or —CH ２ -(OCH ２ CH ２ ) ｐ - ＊＊ Yes Here, ＊＊ LK ６ indicates the point of attachment to R ２２ is C １ -C ６ is alkylene, p is an integer from 1 to 7; d is an integer from 1 to 7, 【Chemistry 42】 is the binding to a Bcl-xL inhibitor compound, 【Chemistry 43】 is a bond to the DSM], or (3) Formula (i), (ii), (iii), (iv), (v), or (vi): 【Chemical 44】 [In the formula, LK １ is a bond or —C(O)—, LK ２ is a bond, —C(O)— or —N(R １６ )—C(O)—CH ２ - ＊ and LK ３ is —C(O)— or —N(R １６ )—C(O)—CH ２ - ＊ and LK ４ is a bond or —C(O)—, LK ５ is a bond or —C(O)—, LK ６ is a bond, —O—CH ２ -C(O)- ＊ , or -N(R １６ )-C(O)-C H ２ - ＊ and R １６ is H or methyl, R １７ is C １ -C ２０ Alkylene, C ３－１０ Cycloalkylene, phenylene, or Ha-CH ２ -(OCH ２ CH ２ ) ｐ -OCH ２ -, wherein said C １ -C ２０ Al The alkylene or the phenylene may have one or two R １７ａ is optionally replaced by 、 R １７ａ is, for each occurrence, independently a straight or branched chain C １－６ a alkyl or halogen, or two R １７ａ together with the carbon atoms to which they are attached. To, C ３－６ forming a cycloalkyl, R １８ is C １－２０ Alkylene or —CH ２ CH ２ -(OCH ２ CH ２ ) ｐ - ＊＊ where: ＊＊ LK ３ indicates the point of attachment to R １９ is C １－６ is alkylene, R ２０ is C ３－１０ Cycloalkylene, phenylene, -S- or -N(R １６ )- and R ２１ is C １－２０ Alkylene or —CH ２ -(OCH ２ CH ２ ) ｐ - ＊＊ and , where: ＊＊ LK ６ indicates the point of attachment to p is an integer from 1 to 7; d is an integer from 1 to 7 【Chemistry 45】 is the binding to a Bcl-xL inhibitor compound, 【Chemistry 46】 is a bond to the DSM; or （４） 【Chemistry 47-1】 【Chemistry 47-2】 【Chemistry 47-3】 【Chemistry 47-4】 【Chemistry 47-5】 【Chemistry 47-6】 【Chemistry 47-7】 【Chemistry 47-8】 【Chemistry 47-9】 【Chemistry 47-10】 【Chemistry 47-11】 [In the formula, 【Chemistry 48】 is the binding to a Bcl-xL inhibitor compound, 【Chemistry 49】 is the bond to the DSM] The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. D is, (1) Compound of formula (I): 【Chemistry 50】 [In the formula, ・R １ and R ２ are each independently hydrogen; hydroxyl or C １ -C ６ Arco Straight or branched chain C optionally substituted with an oxy group １ -C ６ Alkyl; C ３ - C ６ cycloalkyl; trifluoromethyl; and straight or branched chain C １ -C ６ Alkire represents a group selected from the group consisting of cycloalkyl-heterocycloalkyl, The alkyl group may be a straight or branched C １ -C ６ optionally substituted with alkyl groups And, ・or R １ and R ２ together with the carbon atom that carries them, ３ -C ６ Cycloa It forms an alkylene group, ・R ３ is hydrogen; C ３ -C ６ Cycloalkyl; straight or branched chain C １ -C ６ Alkyl;- X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 51】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Chemistry 52】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ It forms or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ - C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemistry 53】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemical 54】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Hide -C optionally substituted with a hydroxyl group １ -C ６ Alkyl, halogen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogens, C optionally substituted by atoms １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C １ -C ６ C substituted with an alkoxy group １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemistry 55】 [where R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ -C ６ C substituted by alkyl, hydroxyl １ -C ６ Alkyl, C １ -C ６ C substituted with an alkoxy group １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ - C ６ Alkynyl and C ３ -C ６ cycloalkyl] and R Ｇ５ is optionally represented by a hydrogen atom or 1 to 3 halogen atoms. C substituted by １ -C ６ represents an alkyl group, ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen; and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ basis, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Chemical Formula 56】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemical 57】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ ;-X’ ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Chemistry 58】 represents a group selected from the group consisting of ・R ９ is a straight or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH= CH-CHO, C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterogeneity Chloroalkylene-CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemical Formula 59】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a straight or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: Here, R ３ and R ８ One of the groups, if present, is covalently attached to the linker , the valency of an atom is not exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharmaceutically with an acceptable salt, or (2) Compound of formula (I): 【Chemistry 60】 [In the formula, ・R １ and R ２ are each independently hydrogen; hydroxyl or C １ -C ６ Arco Straight or branched chain C optionally substituted with an oxy group １ -C ６ Alkyl; C ３ - C ６ cycloalkyl; trifluoromethyl; and straight or branched chain C １ -C ６ Alkire represents a group selected from the group consisting of cycloalkyl-heterocycloalkyl, The alkyl group may be a straight or branched C １ -C ６ optionally substituted with alkyl groups And, or R １ and R ２ together with the carbon atom that carries them, ３ -C ６ Cycloa It forms an alkylene group, ・R ３ is hydrogen; C ３ -C ６ Cycloalkyl; straight or branched chain C １ -C ６ Alkyl;- X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ;-X １ -SO ２ (OH); -X １ -N ３ and 【Hua 61】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Hua 62】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ Forming the law of nature, or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemistry 63】 represents a group selected from the group consisting of ・Het ２ teeth, 【Hua 64】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Halo Gen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogens, C optionally substituted by atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -Fe is selected from the group consisting of: -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemistry 65】 [In the formula, R Ｇ４ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl selected from the group consisting of selected from the group consisting of ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen; and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ basis, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Hua 66】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Hua 67】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ ;-X’ ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Chemistry 68】 represents a group selected from the group consisting of ・R ９ is a straight or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH= CH-CHO, C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterogeneity Chloroalkylene-CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemical Formula 69】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a straight or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: Here, R ３ and R ８ One of the groups, if present, is covalently attached to the linker , the valency of an atom is not exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharmaceutically The compound of any one of claims 1 to 4, including an acceptable salt thereof.

6. R １ is a straight or branched chain C １ -C ６ alkyl, and R ２ The compound of claim 5, wherein is H.

7. D is, (1) Compound of formula (II): 【Chemistry 70】 [In the formula, n=0, 1 or 2, represents a single bond or a double bond, ・A ４ and A ５ each independently represents a carbon or nitrogen atom, ・Z １ represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or Branched Chain C １ -C ６ represents alkyl, ・R １ is hydrogen; hydroxyl or C １ -C ６ Optionally substituted with alkoxy groups Linear or branched chain C １ -C ６ Alkyl; C ３ -C ６ Cycloalkyl; trifluoromethyl and straight or branched chain C １ -C ６ From the group consisting of alkylene-heterocycloalkyl wherein the heterocycloalkyl group is a straight or branched chain C １ -C ６ optionally substituted with alkyl groups; ・R ２ represents hydrogen or methyl, ・R ３ is hydrogen; straight or branched chain C １ -C ４ Alkyl; -X １ -NR ａ R ｂ ;-X １ - N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ; -X １ -SO ２ (OH); -X １ -N ３ and 【Chemical 71】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: [Chemical 72] represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ Forming the law of nature, or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemical 73】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemical 74】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C (O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NC N)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S (O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C(=NR Ｇ２ )N R Ｇ１ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ , Hide -C optionally substituted with a hydroxyl group １ -C ６ Alkyl, halogen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen, 1 to 3 halogens, C optionally substituted by atoms １ -C ６ Alkyl, hydroxyl substituted C １ -C ６ Alkyl, C １ -C ６ C substituted with an alkoxy group １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Lukil, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemistry 75】 [In the formula, R Ｇ４ is hydrogen, C optionally substituted with 1 to 3 halogen atoms １ -C ６ C substituted by alkyl, hydroxyl １ -C ６ Alkyl, C １ -C ６ a C substituted with an alkoxy group １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl] and R Ｇ５ is optionally represented by a hydrogen atom or 1 to 3 halogen atoms. C substituted by １ -C ６ represents an alkyl group, ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ base, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Chemical 76】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a linear or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemical 77】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ 、-X’ ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Chemical 78】 represents a group selected from the group consisting of ・R ９ is a linear or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, halogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Archi Ren-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ４ represents an alkylene group, ・X ２ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ６ represents an alkylene group, ・X' ２ is a linear or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched chain C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemical 79】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a linear or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: Here, R ３ , R ８ and one of the G groups, if present, is covalently attached to the linker and the valency of an atom is not exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharmaceutically with an acceptable salt, or (2) Compound of formula (II): 【Chemistry 80】 [In the formula, n=0, 1 or 2, represents a single bond or a double bond, ・A ４ and A ５ each independently represents a carbon or nitrogen atom, ・Z １ represents a bond, -N(R)-, or -O-, where R is hydrogen or a straight or Branched Chain C １ -C ６ represents alkyl, ・R １ is hydrogen; hydroxyl or C １ -C ６ Optionally substituted with alkoxy groups Linear or branched chain C １ -C ６ Alkyl; C ３ -C ６ Cycloalkyl; trifluoromethyl and straight or branched chain C １ -C ６ From the group consisting of alkylene-heterocycloalkyl wherein the heterocycloalkyl group is a straight or branched chain C １ -C ６ optionally substituted with alkyl groups; ・R ２ represents hydrogen or methyl ・R ３ is hydrogen; straight or branched chain C １ -C ４ Alkyl; -X １ -NR ａ R ｂ ;-X １ - N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -COOR ｃ ;-X １ -PO(OH) ２ ; -X １ -SO ２ (OH); -X １ -N ３ and 【Chemistry 81】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; heterocycloalkyl; ２ -Fe phenyl (wherein the phenyl is a straight or branched C １ -C ６ substituted with alkyl linear or cyclic alkyl groups optionally substituted with one or two hydroxyl groups; Branched Chain C １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Archi Ren-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ -C ６ Alkylene-PO(O H) ２ ; C １ -C ６ Alkylene -NR ｄ R ｅ ; C １ -C ６ Alkylene-N ＋ R ｄ R ｅ R ｆ ; C １ -C ６ Alkylene-phenyl, wherein said phenyl is C １ -C ６ Alkoxy groups and the group: 【Chemistry 82】 represents a group selected from the group consisting of or R ａ and R ｂ together with the nitrogen atom carrying them form ring B １ Forming the law of nature, or R ａ , R ｂ and R ｃ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・R ｃ , R ｄ , R ｅ , R ｆ are each independently hydrogen or a straight or branched chain C １ - C ６ represents an alkyl group, or R ｄ and R ｅ together with the nitrogen atom carrying them form ring B ２ Forming the law of nature, or R ｄ , R ｅ and R ｆ together with the nitrogen atoms carrying them form a bridged C ３ -C ８ forming a heterocycloalkyl, ・Het １ teeth, 【Chemistry 83】 represents a group selected from the group consisting of ・Het ２ teeth, 【Chemistry 84】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ２ 、-NR Ｇ１ C(O )R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ １ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(=NCN) NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O) ２ R Ｇ３ 、-S(O ) ２ NR Ｇ１ R Ｇ２ ,-NR Ｇ１ S (O) ２ R Ｇ２ ,-NR Ｇ１ C(=NR) Ｇ２ )NR Ｇ １ R Ｇ２ , -C(=S)NR Ｇ１ R Ｇ２ , -C(=NR Ｇ１ ) NR Ｇ１ R Ｇ２ ,halogen , -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ are each independently hydrogen, 1 to 3 halogen atoms, C optionally replaced by １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ - C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phenyl and -(CH ２ ) １－４ -Feni and -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Al Kill, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, phen nyl and -(CH ２ ) １－４ -phenyl, or R Ｇ１ and R Ｇ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterocycloalkyl or alternatively, G is linked to form 【Chemistry 85】 [In the formula, R Ｇ４ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl and C ３ -C ６ cycloalkyl selected from the group consisting of selected from the group consisting of ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi Lu; C ２ -C ６ Alkenyl; C ２ -C ６ alkynyl; halogen and -CN represents a group selected from ・R ６ teeth, hydrogen, Straight or branched chain - C １ -C ６ Alkylene-R ８ base, -C ２ -C ６ alkenyl, -X ２ -O-R ７ 、 【Chemistry 86】 -X ２ -NSO ２ -R ７ 、 -C=C(R ９ )-Y １ -O-R ７ 、 C ３ -C ６ cycloalkyl, C optionally substituted with a hydroxyl group ３ -C ６ heterocycloalkyl, C ３ -C ６ Cycloalkylene-Y ２ -R ７ , C ３ -C ６ Heterocycloalkylene-Y ２ -R ７ Groups, and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Hua 87】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ 、-X’ ２ -NR' ａ R' ｂ , -NR' ｃ -X' ２ -N ３ and 【Hua 88】 represents a group selected from the group consisting of ・R ９ is a straight or branched chain C １ -C ６ Alkyl, trifluoromethyl, hydroxyl, Halogens and C １ -C ６ represents a group selected from the group consisting of alkoxy, ・R １０ is hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, halogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Archi Ren-R ８ , —CO—NR ｈ R ｉ and -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=CH-CHO,C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterocycloalkylene -CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ４ represents an alkylene group, ・X ２ is trifluoromethyl, hydroxyl, halogen, and C １ -C ６ Alkoxy A straight or branched chain optionally substituted with one or two groups selected from the group consisting of Branched chain C １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 89】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Forming the law of nature, or R' ａ , R' ｂ and R' ｃ together with the nitrogen atoms that carry them, C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Forming the law of nature, or R' ｄ , R' ｅ and R' ｆ together with the nitrogen atoms that carry them, C ３ -C ８ forming a heterocycloalkyl, ・Y １ is a straight or branched chain C １ -C ４ represents alkylene, ・Y ２ represents a bond, —O—, —O—CH ２ -, -O-CO-, -O-SO ２ -, -CH ２ -、-CH ２ -O、-CH ２ -CO-、-CH ２ -SO ２ -、-C ２ H ５ -、-CO-、 -CO-O-、-CO-CH ２ -、-CO-NH-CH ２ -、-SO ２ -、-SO ２ -C H ２ -, -NH-CO-, or -NH-SO ２ represents -, m=0, 1 or 2, ・B １ , B ２ , B ３ and B ４ are each independently C ３ -C ８ Heterocycloalkyl (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; and (ii) in addition to the nitrogen atom, (iii) may contain one or two heteroatoms selected from fluorine, bromine, chlorine, Linear or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: Here, R ３ and R ８ One of the groups, if present, is covalently attached to the linker , the valency of an atom is not exceeded by one or more substituents attached thereto. or any one of its enantiomers, diastereoisomers, and / or pharmaceutically The compound of any one of claims 1 to 4, including an acceptable salt thereof.

8. A ４ and A ５ Both represent nitrogen atoms, and R １ is a straight or branched chain C １－６ is alkyl, R ２ The compound according to claim 7, wherein is H, n is 1, and represents a single bond.

9. D is, (1) A compound of formula (IA) or (IIA): 【Chemistry 90】 [In the formula, ・Z １ represents a bond or —O—; ・R ３ is hydrogen; C ３ -C ６ Cycloalkyl; straight or branched chain C １ -C ６ Alkyl;- X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -N ３ and 【Chemistry 91】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; Straight or branched chain C substituted with １ -C ６ alkyl; and C １ -C ６ Alkylene -SO ２ O － represents a group selected from the group consisting of ・R ｃ is hydrogen or a straight or branched chain C １ -C ６ represents an alkyl group, ・Het ２ teeth, 【Chemistry 92】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OH、-C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O ) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C (=NR) Ｇ２ )NR Ｇ１ R Ｇ２ 、-C(=S)NR Ｇ１ R Ｇ２ ,-C(=NR) Ｇ１ )NR Ｇ１ R Ｇ２ , optionally substituted with a hydroxyl group -C １ -C ６ Alkyl, - C(O)NR Ｇ５ S (O) ２ R Ｇ４ , halogen, -NO ２ and —CN. is selected, where -R Ｇ１ , R Ｇ２ , R Ｇ４ and R Ｇ５ are each independently, when present, hydrogen, and and C optionally substituted by 1 to 3 halogen atoms １ -C ６ consisting of alkyl selected from the group -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Rukill, or R Ｇ１ and R Ｇ２ Each atom, together with the atom to which it is bonded, is C ３ -C ８ Heterogeneity bonded to form a chloroalkyl ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi represents a group selected from the group consisting of halogen and —CN, ・R ６ teeth, Straight or branched chain - C １ -C ６ Alkylene-R ８ basis, -X ２ -O-R ７ , and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a straight or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Chemistry 93】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ ;-X’ ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Chemistry 94】 represents a group selected from the group consisting of ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ , -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=C H-CHO, C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterocyclo Alkylene -CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 95】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. Retard C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. Retard C ３ -C ８ forming a heterocycloalkyl, m=0, 1 or 2, p=1, 2, 3 or 4, ・B ３ and B ４ are each independently C ３ -C ８ represents a heterocycloalkyl group, The group is (i) a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems. (ii) in addition to the nitrogen atom, one or more independently selected from oxygen, sulfur, and nitrogen; (iii) may contain two heteroatoms; and (iii) may be fluorine, bromine, chlorine, straight-chain or branched. Chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: or any one of its enantiomers, diastereoisomers, and / or pharmaceutically with an acceptable salt, or (2) Compounds of formula (IA) or (IIA): 【Chemistry 96】 [In the formula: ・Z １ represents a bond or —O—; ・R ３ is hydrogen; C ３ -C ６ Cycloalkyl; straight or branched chain C １ -C ６ Alkyl;- X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -N ３ and 【Chemistry 97】 represents a group selected from the group consisting of ・R ａ and R ｂ are each independently hydrogen; Straight or branched chain C substituted with １ -C ６ alkyl; and C １ -C ６ Alkylene -SO ２ O － represents a group selected from the group consisting of ・R ｃ is hydrogen or a straight or branched chain C １ -C ６ represents an alkyl group, ・Het ２ teeth, 【Chemistry 98】 represents a group selected from the group consisting of ・A １ is -NH-, -N(C １ -C ３ alkyl), O, S or Se; ・A ２ is N, CH or C(R ５ ) and ・G is -C(O)OH、-C(O)OR Ｇ３ 、-C(O)NR Ｇ１ R Ｇ２ 、-C(O)R Ｇ ２ 、-NR Ｇ１ C(O)R Ｇ２ 、-NR Ｇ１ C(O)NR Ｇ１ R Ｇ２ 、-OC(O)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ C(O)OR Ｇ３ 、-C(=NOR Ｇ１ )NR Ｇ１ R Ｇ２ 、-N R Ｇ１ C(=NCN)NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ NR Ｇ１ R Ｇ２ 、-S(O ) ２ R Ｇ３ 、-S(O) ２ NR Ｇ１ R Ｇ２ 、-NR Ｇ１ S(O) ２ R Ｇ２ 、-NR Ｇ１ C (=NR) Ｇ２ )NR Ｇ１ R Ｇ２ 、-C(=S)NR Ｇ１ R Ｇ２ ,-C(=NR) Ｇ１ )NR Ｇ１ R Ｇ２ , halogen, -NO ２ and —CN, wherein -R Ｇ１ and R Ｇ２ each occurrence independently represents hydrogen and 1 to 3 halo C optionally substituted with a fluorine atom １ -C ６ is selected from the group consisting of alkyl, -R Ｇ３ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ a Rukill, or R Ｇ１ and R Ｇ２ Each of them, together with the atom to which it is bonded, is C ３ -C ８ Heterogeneity bonded to form a chloroalkyl ・R ４ represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, hydroxyl or methoxy group Represents, ・R ５ is a C optionally substituted with 1 to 3 halogen atoms １ -C ６ Archi represents a group selected from the group consisting of halogen and —CN, ・R ６ teeth, Straight or branched chain - C １ -C ６ Alkylene-R ８ base, -X ２ -O-R ７ , and Linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ base represents a group selected from the group consisting of ・R ７ is a linear or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) cycloalkylene- R ８ ; 【Hua99】 wherein Cy represents a group selected from the group consisting of C ３ -C ８ represents cycloalkyl 、 ・R ８ is hydrogen; straight or branched chain C １ -C ６ Alkyl, —NR′ ａ R' ｂ -NR' ａ ----OR' ｃ ;-NR' ａ ----R' ｃ ;-N ＋ R' ａ R' ｂ R' ｃ ;-O-R' ｃ ;-NH-X’ ２ -N ＋ R’ ａ R’ ｂ R’ ｃ ;-O-X’ ２ -NR’ ａ R’ ｂ ;-X’ ２ -NR' ａ R' ｂ -NR' ｃ -X' ２ -N ３ and 【Chemistry 100】 represents a group selected from the group consisting of ・R １０ represents hydrogen, fluorine, chlorine, bromine, -CF ３ and methyl represents a group ・R １１ is hydrogen, C １ -C ３ Alkylene-R ８ , —O—C １ -C ３ Alkylene-R ８ , —CO—NR ｈ R ｉ , -CH=CH-C １ -C ４ Alkylene -NR ｈ R ｉ , -CH=C H-CHO, C ３ -C ８ Cycloalkylene -CH ２ -R ８ , and C ３ -C ８ Heterocyclo Alkylene -CH ２ -R ８ represents a group selected from the group consisting of ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents a hydrogen atom or a methyl group, or R １４ and R １５ together with the carbon atom that carries them form cyclohexyl. 、 ・R ｈ and R ｉ are each independently hydrogen or a straight or branched chain C １ -C ６ Archi represents a methyl group, ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a linear or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; heterocycloalkyl; ２ - Phenyl (wherein the phenyl is a straight or branched chain C １ -C ６ Alkyl substituted one or two hydroxyl or C １ -C ６ Depending on the alkoxy group A straight or branched chain C substituted with １ -C ６ Alkyl; C １ -C ６ Alkylene-SO ２ OH;C １ -C ６ Alkylene-SO ２ O － ; C １ -C ６ Alkylene-COOH; C １ - C ６ Alkylene-PO(OH) ２ ; C １ -C ６ Alkylene-NR' ｄ R' ｅ ; C １ -C ６ Alkylene-N ＋ R' ｄ R' ｅ R' ｆ ; C １ -C ６ Alkylene -O-C １ -C ６ Alkire C １ -C ６ alkylene-phenyl, wherein the phenyl is hydroxyl or C １ -C ６ and the group: 【Chemistry 101】 represents a group selected from the group consisting of or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, or R' ａ , R' ｂ and R' ｃ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, ・R' ｃ , R' ｄ , R' ｅ , R' ｆ are each independently hydrogen or a straight-chain or branched Chain C １ -C ６ represents an alkyl group, or R' ｄ and R' ｅ together with the nitrogen atom carrying them form ring B ４ Form And, or R' ｄ , R' ｅ and R' ｆ are bridged together with the nitrogen atoms that carry them. C ３ -C ８ forming a heterocycloalkyl, m=0, 1 or 2, p=1, 2, 3 or 4, B ３ and B ４ are each independently C ３ -C ８ represents a heterocycloalkyl group, (i) can be a monocyclic or bicyclic group, including fused, bridged, or spiro ring systems; (ii) in addition to a nitrogen atom, one or two independently selected from oxygen, sulfur, and nitrogen (iii) may contain heteroatoms of fluorine, bromine, chlorine, straight or branched chain C １ -C ６ Alkyl, hydroxyl, -NH ２ , oxo, and piperidinyl and optionally substituted with one or two groups selected from the group consisting of: or any one of its enantiomers, diastereoisomers, and / or pharmaceutically The compound of any one of claims 1 to 8, including an acceptable salt thereof.

10. R ７ but, (1) Linear or branched chain C １ -C ６ Alkyl group; (C ３ -C ６ ) Cycloalkylene-R ８ ； 【Chemistry 102】 [Wherein Cy is C ３ -C ８ represents a group selected from the group consisting of: （２） 【Chemistry 103】 The compound according to any one of claims 1 to 9, wherein the compound represents a group selected from the group consisting of:

11. D is, (1) Compound of formula (IB), (IC-1), (IIB) or (IIC-1): 【Chemistry 104】 [In the formula, With respect to formula (IB) or (IC-1), R ３ is hydrogen; straight or branched chain C １ -C ６ a Rukill;-X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ - N ３ and 【Chemistry 105】 represents a group selected from the group consisting of With respect to formula (IIB) or (IIC-1), Z １ represents a bond, R ３ represents hydrogen? , or Z １ represents —O—, and R ３ Ha-X １ -NR ａ R ｂ represents With respect to formula (IC-1), G is —C(O)OH and —C(O)NR Ｇ１ R Ｇ２ from is selected from the group consisting of Regarding formula (IIC-1), G is —C(O)OH, —C(O)NR Ｇ１ R Ｇ２ ,- C(O)R Ｇ２ , optionally substituted with a hydroxyl group -C １ -C ６ Alkyl and —C(O)NR Ｇ５ S (O) ２ R Ｇ４ wherein R Ｇ１ , R Ｇ２ , R Ｇ４ and R Ｇ５ each occurrence independently represents hydrogen and 1 to 3 halo C optionally substituted with a fluorine atom １ -C ６ is selected from the group consisting of alkyl, ・R ａ and R ｂ are each independently hydrogen; Straight or branched chain C substituted with １ -C ６ alkyl; and C １ -C ６ Alkylene -SO ２ O － represents a group selected from the group consisting of ・R ｃ is hydrogen or a straight or branched chain C １ -C ６ Represents an alkyl group ・R ６ is a straight or branched chain -C １ -C ６ Alkylene-R ８ group, -X ２ -O-R ７ , or linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Liren-R ７ represents a group, ・R ７ teeth, 【Chemistry 106】 represents a group selected from the group consisting of ・R ８ is -NR' ａ R' ｂ ;-O-X' ２ -NR' ａ R' ｂ and -X' ２ -NR' ａ R' ｂ represents a group selected from the group consisting of ・R １０ represents fluorine, ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents hydrogen or a methyl group; ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a linear or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; one or two hydroxyl or is C １ -C ６ A straight or branched chain C optionally substituted with an alkoxy group １ -C ６ a Rukyr; and C １ -C ６ Alkylene-NR' ｄ R' ｅ represents a group selected from the group consisting of 、 or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, ・R' ｄ , R' ｅ are each independently hydrogen or a straight or branched chain C １ -C ６ Al represents a alkyl group, ・B ３ is C ３ -C ８ represents a heterocycloalkyl group, said group being (i) monocyclic, or (ii) a bicyclic group, including fused, bridged, or spiro ring systems, attached to a nitrogen atom; In addition, it may contain one or two heteroatoms independently selected from oxygen and nitrogen. (iii) fluorine, bromine, chlorine, straight-chain or branched-chain C １ -C ６ Alkyl, hydroxy and oxo. or any one of its enantiomers, diastereoisomers, and / or pharmaceutically with an acceptable salt, or (2) Compounds of formula (IB), (IC), (IIB) or (IIC): 【Chemistry 107】 [In the formula, With respect to formula (IB) or (IC), R ３ is hydrogen; straight or branched chain C １ -C ６ Archi ル;-X １ -NR ａ R ｂ ;-X １ -N ＋ R ａ R ｂ R ｃ ;-X １ -O-R ｃ ;-X １ -N ３ and 【Chemistry 108】 represents a group selected from the group consisting of With respect to formula (IIB) or (IIC), Z １ represents a bond, R ３ represents hydrogen, or is Z １ represents —O—, and R ３ Ha-X １ -NR ａ R ｂ represents ・R ａ and R ｂ are each independently hydrogen; Straight or branched chain C substituted with １ -C ６ alkyl; and C １ -C ６ Alkylene -SO ２ O － represents a group selected from the group consisting of ・R ｃ is hydrogen or a straight or branched chain C １ -C ６ Represents an alkyl group ・R ６ is a straight or branched chain -C １ -C ６ Alkylene-R ８ group, -X ２ -O-R ７ , or linear or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Liren-R ７ represents a group, ・R ７ teeth, 【Chemistry 109】 represents a group selected from the group consisting of ・R ８ is -NR' ａ R' ｂ ;-O-X' ２ -NR' ａ R' ｂ and -X' ２ -NR' ａ R' ｂ represents a group selected from the group consisting of ・R １０ represents fluorine, ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group, ・R １４ and R １５ each independently represents hydrogen or a methyl group; ・X １ and X ２ are each independently trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a linear or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; one or two hydroxyl or is C １ -C ６ A straight or branched chain C optionally substituted with an alkoxy group １ -C ６ a Rukyr; and C １ -C ６ Alkylene-NR' ｄ R' ｅ represents a group selected from the group consisting of 、 or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, ・R' ｄ , R' ｅ are each independently hydrogen or a straight or branched chain C １ -C ６ Al represents a alkyl group, ・B ３ is C ３ -C ８ represents a heterocycloalkyl group, said group being (i) monocyclic, or (ii) a bicyclic group, including fused, bridged, or spiro ring systems, attached to a nitrogen atom; In addition, it may contain one or two heteroatoms independently selected from oxygen and nitrogen. (iii) fluorine, bromine, chlorine, straight-chain or branched-chain C １ -C ６ Alkyl, hydroxy and oxo. or any one of its enantiomers, diastereoisomers, and / or pharmaceutically The compound of any one of claims 1 to 10, including an acceptable salt thereof.

12. R ６ but, (1)-X ２ -O-R ７ represents R ７ is the following group: 【Chemistry 110】 represents or (2) Linear or branched chain C １ -C ６ Heteroarylene -R optionally substituted with alkyl group ７ represents a group, and R ７ but, 【Chemistry 111】 The compound according to any one of claims 1 to 11, wherein the compound represents a group selected from the group consisting of:

13. B ３ but, (1) C selected from the group consisting of a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, an azepanyl group, and a 4,4-difluoropiperidin-1-yl group ３ -C ８ represents a heterocycloalkyl group, or (2) B ３ represents a pyrrolidinyl group, or (3) represents a piperazinyl group, The compound according to any one of claims 1 to 12.

14. R ８ but, （１） 【Chemistry 112】 [In the formula, 【Chemistry 113】 is a bond to a linker; or （２） 【Chemistry 114】 [In the formula, 【Chemistry 115】 is a bond to a linker. The compound according to any one of claims 1 to 4.

15. With respect to formula (IB) or (IC-1), R ３ is hydrogen; straight or branched chain C １ -C ６ Alkyl; -X １ -NR ａ R ｂ ;-X １ -N ３ and 【Chemistry 116】 represents a group selected from the group consisting of With respect to formula (IIB) or (IIC-1), Z １ represents a bond, and R ３ represents hydrogen, With respect to formula (IC-1), G is —C(O)OH and —C(O)N(CH ３ ) ２ from is selected from the group consisting of With respect to formula (IIC-1), G is —C(O)NHS(O) ２ H, —C(O)NH ２ 、-C(O)NXCH ３ 、-C(O)NXC(CH ３ ) ２ 、-C(O)N(CH ３ ) ２ 、 -C(O)OH and -CH ２ OH; ・R ６ is a straight or branched chain -C １ -C ６ Alkylene-R ８ group, -X ２ -O-R ７ also is a straight or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ represents a group, ・R ７ but, 【Chemistry 117】 represents a group selected from the group consisting of ・R ８ But -NR' ａ R' ｂ and —O—X′ ２ -NR' ａ R' ｂ Selected from the group consisting of represents a group ・R １０ represents fluorine, ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group; ・R １４ and R １５ each independently represents hydrogen or a methyl group; ・X １ and X ２ each independently represents trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; one or two hydroxyl or is C １ -C ６ A straight or branched chain C optionally substituted with an alkoxy group １ -C ６ a Rukyr; and C １ -C ６ Alkylene-NR' ｄ R' ｅ represents a group selected from the group consisting of 、 or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Forming the law of nature, ・R' ｄ , R' ｅ are each independently hydrogen or a straight or branched chain C １ -C ６ Al represents a alkyl group, ・B ３ But C ３ -C ８ represents a heterocycloalkyl group, said group being (i) monocyclic, or (ii) a bicyclic group, including fused, bridged, or spiro ring systems, attached to a nitrogen atom; In addition, it may contain one or two heteroatoms independently selected from oxygen and nitrogen. (iii) fluorine, bromine, chlorine, straight-chain or branched-chain C １ -C ６ Alkyl, hydroxy and oxo, The compound according to claim 11.

16. With respect to formula (IB) or (IC), R ３ is hydrogen; straight or branched chain C １ -C ６ Al Kill; -X １ -N ３ and 【Chemistry 118】 represents a group selected from the group consisting of With respect to formula (IIB) or (IIC), Z １ represents a bond, and R ３ represents hydrogen, ・R ６ is a straight or branched chain -C １ -C ６ Alkylene-R ８ group, -X ２ -O-R ７ also is a straight or branched chain C １ -C ６ Heteroaryl optionally substituted with alkyl groups Ren-R ７ represents a group, ・R ７ but, 【Chemistry 119】 represents a group selected from the group consisting of ・R ８ But -NR' ａ R' ｂ and —O—X′ ２ -NR' ａ R' ｂ Selected from the group consisting of represents a group ・R １０ represents fluorine, ・R １２ and R １３ each independently represents a hydrogen atom or a methyl group; ・R １４ and R １５ each independently represents hydrogen or a methyl group; ・X １ and X ２ each independently represents trifluoromethyl, hydroxyl, halogen , and C １ -C ６ optionally substituted by one or two groups selected from the group consisting of alkoxy; Straight or branched chain C substituted with １ -C ６ represents an alkylene group, ・X' ２ is a straight or branched chain C １ -C ６ represents alkylene, ・R' ａ and R' ｂ are each independently hydrogen; one or two hydroxyl or is C １ -C ６ A straight or branched chain C optionally substituted with an alkoxy group １ -C ６ a Rukyr; and C １ -C ６ Alkylene-NR' ｄ R' ｅ represents a group selected from the group consisting of 、 or R' ａ and R' ｂ together with the nitrogen atom carrying them form ring B ３ Form And, ・R' ｄ , R' ｅ are each independently hydrogen or a straight or branched chain C １ -C ６ Al represents a alkyl group, ・B ３ is C ３ -C ８ (i) a monocyclic or fused heterocyclic group; (ii) in addition to the nitrogen atom, it can be a bicyclic group, including a bridged or spiro ring system; and may contain one or two heteroatoms independently selected from oxygen and nitrogen. (iii) fluorine, bromine, chlorine, straight-chain or branched-chain C １ -C ６ Alkyl, hydroxyl and oxo, Item 12. The compound according to item 11.

17. B ３ 17. The compound according to claim 15 or 16, wherein represents a pyrrolidinyl group or a piperazinyl group.

18. R ８ but, （１） 【Chemistry 120】 [In the formula, 【Chemistry 121】 is a bond to a linker; or （２） 【Chemistry 122】 [In the formula, 【Chemical 123】 is a bond to a linker. The compound described.

19. D is any one of the following attached to L: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 [In the formula, 【Chemical 124】 is the bond to the linker] or any one of its enantiomers, diastereoisomers, and / or pharmaceutically A compound according to any one of claims 1 to 18, representing an acceptable salt thereof.

20. D-L, 【Chemistry 125-1】 【Chemistry 125-2】 【Chemistry 125-3】 【Chemistry 125-4】 【Chemistry 125-5】 【Chemistry 125-6】 【Chemistry 125-7】 【Chemistry 125-8】 【Chemistry 125-9】 【Chemistry 125-10】 【Chemistry 125-11】 【Chemistry 125-12】 【Chemistry 125-13】 【Chemistry 125-14】 【Chemistry 125-15】 【Chemistry 125-16】 【Chemistry 125-17】 【Chemistry 125-18】 【Chemistry 125-19】 【Chemistry 125-20】 【Chemistry 125-21】 【Chemistry 125-22】 【Chemistry 125-23】 【Chemistry 125-24】 【125-25】 【Chemistry 125-26】 【Chemistry 125-27】 【Chemistry 125-28】 [In the formula, 【Chemical 126】 is a bond to the DSM. 。

21. The degradation signaling compound (1) Is it an E3 ligase recognition agent? (2) VHL ligand, thalidomide cereblon binding agent, or apo an inhibitor of IAP E3 ligase; or (3) any one of the following attached to L: 【Table 2-1】 【Table 2-2】 [In the formula, 【127】 represents a bond to a linker (L)] or any one of its enantiomers, diastereoisomers, and / or pharmaceutically 21. A compound according to any one of claims 1 to 20, representing an acceptable salt thereof.

22. The following in which DSM is attached to L: 【128】 [In the formula, 【Chemical 129】 represents a bond to a linker (L)] or any one of its enantiomers, diastereoisomers, and / or pharmaceutically 22. A compound according to any one of claims 1 to 21, representing an acceptable salt thereof.

23. Any one of the compounds in Table 7, or any one of the enantiomers thereof, dimers thereof 10. The compound of claim 1, which is an asterisk and / or a pharmaceutically acceptable salt.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier. Finished product.

25. A pharmaceutical composition for use in treating a subject having or suspected of having cancer, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24, optionally comprising: (1) whether the cancer is a solid tumor or a blood cancer; (2) A pharmaceutical composition wherein the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, prostate cancer, small cell lung cancer, or splenic cancer.

26. (1) The compound is administered as a monotherapy, or (2) the compound is administered as an adjunct to another therapeutic agent or radiation therapy; The compound may be capable of inhibiting tumor cells from responding to one or more additional therapeutic agents and / or radiation therapy.

26. The pharmaceutical composition of claim 25, administered in a sensitizing effective amount.

27. further comprising administering to a subject in need thereof at least one additional therapeutic agent; 26. The pharmaceutical composition of claim 25, optionally wherein the additional therapeutic agent is a Bcl-2 inhibitor, a taxane, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor.

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