Targeted Protease Degradation (TED) Platform

Abstract

A targeted protease degradation (TED) platform, specifically, relates to a conjugate of a target molecule-linker-E3 ligase ligand as shown in Formula I, R T -L1-R E3 (Formula I), wherein the R T The R is a monovalent group of the target molecule; E3 The L1 is a monovalent group of the E3 ligase ligand; L1 is the linker connecting A and B; and L1 is shown in Formula II as follows: -W-L2-W 2 -(II).

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a targeted protease degradation (TED) platform. Background Technology

[0002] Modern molecular biology regulates protein expression levels at three basic levels: First, at the DNA level, gene knockout inactivates the DNA of the target protein; second, at the mRNA level, small RNA molecules bind to the mRNA of the target protein, thereby inhibiting mRNA translation and expression; and third, at the protein level, modifications to the post-translational target protein, such as methylation, phosphorylation, and glycosylation, adjust the amount and activity of the target protein.

[0003] From the overall perspective of drug development, both small molecule and large molecule drugs have their own advantages and disadvantages. For example, the development of small molecule drugs has always faced key challenges such as maintaining in vivo drug concentrations and preventing drug resistance. Some target sites have shapes unfavorable for small molecule drug design, becoming "undruggable" targets. Currently, no effective regulatory mechanisms have been found for these targets. While monoclonal antibodies have advantages over small molecules in terms of high affinity and selectivity, making them easier to develop into highly efficient and selective drugs, their biggest drawback is their inability to cross cell membranes, thus preventing them from acting on intracellular targets. Antibody-drug conjugates (ADCs) utilize endocytic antibodies to provide targeting and act as carriers to deliver supertoxin drugs to the target site. A bottleneck in ADC drug development is the insufficient therapeutic window. Besides the toxic side effects caused by the antibody itself, the supertoxin may detach before reaching the target site due to the heterogeneity of the conjugation, causing serious toxic side effects. Furthermore, the ubiquitin-proteasome system is normally responsible for clearing denatured, mutated, or harmful proteins from cells.

[0004] In summary, there is an urgent need in this field to develop compounds that can more efficiently and reusably degrade target proteins to treat related diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a compound that can more efficiently and reusably degrade target proteins to treat related diseases.

[0006] In a first aspect of the invention, a conjugate as shown in Formula I or a pharmaceutically acceptable salt thereof is provided, characterized in that...

[0007] R T -L1-R E3 (I)

[0008] in,

[0009] (a) The R E3This is the E3 ligase ligand portion;

[0010] (b) The R T For the target molecule portion;

[0011] (c) The L1 is a connection to R E3 and R T Partial connector, and L1 as shown in Formula II;

[0012] -W 1 -L2-W 2 - (II)

[0013] in,

[0014] W 1 and W 2 Each independently constitutes -(W) s -;

[0015] W is selected independently from the following groups: none, -C(R) b )2-、-O-、-S-、-N(R a )-, -C(=O)-, -SO2-, -SO-, -PO3-, -C(R b )=C(R b )-, -C≡C-, NR, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted C6- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0016] s = 0, 1, 2, 3, or 4;

[0017] L2 is shown in Equation III.

[0018] -(M L ) o - (III)

[0019] in,

[0020] M L Each independently is M, M T Or M N ;

[0021] in,

[0022] o is an integer between 5 and 50;

[0023] M is independently a divalent group selected from the following group: -C(R b )2-、、-O-、-S-、-N(R a )-, -C(=O)-, -SO2-, -SO-, -PO3-, -C(R b )=C(Rb -, -C≡C-, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, amino acid residues;

[0024] M N Each of the following is independently a divalent group selected from the group consisting of: -N(R')-, -N (a 4- to 10-membered heterocyclic alkyl group containing an N(R') ring atom)-, a 4- to 10-membered heterocyclic alkyl group containing an N(R') ring atom, or a divalent group containing at least one -N(R') ring atom. b -C(R) replaced by R' (preferably, -NHR') b )2-、C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic alkyl, C 6-10 Aryl or 5 to 10-membered heteroaryl;

[0025] M T Each of the following is independently a divalent group selected from the group consisting of: -N(R")-, -N (a 4- to 10-membered heterocyclic alkyl group containing an N(R") ring atom)-, a 4- to 10-membered heterocyclic alkyl group containing an N(R") ring atom, or a divalent group containing at least one -N(R) ring atom. b -C(R) is replaced by -NHR" (preferably). b )2-、C 3-8 Cycloalkyl, 4- to 10-membered heterocyclic alkyl, C 6-10 Aryl or 5 to 10-membered heteroaryl;

[0026] R is either R' or R";

[0027] R' is independently selected from the following groups: H, C 1-6 Alkyl, OH, SH, -COO-C 1-6 Alkyl, -OC(O)-C 1-6 Alkyl and amino protecting groups;

[0028] R" is -W 3 -L3-W 4 -(R P ) q ;

[0029] W 3 and W 4 Each independently constitutes -(W) s -; and the definitions of W and s are the same as those of W. 1 and W 2 Definition of a group;

[0030] L3 is a divalent linker;

[0031] R PFor peptide elements or target molecules T;

[0032] q is >0 (preferably, m is 0.1 to 10, more preferably, 0.2 to 5);

[0033] R a Each is independently selected from the following groups: H, OH, SH, substituted or unsubstituted C. 1-6 Alkyl, amino protecting groups, N(R) protected groups c )4- to 10-membered heterocyclic alkyl groups with ring atoms;

[0034] R b Each is independently selected from the following groups: H, halogen, OH, SH, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Alkyl acyl (-C(O)-C) 1-6 Alkyl), carboxyl, -COO-C 1-6 Alkyl, -OC(O)-C 1-6 Alkyl group; or, two R groups on the same carbon atom. b Together with the carbon atoms attached to them, they constitute substituted or unsubstituted C atoms. 3-8 Cycloalkyl, substituted or unsubstituted 4- to 10-membered heterocyclic alkyl groups;

[0035] R c Each is independently selected from the following groups: H, OH, SH, substituted or unsubstituted C. 1-6 Alkyl and amino protecting groups;

[0036] Unless otherwise specified, substitution refers to the substitution of one or more (e.g., 1, 2, or 3) hydrogen atoms in a group by a substituent selected from the group consisting of: halogen (preferably F, Cl, Br, or I), cyano (CN), oxo (=O), thio (=S), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl acyl (C 1-6 Alkyl-C(O)-), -COO-C 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, NH2, NH(C) 1-6 Alkyl), N(C) 1-6 Alkyl)2.

[0037] In another preferred example, W is not NR.

[0038] In another preferred example, L2 does not have -OO-.

[0039] In another preferred embodiment, in L2, at least one M L For M T Or M N .

[0040] In another preferred example, in L2, all M L All are M.

[0041] In another preferred embodiment, in L2, when two or more M L For M T Or M N At that time, L2 includes M T and M N or L2 only includes M T Or L2 only includes M N .

[0042] In another preferred embodiment, in L2, at least one M L For M N .

[0043] In another preferred embodiment, in L2, at least one M L For M T .

[0044] In another preferred embodiment, L2 contains 1, 2, or 3 M's. L M independently T Or M N .

[0045] In another preferred embodiment, L2 contains 1, 2, or 3 M's. L M independently N .

[0046] In another preferred embodiment, L2 contains 1, 2, or 3 M's. L M independently T .

[0047] In another preferred embodiment, L2 is L5, and L5 is as shown in equation IIIc;

[0048] -(M) o1 -(M')-(M) o2 - (IIIc)

[0049] in,

[0050] M' is independent of M T Or M N ;

[0051] M, M Tand M N As defined in Equation I;

[0052] o1 and o2 are each independent integers from 1 to 50, and 4 ≤ o1 + o2 ≤ 49.

[0053] In another preferred embodiment, L2 is L6, and L6 is as shown in equation IIIa;

[0054] -(M) o1 -(M N )-(M) o2 - (IIIa)

[0055] in,

[0056] M, M N As defined above;

[0057] o1 and o2 are each independent integers from 1 to 50, and 4 ≤ o1 + o2 ≤ 49.

[0058] In another preferred embodiment, o1 and o2 are each independently 1, 2, 3, 4, 5, 6, 7 or 8.

[0059] In another preferred embodiment, in L6, M is independently selected from the following groups: -CH2-, -CH(C 1-4 Alkyl group, -CH(NH2)-, -O-, -NH-, -N(C 1-4 alkyl)-,

[0060] In another preferred embodiment, the coupling is as shown in Formula IV;

[0061] R T -W 1 -L6-W 2 -R E3 (IV)

[0062] Among them, L6, W 1 W 2 R T and R E3 As defined in Equation I.

[0063] In another preferred embodiment, L2 is L7, and L7 is as shown in equation IIIb;

[0064] -(M) o1 -(M T )-(M) o2 - (IIIb)

[0065] Among them, M, M T As defined above;

[0066] o1 and o2 are each independent integers from 1 to 50, and 4 ≤ o1 + o2 ≤ 49.

[0067] In another preferred embodiment, o1 and o2 are each independently 1, 2, 3, 4, 5, 6, 7 or 8.

[0068] In another preferred embodiment, the coupling is as shown in Formula V;

[0069] R T -W 1 -L7-W 2 -R E3 (V);

[0070] Among them, L7, W 1 W 2 R T and R E3 As defined in Equation I.

[0071] In another preferred embodiment, the coupling is as shown in formula 1-1, 1-2, 1-3, 2 or 3;

[0072] R T -W 1 -L5-W b -C≡CR E3 (1-1);

[0073] R T -W 1 -L5-CO-R E3 (1-2);

[0074] R T -W 1 -L5-CONH-R E3 (1-3);

[0075] R T -W a -Cr 1 -W a -Cr 2 -L5-W 2 -R E3 (2)

[0076] R T -Ar1-L5-W 2 -R E3 (3)

[0077] in,

[0078] Ar1 is a five- or six-membered nitrogen-containing heteroaryl group;

[0079] Cr 1It is none, or it was not replaced or was replaced by C. 1-4 C substituted by alkyl 4-7 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0080] Cr 2 For not replaced or by C 1-4 Alkyl groups substituted with 4 to 6 nitrogen-containing heterocyclic groups, and Cr 2 At least one nitrogen heteroatom is attached to L7;

[0081] W a and W b The definition is the same as W; and W and W 1 W 2 R T R E3 L5 is defined as previously.

[0082] In another preferred embodiment, the coupling is as shown in formula 1a-1, 1a-2, 1a-3, 2a or 3a;

[0083] R T -W 1 -L6-W b -C≡CR E3 (1a-1);

[0084] R T -W 1 -L6-CO-R E3 (1a-2);

[0085] R T -W 1 -L6-CONH-R E3 (1a-3);

[0086] R T -W a -Cr 1 -W a -Cr 2 -L6-W 2 -R E3 (2a)

[0087] R T -Ar1-L6-W 2 -R E3 (3a)

[0088] in,

[0089] Ar1, Cr 1 Cr 2 W a W b W 1 W 2R T R E3 L6 is defined as previously.

[0090] In another preferred embodiment, the coupling is as shown in formula 1b-1, 1b-2, 1b-3, 2b or 3b;

[0091] R T -W 1 -L7-W b -C≡CR E3 (1b-1);

[0092] R T -W 1 -L7-CO-R E3 (1b-2);

[0093] R T -W 1 -L7-CONH-R E3 (1b-3);

[0094] R T -W a -Cr 1 -W a -Cr 2 -L7-W 2 -R E3 (2b)

[0095] R T -Ar1-L7-W 2 -R E3 (3b)

[0096] in,

[0097] Ar1 is a five- or six-membered nitrogen-containing heteroaryl group;

[0098] Cr 1 It is none, or it was not replaced or was replaced by C. 1-4 C substituted by alkyl 4-7 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0099] Cr 2 For not replaced or by C 1-4 Alkyl groups substituted with 4 to 6 nitrogen-containing heterocyclic groups, and Cr 2 At least one nitrogen heteroatom is attached to L7;

[0100] W a and W b The definition is the same as W; and W and W 1 W 2 R T R E3And L7 is defined as in Equation I.

[0101] In another preferred embodiment, L2 is L8, and L8 is as shown in equation IIId;

[0102] -(M) o3 - (IIId)

[0103] Wherein, M is as defined above (preferably, M is CH2), and o3 is 1, 2, 3, 4, or 5.

[0104] In another preferred embodiment, the coupling agent such as R T -W 1 -L8-W 2 -R E3 As shown; where R T W 1 L8, W 2 and R E3 As defined above. Preferably, W 1 For W a -Cr 1 -Cr 2 (More preferably, NH-Cr) 1 -Cr 2 ), Cr 1 and Cr 2 As defined above.

[0105] In another preferred embodiment, when the heterocyclic alkyl group (e.g., a 4- to 10-membered heterocyclic alkyl group) is a divalent group, the 4- to 10-membered heterocyclic alkyl group includes: Wherein, k1 and k2 are each independently 0, 1, 2 or 3; preferably, the 4 to 10-membered heterocyclic alkyl group is selected from the group consisting of:

[0106] In another preferred embodiment, when the cycloalkyl group (such as C...) 3-8 When the cycloalkyl group is a divalent group, the cycloalkyl group (such as C...) 3-8 Cycloalkyl groups include: Wherein, k1 and k2 are each independently 1, 2, or 3; more preferably, the C 3-8 Cycloalkyl groups are selected from the following group:

[0107] In another preferred embodiment, when the heteroaryl group (e.g., a 5- to 10-membered heteroaryl group) is a divalent group, the heteroaryl group (e.g., a 5- to 10-membered heteroaryl group) is... Wherein, V1, V2, and V4 are each independently selected from: -O-, -S-, -N=, -NH-, -CH=, -CH2-; V3 is selected from the group consisting of: -N=, -CH=; preferably, the 5- to 10-membered heteroaryl groups are selected from the group consisting of:

[0108] In another preferred embodiment, M is independently selected from the following groups: -CH2-, -CH(C 1-4 Alkyl group, -CH(NH2)-, -O-, -NH-, -N(C 1-4 alkyl)-,

[0109] In another preferred embodiment, when the 4- to 10-membered heterocyclic alkyl group containing the N(R) ring atom is a divalent group, the 4- to 10-membered heterocyclic alkyl group containing the N(R) ring atom is selected from the group consisting of: Where R is either R' or R".

[0110] In another preferred embodiment, M T Each is independently selected from the following groups: -N(R")-, -C(R)-. b (NHR")-、

[0111] In another preferred embodiment, M N Each is independently selected from the following groups: -N(R')-, -C(R)-. b (NHR')-、

[0112] In another preferred embodiment, M is independently selected from the following groups: O, C(R) b )2; Preferably, R b Each independently is H or C 1-6 Alkyl groups (such as methyl groups).

[0113] In another preferred example, W is selected from the group consisting of: none, -C(R) b )2-、-O-、-S-、-N(R a )-, -C(=O)-, -SO2-, -SO-, -PO3-, -C(R b )=C(R b -, -C≡C-; or W is a substituted or unsubstituted group selected from the group consisting of:

[0114] In another preferred embodiment, R a Each independently is H or C 1-6 Alkyl groups (such as methyl groups).

[0115] In another preferred embodiment, R b Each independently is H or C 1-6 Alkyl groups (such as methyl groups).

[0116] In another preferred embodiment, Rc Each independently is H or C 1-6 Alkyl groups (such as methyl groups).

[0117] In another preferred embodiment, L3 is -(M a ) p -; where M a The definition is the same as M, where p is an integer from 1 to 50.

[0118] In another preferred embodiment, p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0119] In another preferred embodiment, M a Each is independently a divalent group selected from the group consisting of: -C(R b )2-、-O-、-S-、-N(R a )-, -C(=O)-, -SO2-, -SO-, -PO3-, -C(R b )=C(R b -, -C≡C-, substituted or unsubstituted -C3-8 cycloalkyl-, substituted or unsubstituted -4 to 10-membered heterocyclic alkyl, substituted or unsubstituted -C6-10 aryl, substituted or unsubstituted 5 to 10-membered heteroaryl, amino acid residues.

[0120] In another preferred example, -W 3 -L3-W 4 -R P Selected from the following group:

[0121]

[0122] Where L4 is -(M) q - where the definition of M is the same as that in L2;

[0123] q is an integer from 0 to 50 and q is less than p (preferably, q = an integer from 0 to 30; more preferably, q = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), n5 is an integer from 0 to 30 (preferably, n5 = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R 20 and R 21 Each can be independently selected from the following groups: -H, -Me, -Et, -nPr, iPro, cPro.

[0124] In another preferred embodiment, the conjugate is not one of the specific compounds disclosed in PCT / CN2019 / 110225.

[0125] In another preferred embodiment, the coupling agent is not one of the specific compounds listed in Table B1-11 of PCT / CN2019 / 110225. The specific compounds listed in Table B1-11 are as follows:

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] In another preferred embodiment, the conjugate is not a specific compound listed in Table D of PCT / CN2019 / 110225, and the specific compounds in Table D are as follows:

[0168]

[0169] In another preferred embodiment, the coupling agent is selected from Group 1, Group 2 and Group 3.

[0170] In another preferred embodiment, the coupling agent is selected from group 1a, group 2a and group 3a.

[0171] In another preferred embodiment, the coupling agent is selected from group 1, group 2, and group 3; wherein R and R 1 R" (i.e., R and R) 1Each independently as -W 3 -L3-W 4 -(R P ) q ).

[0172] In another preferred embodiment, the coupling shown in Formula I is the coupling shown in Formula X.

[0173] R P -(W 4 -L3-W 3 -R TED ) t (X)

[0174] Where t = 1 / q (preferably, t = 1-8; more preferably, t = 2-7);

[0175] R P As defined above, R is preferred. P It is a polypeptide element, more preferably an antibody;

[0176] R TED -W 4 -L3-W 3 - for the loss of R of the coupling shown in Equation I P The remaining part after the group.

[0177] In another preferred embodiment, R TED The term refers to a monovalent group derived from the conjugates in Tables A1, A2, and A3, the conjugates in Groups 1a, 2a, and 3a, or the specific compound of Example 1.5 (wherein, "derivation" means the formation of a monovalent group by the removal of NH or NH2 hydrogens from the main chain or the side chain of the linking group of the specific compound shown in Tables A1, A2, and A3 or Example 1.5).

[0178] In another preferred embodiment, Ab is reacted with W as shown in Formula III via an N-terminal or C-terminal amino acid, or an amino acid side chain (preferably selected from the group consisting of Lys, Cys), or a thiol group formed by the reduction and opening of disulfide bonds. 4 -L3 W 3 -(Preferably, W) 4 -L3-W 3 -in (Or linked with -NH2 group).

[0179] In another preferred embodiment, the target molecule is target molecule A or target molecule T.

[0180] In another preferred embodiment, the target molecule A or T includes: a small molecule, a nanocarrier, or a combination thereof.

[0181] In another preferred embodiment, the target molecules A and T are each independently selected from the group consisting of: folic acid, HSP90, TINFRm, TNFR2, NADPH oxidase, BclIBax, C5a receptor, HMG-CoA reductase, PDE IV, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1-2, 5HT receptors, dopamine receptors, G-proteins, Gq, histamine receptors, lipoxygenases, tryptase serine protease, thymidylate synthase, purine nucleotide phosphorylase, and GAPDH trypanosomes. Trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and their analogues, HIV 1 protease, HIV 1 integrase, influenza, hepatitis B reverse transcriptase, neuraminidase, sodium channel, MDR, protein P1-glycoprotein, tyrosine kinases, CD23, CD124, TKp56 lck, CD4, CD5, IL-1 receptor, IL-2 receptor, TNF-αR, ICAM1,Ca+ channels, VCAM, VLA-4 integrin, Selectins, CD40 / 40L, Neokinins and receptors, Inosine monophosphate dehydrogenase, p38 MAP kinase, Interleukin-1 converting enzyme, Caspase, HCV NS3 protease, HCV-NS3 RNA helicase, Glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, HSV-I, CMV, ADP1-polymerase, CDK, VEGF, oxytocin receptor The following receptors are listed: msomal transfer protein inhibitor, bile acid transfer protein inhibitor, 5-α reductase, angiotensin 11, glycine receptors, noradrenaline reuptake receptor, endothelin receptors, neuropeptide Y and receptors, estrogen receptors, AMP, AMP deaminase, ACC, EGFR, and farnesyltransferase.

[0182] In another preferred embodiment, the polypeptide element includes: an antibody, a protein, or a combination thereof.

[0183] In another preferred embodiment, the antibody includes: nanobodies, minibody antibodies, or combinations thereof.

[0184] In another preferred embodiment, the polypeptide element is an antibody; preferably, the antibody includes nanobodies and / or minibodies.

[0185] In another preferred embodiment, the antibody may bind to an antigen or receptor selected from the group consisting of: DLL3, EDAR, CLL1, BMPR1B, E16, STEAP1, O772P, MPF, 5T4, NaPi2b, Sema 5b, PSCA. hlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD22, CD79b, CD19, CD37, CD38, CD138, FcRH2, B7-H4, HER2, NCA, MDP, IL20Rα, Brevican, EphB2R, ASLG659, PSCA , GEDA, BAFF-R, CD79a, CXCR5, HLA-DOB, P2X5, CD72, LY64, FcRH1, IRTA2, TENB2, PMEL17, TMEFF1, GDNF-Ra1, Ly6E, TMEM46, Ly6G6D, LGR5, RET, LY6K, GPR19, GPR54, ASPHD1 Tyrosinase, TMEM118, GPR172A, MUC1, CD70, CD71, MUC16, methotrelin, FOLR1, TroP1-2, gpNMB, EGFR, ENPP3, PSMA, CA6, GPC-3, PTK7, CD44, CD56, TIM-1, Cadherin-6, ASG-15ME, ASG-22ME, CanAg, AXL, CEACAM5, EphA4, cMet, FGFR2, FGFR3, CD123, Her3, LAMP1, LRRC15, TDGF1, CD66, CD25, BCMA, GCC, Noch3, cMet, EGFR, and CD33.

[0186] In another preferred embodiment, R T Selected from the groups shown in Table B.

[0187] In another preferred embodiment, the E3 ligase ligand portion A1 is selected from A in WO2017 / 176957A1. 1 Group (preferably, the corresponding portion of A-10, A-11, A-15, A-28, A-48, A-69, A-85, A-93, A-98, A-99 or A-101 in WO2017 / 176957A1).

[0188] In another preferred embodiment, the E3 ligase ligand portion is selected from:

[0189]

[0190] In each formula, the dashed line indicates the position where it connects to other parts (i.e., with R). T -L1 connection location);

[0191] Rx is independently selected from the following groups: none, NH, NH-CO, O, S, SO, SO2, SO2(NH2)NH, C1-C4 alkylene, C2-C5 alkenylene, C2-C5 ynylene; R y It can be C=O, C=S, or CH2.

[0192] In another preferred embodiment, the E3 ligase ligand portion is selected from the groups shown in Table C.

[0193] In another preferred example, when R E3 for When (preferably A1.2 in Table B), the coupling of formula I is as shown in formula 1-1, R T -W 1 -L5-W b -C≡CR E3 (1-1); Preferably, at least one M in L5 is O and / or W. 1 NH or NH-Cr 2 , and / or W b For CH 2 More preferably, in L5, 7≤o1+o2≤12.

[0194] In another preferred example, when R E3 for (Preferably A1.2 in Table B), when the coupling agent of Formula I is such as R T -W a -Cr 1 -Cr 2 -(M) o3 -W 2 -R E3 As shown, and Cr 1 and Cr 2 Neither is zero; preferably, L2 is -(M). o3 - and the subscript o3 o3 is 1, 2, 3, 4, or 5.

[0195] In another preferred embodiment, R T R E3 R P ,L1,L2,L3,L4,L5,L6,L7,W 1 W 2 W3 W 4 W a W b W, M L M, M', M T M N Subscripts s, p, q, o, o1, o2, R a R b R c 、R、R'、R"、Cr 1 Cr 2 Ar1 and Ar2 are each independently the specific compounds or the corresponding groups in the general formulas described herein; preferably, they are the specific compounds or the corresponding groups in the general formulas shown in Group 1, Group 2, Group 3, Group 1a, Group 2a, Group 3a, Tables A1, A2, A3, Table B, Table C and Table D.

[0196] In another preferred embodiment, the coupling agent is a TED compound as described in the sixth aspect.

[0197] In another preferred embodiment, the coupling agent is the ACTED compound as described in the seventh aspect.

[0198] In a second aspect of the invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises a conjugate as described in the first aspect and a pharmaceutically acceptable carrier.

[0199] In a third aspect of the invention, the use of the conjugate as described in the first aspect is provided in the preparation of a medicament for treating or preventing diseases associated with overdose of a target protein.

[0200] In a fourth aspect of the invention, the use of the conjugate as described in the first aspect in the treatment or prevention of diseases associated with overdose of a target protein is provided.

[0201] In a fifth aspect of the invention, a method for reducing the content of target proteins in cells is provided, wherein the cells are contacted with a conjugate as described in the first aspect, thereby reducing the content of target proteins in the cells.

[0202] In another preferred embodiment, the method is an in vitro method.

[0203] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0204] In a sixth aspect of the invention, a TED compound or a pharmaceutically acceptable salt thereof is provided, wherein the TED compound is as shown in Formula VI;

[0205] R T W 1 -(M L )o -W 2 -R E3 (VI)

[0206] in,

[0207] M L Each independently is M or M N

[0208] M, M N R E3 R T W 1 W 2 The subscript o is defined as in formula I.

[0209] In another preferred embodiment, the TED compound is as shown in Formula IV.

[0210] In another preferred embodiment, the TED compound is as shown in formula 1a-1, 1a-2, 1a-3, 2a or 3a.

[0211] In another preferred embodiment, the TED compound is used with R P Couplet.

[0212] In another preferred embodiment, the TED compound is via -W 3 -L3-W 4 -with R P Couplet.

[0213] In another preferred embodiment, the TED compound is a compound selected from Group 1, Group 2 and Group 3, and R and R 1 Each is independently represented by R'.

[0214] In another preferred embodiment, the TED compound is a compound selected from Tables A1, A2 and A3, Group 1a, Group 2a and Group 3a.

[0215] In a seventh aspect of the invention, an ACTED compound or a pharmaceutically acceptable salt thereof is provided, wherein the ACTED compound is as shown in Formula VII;

[0216] R T W 1 -(M L ) o -W 2 -R E3 (VII)

[0217] in,

[0218] M L Each independently is M or M T

[0219] M, M T R E3 R T W 1 W 2 The subscript o is defined as in formula I.

[0220] In another preferred embodiment, the ACTED compound is as shown in Formula V.

[0221] In another preferred embodiment, the ACTED compound is shown as Formula X.

[0222] In another preferred embodiment, the ACTED compound is as shown in formula 1b-1, 1b-2, 1b-3, 2b or 3b.

[0223] In another preferred embodiment, the ACTED compound is a compound selected from Group 1, Group 2 and Group 3, and R and R 1 Each is independently represented by R".

[0224] In another preferred embodiment, the ACTED compound is selected from:

[0225]

[0226]

[0227] Compounds 1216, 1229, 1231, and 1233 in Table D.

[0228] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0229] Figure 1 The degradation of BRD4 and PLK1 in the MV4;11 cell line by the compounds of the present invention is shown.

[0230] Figure 2 The degradation of BRD4 and PLK1 in the MV4;11 cell line by the compounds of the present invention is shown.

[0231] Figure 3 The degradation of BRD4 and PLK1 in the TMD-8 cell line by the compounds of the present invention is shown.

[0232] Figure 4 The degradation of BRD4 and PLK1 in the MV4;11 cell line by the compounds of the present invention is shown. Detailed Implementation

[0233] Through extensive and in-depth research, the inventors have developed a novel TED conjugate for the first time, which has the structure shown in Formula I. Furthermore, the conjugate is highly suitable for further linking with peptide elements (especially antibodies and protein ligands) and / or other targeted molecules, or for further linking with peptide elements and / or other targeted molecules, or for conjugates containing peptide elements and / or other targeted molecules. This results in the conjugate exhibiting excellent specificity (e.g., specificity targeting tumor cells), significantly improving drug selectivity, enabling more precise degradation of pathogenic proteins, reducing systemic toxicity that may be caused by non-specific degradation, and potentially overcoming difficulties encountered in drug absorption and metabolism, eliminating the opportunity for drug resistance. Based on this, the inventors completed this invention.

[0234] the term

[0235] As used herein, the terms "compound of the present invention" and "conjugate of the present invention" are used interchangeably to refer to the compound or conjugate of Formula I described in the first aspect of the present invention.

[0236] As used herein, unless otherwise defined, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C64 ... 1-6 (Indicates 1-6 carbons). Preferably, the alkyl group specifically has 1-4 carbons, i.e., C1-C2. 1-4 Alkyl groups. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Preferably, the alkenyl group specifically has 2 to 4 carbons, i.e., C10. 2-4 Alkenyl. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Preferably, the alkynyl group specifically has 2 to 4 carbons, i.e., C10. 2-4 Alkynyl. Examples of such unsaturated alkyl groups include, but are not limited to: vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. The term "cycloalkyl" refers to a group having a specified number of ring atoms (e.g., C12, C23 ... 3-6 A cycloalkyl hydrocarbon ring that is fully saturated or has no more than one double bond between the ring apexes.

[0237] As used herein, the term "cycloalkyl" refers to a ring having a specified number of ring atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-8A cycloalkyl group is a hydrocarbon ring that is fully saturated or has no more than one double bond between the ring apexes. The term also includes bicyclic and polycyclic hydrocarbon rings, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc. The term "heterocyclic alkyl" refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heterocyclic alkyl groups can be monocyclic, bicyclic, or polycyclic systems. Non-limiting examples of heterocyclic alkyl groups include pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valeron, imidazolidinone, hydantoin, dioxolane, benzodiimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridinone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, quinine ring, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via a cyclic carbon or heteroatom. Terms such as cycloalkylalkyl and heterocyclic alkylalkyl refer to cycloalkyl or heterocyclic alkyl groups attached to the rest of the molecule via alkyl or alkylene linkers. For example, cyclobutylmethyl is a cyclobutyl ring attached to a methylene linker group that is attached to the rest of the molecule.

[0238] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkane, such as -CH2CH2CH2CH2-. Alkyl (or alkylene) groups typically have 1-24 carbon atoms, with those having 10 or fewer carbon atoms being preferred in this invention. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically having 4 or fewer carbon atoms. Similarly, "alkenyl" or "alkynyl" refers to an unsaturated form of "alkylene" having a double or triple bond, respectively.

[0239] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with other terms refers to a stable straight-chain or branched or cyclic hydrocarbon group or a combination thereof, consisting of a specified number of carbon atoms and 1 to 3 heteroatoms selected from O, N, Si, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. Heteroatoms O, N, and S can be located at any internal position of the heteroalkyl group. Heteroatoms Si can be located at any position of the heteroalkyl group, including positions where the alkyl group is attached to the rest of the molecule. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. The two heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, unless otherwise stated, the terms "heteroalkenyl" and "heteroyneyl" refer, on their own or in combination with another term, to an alkenyl or ynyl group, respectively, containing a specified number of carbon atoms and 1 to 3 heteroatoms selected from O, N, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatoms O, N, and S can be located at any internal position of the heteroalkyl group.

[0240] The term "heteroalkylene" itself, or as part of another substituent, refers to a saturated, unsaturated, or polyunsaturated divalent group derived from a heteroalkyl group, such as -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, -CH2-CH=C(H)CH2-O-CH2-, and -S-CH2-C≡C-. For heteroalkylene, the heteroatom can also occupy any one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.).

[0241] The terms "alkoxy," "alkamino," and "alkithioyl" (or thioalkoxy) are used in their conventional sense to refer to alkyl groups attached to the remainder of a molecule via an oxygen, amino, or sulfur atom, respectively. Furthermore, for dialkylamino groups, the alkyl moiety can be the same or different, and can combine with the nitrogen atom attached to each alkyl group to form a 3-7 membered ring. Therefore, -NR a R b The groups shown represent piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, etc.

[0242] Unless otherwise stated, the terms "halogenated" or "halogen" themselves, or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom. Furthermore, terms such as "halogenated alkyl" indicate the inclusion of monohalogenated or polyhalogenated alkyl groups. For example, the term "C 1-4 "Halogenated alkyl" indicates that it includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0243] Unless otherwise stated, the term "aryl" refers to a polyunsaturated (usually aromatic) hydrocarbon group, which can be monocyclic or fused together or covalently linked polycyclic (up to three rings). The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups can be linked to the rest of the molecule via heteroatoms. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, and isobenzofuranyl. (furyl), isoindolyl, indene, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiaphenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, etc. The substituents in the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents listed below.

[0244] For the sake of brevity, when the term "aryl" is used in combination with other terms (e.g., aryloxy, arylthio, aralkyl), it includes aryl and heteroaryl rings as defined above. Therefore, the term "aralkyl" refers to those groups in which the aryl group is attached to an alkyl group linked to the rest of the molecule (e.g., benzyl, phenethyl, pyridylmethyl, etc.).

[0245] In some embodiments, the terms above (such as “alkyl,” “aryl,” and “heteroaryl”) will include substituted and unsubstituted forms of the specified group. Preferred substituents for each type of group are provided below. For brevity, the terms aryl and heteroaryl will refer to the substituted or unsubstituted forms provided below, while the term “alkyl” and the associated aliphatic group refer to the unsubstituted form unless specified otherwise.

[0246] The substituents of alkyl groups (including those commonly referred to as alkylene, alkenyl, ynyl, and cycloalkyl) can be a variety of groups selected from the group consisting of: -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R"', -OC(O)NR'R"', -NR"C(O)R', -NR'-C(O)NR"R"', -NR" C(O)₂R', -NH-C(NH₂)=NH, -NR'C(NH₂)=NH, -NH-C(NH₂)=NR', -S(O)R', -S(O)₂R', -S(O)₂NR'R", -NR'S(O)₂R", -CN, and -NO₂, in quantities ranging from zero to (2M'+1), where M' is the total number of carbon atoms in this group. R', R" and R"' each independently represent hydrogen, and unsubstituted C 1-8 Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy, or unsubstituted aryl-C 1-4 Alkyl groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form 3-, 4-, 5-, 6-, or 7-membered rings. For example, -NR'R" refers to a group comprising 1-pyrrolidinyl and 4-morpholinyl. The term "acyl" is used alone or as part of another group and refers to a group in which the substituents on the carbon closest to the connection point of the group are substituted with =O (e.g., -C(O)CH3, -C(O)CH2CH2OR', etc.).

[0247] Similarly, the substituents of aryl and heteroaryl groups are diverse and are usually selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH- C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, in numbers ranging from zero to the total number of open valences on the aromatic ring system; wherein R', R" and R"' are independently selected from hydrogen, C 1-8 Alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 Alkyl and unsubstituted aryloxy-C 1-4 Alkyl groups. Other suitable substituents include each of the above aryl substituents attached to the ring atom via an alkylene chain of 1-4 carbon atoms.

[0248] The two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CH2). q The substituents of -U- are used, where T and U are independently -NH-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, the two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -A-(CH2). r -B-, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or single bonds, and r is an integer from 1 to 3. One single bond in the resulting new ring may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -(CH2). s -X-(CH2) t The substituents are substituted, where s and t are independent integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C. 1-6 alkyl.

[0249] In this invention, when the cycloalkyl or heterocycloalkyl group is divalent, the cycloalkyl or heterocycloalkyl group may lose two hydrogens located on the same ring atom (on the ring carbon atom) to connect with other chain atoms on the chain (forming a spiro-like structure), or it may lose two hydrogens located on different ring atoms to connect with other chain atoms on the chain (such as -cyclopentyl-).

[0250] As used in this article, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0251] For the compounds presented herein, a bond from a substituent (typically an R group) to the center of an aromatic ring (e.g., benzene, pyridine, etc.) will be understood as a bond that provides a connection at any available vertex of the aromatic ring. In some embodiments, this description also includes connections on the ring fused to the aromatic ring. For example, a bond drawn to the center of the indole benzene moiety would represent a bond connected to any available vertex of the six- or five-membered ring moiety of indole.

[0252] As used herein, the term "amino acid residue" refers to the group formed by removing a H from the N-terminal -NH2 group and removing a -OH from the C-terminal -COOH group of an amino acid. Unless otherwise defined, amino acids herein include both native and non-native amino acids, including D-type and / or L-type amino acids. Examples of amino acids include, but are not limited to, Ala (A), Arg (R), Asn (N), Asp (D), Cys (C), Gln (Q), Glu (E), Gly (G), His (H), Ile (I), Leu (L), Lys (K), Met (M), Phe (F), Pro (P), Ser (S), Thr (T), Trp (W), Tyr (Y), and Val (V). Preferably, in this document, the amino acid is selected from the group consisting of: L-glycine (L-Gly), L-alanine (L-Ala), β-alanine (β-Ala), L-glutamic acid (L-Glu), L-aspartic acid (L-Asp), L-histidine (L-His), L-arginine (L-Arg), L-lysine (L-Lys), L-valine (L-Val), L-serine (L-Ser), and L-threonine (L-Thr).

[0253] The term "pharmaceutically acceptable salt" is intended to include salts prepared from active compounds with relatively non-toxic acids or bases, depending on the specific substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (solvent-free or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid (solvent-free or in a suitable inert solvent). Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, etc.; and salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galactunoric acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, thereby enabling the conversion of the compound into a basic addition salt or an acid addition salt.

[0254] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but otherwise, for the purposes of this invention, those salts are equivalent to the parent form of the compound.

[0255] In addition to salt forms, the present invention provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of the present invention.

[0256] Some compounds of the present invention may exist in both solvated and hydrated forms, including hydrated forms. The hydrated forms are generally equivalent to the hydrated forms and should be included within the scope of the present invention. Some compounds of the present invention may exist in polymorphic or amorphous forms. Generally, all physical forms are equivalent for the applications contemplated by the present invention and should be included within the scope of the present invention.

[0257] Some compounds of this invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) should all be included within the scope of this invention. When the compounds provided herein have a defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), it will be understood by those skilled in the art that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and at most 100% free of other isomers).

[0258] The compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more isotopic atoms constituting such compounds. A non-natural proportion of an isotope can be defined as ranging from the amount of the atom in question that is naturally found to 100% of that atom. For example, the compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium (C). 2 H) or carbon-13 ( 13 C). In addition to the uses described in this application, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, regardless of radioactivity, should be included within the scope of this invention.

[0259] Targeted Enzyme Degradation (TED) Platform

[0260] This invention provides a targeted protease degradation (TED) platform based on conjugates of this invention, which utilizes the intracellular "cleaner"—the ubiquitin-proteasome system.

[0261] Typically, based on the TED technology of this invention, specific oncogenic proteins can be removed from cells by utilizing the cell's own protein destruction mechanisms, thus providing an alternative to targeted therapy.

[0262] Unlike traditional protein inhibitors, the TED technology of this invention is a bifunctional hybrid compound. One side binds to the target protein, and the other side binds to an E3 ligase, allowing the target protein to bind to the E3 ligase, ubiquitinate it, and thus be degraded by the proteome. Theoretically, the TED technology only provides binding activity without directly inhibiting the functional activity of the target protein, and it can be reused, therefore, it has excellent application prospects.

[0263] polypeptide elements

[0264] As used herein, the term "peptide element" includes peptide segments (such as short peptides of 3-20 aa) or proteins. Furthermore, the term also includes complete proteins or fragments thereof. Preferred peptide elements include antibodies (such as complete antibodies, single-chain antibodies, nanobodies, Fab), particularly antibodies targeting tumor cell markers (such as tumor markers located on the surface of tumor cells, such as receptors on the cell surface) or inflammatory factors (such as inflammatory factors associated with autoimmune diseases).

[0265] As used herein, the terms "antibody" or "immunoglobulin" refer to isotetraglycoproteins of approximately 150,000 Daltons with identical structural features, consisting of two identical light chains (L) and two identical heavy chains (H). Each light chain is linked to the heavy chain by a covalent disulfide bond, although the number of disulfide bonds between heavy chains varies among different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bonds. Each heavy chain has a variable region (VH) at one end, followed by multiple constant regions. Each light chain has a variable region (VL) at one end and a constant region at the other; the constant regions of the light chains are opposite the first constant region of the heavy chains, and the variable regions of the light chains are opposite the variable regions of the heavy chains. Specific amino acid residues form interfaces between the variable regions of the light and heavy chains.

[0266] As used herein, the terms "single-domain antibody" and "nanobody" have the same meaning: to clone the variable region of an antibody heavy chain to construct a single-domain antibody consisting of only one heavy chain variable region. It is the smallest antigen-binding fragment with complete function. Typically, antibodies that are naturally missing the light chain and the heavy chain constant region 1 (CH1) are first obtained, and then the variable region of the antibody heavy chain is cloned to construct a single-domain antibody consisting of only one heavy chain variable region.

[0267] As used herein, the term "variable" refers to the fact that certain portions of the variable region of an antibody differ sequentially, contributing to the binding and specificity of various specific antibodies to their specific antigens. However, variability is not uniformly distributed throughout the entire variable region of an antibody. It is concentrated in three segments within the variable regions of the light and heavy chains, known as complementarity-determining regions (CDRs) or hypervariable regions. The more conserved portions of the variable region are called framework regions (FRs). The variable regions of the native heavy and light chains each contain four FRs, which are generally β-sheeted and linked by three CDRs forming a linking loop, and in some cases, partially folded structures. The CDRs in each chain are tightly packed together by the FR regions and, together with the CDRs of the other chain, form the antigen-binding site of the antibody (see Kabat et al., NIH Publ. No. 91-3242, Vol. I, pp. 647-669 (1991)). Constant regions do not directly participate in antibody-antigen binding, but they exhibit different effector functions, such as participating in antibody-dependent cytotoxicity.

[0268] Vertebrate antibodies (immunoglobulins) can be classified into two distinct classes (denoted as κ and λ) based on the amino acid sequence of their constant region. Immunoglobulins can be further classified into different types based on the amino acid sequence of their heavy chain constant region. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are respectively called α, δ, ε, γ, and μ. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well known to those skilled in the art.

[0269] Generally, the antigen-binding properties of an antibody can be described by three specific regions located in the variable regions of the heavy and light chains, called variable regions (CDRs). These regions are divided into four frame regions (FRs). The amino acid sequences of the four FRs are relatively conserved and do not directly participate in the binding reaction. These CDRs form a ring structure, and are spatially close to each other through β-sheets formed by the FRs between them. The CDRs on the heavy chain and the corresponding CDRs on the light chain constitute the antigen-binding site of the antibody. The amino acid sequences of antibodies of the same type can be compared to determine which amino acids constitute the FR or CDR regions.

[0270] In this invention, polypeptide elements may include not only complete antibodies, but also fragments of immunologically active antibodies (such as Fab or (Fab')2 fragments; antibody heavy chains; or antibody light chains) or fusion proteins formed by antibodies and other sequences. Therefore, this invention also includes fragments, derivatives, and analogs of said antibodies.

[0271] Targeted ligands

[0272] Targeting ligands (or target protein portions, target protein ligands, or ligands) are small molecules that can bind to a target protein.

[0273] Some embodiments of this application involve target molecules, including but not limited to: folic acid, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting proteins containing human BET bromine domains, compounds targeting the cytoplasmic signaling protein FKBP12, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHR).

[0274] In some implementations, the targeting ligand is a protein capable of binding to kinases, proteins with a bromine-containing BET domain, cytoplasmic signaling proteins (e.g., FKBP12), nucleoproteins, histone deacetylases, lysine methyltransferases, proteins that regulate angiogenesis, proteins that regulate immune responses, aryl hydrocarbon receptors (AHR), estrogen receptors, androgen receptors, glucocorticoid receptors, or transcription factors (e.g., SMARCA4, SMARCA2, TRIM24).

[0275] In some embodiments, the kinases that the targeting ligand can bind to include, but are not limited to: tyrosine kinases (e.g., AATK, ABL, ABL2, ALK, AXL, BLK, BMX, BTK, CSF1R, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1, FLT3, FLT4, FRK, FYN, GSG2, HCK, HRAS, HSP90, IGF1R, ILK, INSR, INSRR, IRAK4, ITK, JAK1, JAK2, JAK3, KDR, KIT, K RA S, KSP, KSR1, LCK, LMTK2, LMTK3, LTK, LYN, MATK, MERTK, MET, MLTK, MST1R, MUSK, NPR1, N RA S, NTRK1, NTRK2, NTRK3, PDGF RA PDGF RBPLK4, PTK2, PTK2B, PTK6, PTK7, RET, ROR1, ROR2, ROS1, RYK, SGK493, SRC, SRMS, STYK1, SYK, TEC, TEK, TEX14, TIE1, TNK1, TNK2, TNNI3K, TXK, TYK2, TYRO3, YES1 or ZAP70), serine / threonine kinases (e.g., casein kinase 2, protein kinase A, protein kinase B, protein kinase C, ... Ra f-kinase, CaM-kinase, AKT1, AKT2, AKT3, ALK1, ALK2, ALK3, ALK4, Auro ra A、Auro ra B, Auro ra C. CHK1, CHK2, CLK1, CLK2, CLK3, DAPK1, DAPK2, DAPK3, DMPK, ERK1, ERK2, ERK5, GCK, GSK3, HIPK, KHS1, LKB 1. LOK, MAPKAPK2, MAPKAPK, MEK, MNK1, MSSK1, MST1, MST2, MST4, NDR, NEK2, NEK3, NEK6, NEK7, NEK9, NEK11, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, PIM1, PIM2, PLK1, RIP2, RIP5, RSK1, RSK2, SGK2, SGK3, SIK1, STK33, TAO1, TAO2, TGF-β, TLK2, TSSK1, TSSK2, MLK1 or MLK2), cyclin-dependent protein kinases (e.g., Cdk1-Cdk11), and leucine-rich repeat kinases (e.g., LRRK2).

[0276] target molecules

[0277] In the coupling shown in Formula I of the present invention, through R in the coupling... T (Target molecule portion) to bind to target protein.

[0278] In this invention, the target molecule can be target molecule A, target molecule T, or a combination thereof.

[0279] In this invention, the target molecule can be any inhibitor of the target protein. The target molecule can be a highly effective inhibitor of the target protein, or it can be an inhibitor with relatively poor activity. Specifically, the target molecule of this invention can be a small molecule inhibitor known in the art for any target protein.

[0280] In some embodiments, the target molecule used herein has groups that can be linked to the linker (such as -O-, -NR). a -(where R) a For H or C 1-6 Alkyl substituents (such as -CO-, -COO-, etc.) are monovalently docked with the linker molecule of the present invention (such as L1 in the present invention) to form ethers, amines, amides, etc., thereby forming the target molecule moiety.

[0281] The target protein can be any of the target proteins known in the art, and representative examples include (but are not limited to): MDM2, AKT, BCR-ABL, Tau, BET (BRD2, BRD3, BRD4), ERRα, FKBP12, RIPK2, E RB B3, androgen receptor, MetAP2, TACC3, FRS2α, PI3K, DHFR, GST, Halo Tag, C RA BPI,C RA BPII, RA R, aryl hydrocarbon receptor, estrogen receptor. Different target proteins and some corresponding inhibitors are commercially available or prepared using conventional methods. For example, for MDM2, inhibitors can be found in literature such as WO 2017176957 and WO2017176958A1.

[0282] In another specific implementation scheme, R T Selected from Table B

[0283] Table B

[0284]

[0285] E3 ligase ligand

[0286] In this invention, the E3 ligase ligand moiety (R) E3 It is used to bind E3 ligase.

[0287] In one specific implementation, a representative E3 ligase ligand moiety has a structure as shown in formula A1 or A2:

[0288]

[0289] In formula A, R X Selected from: none, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, O, NH, S, CO or SO n (n is 1 or 2), etc.; R Y For CH2, C=S, CO; and, the E3 ligase ligand (R in Formula I) E3 ) can be obtained through R in it XThe group is connected to L1 of the present invention, such as -R x -L1-R T (e.g. -O-L1-R) T );

[0290] Alternatively, a representative E3 ligase ligand moiety has a structure as shown in Formula A1b:

[0291]

[0292] In formula A1b, R' is H or a C1-C6 alkyl group (such as Me), and R is H or a C1-C6 alkyl group (such as Me or Et).

[0293] In some embodiments, the E3 ligase ligands used herein have groups that can be linked to the linker (such as -O-, -NR). a -(where R) a Substituents such as H, or C1-C6 alkyl, -CO-, -COO-, etc., can be monovalently docked with the linker molecule of the present invention (such as L1 in the present invention) to form ethers, amines, amides, etc.

[0294] In another specific embodiment, the R used in this invention E3 (E3 ligase ligand portion) is selected from Table C:

[0295] Table C

[0296]

[0297]

[0298] Linker molecules (such as L1 as described in this article)

[0299] The linker molecule of the present invention is used to link target molecules and E3 ligase ligands. For example, it can be linked to a target molecule or an E3 ligase ligand via functional groups at both ends (e.g., -OH, -SH, -NH2, -NHR, -SOOH, or -COOH); where R is selected from: substituted or unsubstituted C1-C10 alkyl groups, -(C=O)-R', (C=O)NH-R', -NH(C=O)-R', -SO2-R', -NHSO2-R', -SO2NH-R', -SO-R', -NHSO-R', -SONH-R', -PO3-R', -NHCOO-R', -COO-R', or -NH-CO-NH-R', -NH-CO-O-R', or -X'-L3-Z; where L3 is the linking group, and Z is a polypeptide element (such as a ligand, antibody, or its peptide fragment) or a target molecule such as a small molecule with targeting function (such as folic acid, HSP90 inhibitors, etc.).

[0300] Connector (header) and coupling method

[0301] The linker (head) L1 of the present invention is used to link the target molecule (part) P1 and the E3 ligase ligand (part) A1.

[0302] Preferably, the target molecule (partial) or E3 ligase ligand (partial) can be linked to the linker via groups such as -O-, -S-, -NH-, -NR-, -(C=O)-, -(C=O)O-, and -SO2-.

[0303] The linker of the present invention may further contain various other functional groups, such as -OH, -NHR, -SH and other functional groups.

[0304] Typically, the connector L1 of the present invention can be represented by the following general formula II:

[0305] -W 1 -L2-W 2 - Formula II

[0306] In the formula, W 1 L2, W 2 The definition is as described in the first aspect of this invention.

[0307] In another preferred embodiment, W 1 and W 2 Each of the following divalent groups, formed by the loss of one hydrogen atom from a monovalent group, can be independently represented by: -OH, -NH2, -SH, -COOH, -SO2H, etc. For example, the linker can be connected to the target molecule via linking groups as shown below:

[0308]

[0309] Or, W 1 and W 2 Each of these components independently comprises a divalent linker having a rigid portion (such as a four-, five-, or six-membered aliphatic ring (saturated carbide ring) portion, or a five- or six-membered aromatic heterocyclic portion, etc.), as exemplary examples are shown below and in the embodiments:

[0310]

[0311] In the above formulas, R is defined as above; n is 1, 2, or 3.

[0312] In one specific implementation plan, W 1 and W 2 Each person independently selects from the following groups:

[0313] None, -N(R) a )-、-C(Rb )2-、-N(R a )-C(R b )2-、-C(=O)-、-C(O)-N(R a )-、-C(R b )2-C≡C-, -C≡C-, -C(O)-C≡C-, -CH(OH)-C≡C-, -O-, -S-, -SO2-, -SO-, -PO3-, -C(R b )=C(R b )-, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted 4- to 10-membered heterocycloalkyl, substituted or unsubstituted C6- to 10-membered aryl, substituted or unsubstituted 5- to 10-membered heteroaryl.

[0314] Active ingredients

[0315] As used herein, the term "compound of the invention" refers to a compound or conjugate of Formula I. The term also includes various crystalline forms of compounds of Formula I, or pharmaceutically acceptable salts.

[0316] Specifically, the present invention provides a class of conjugates as shown in Formula I that are suitable for further linking to or having linked to a polypeptide element (e.g., an antibody, a protein ligand, etc.) or a target molecule T.

[0317] R T -L1-R E3 (I)

[0318] Among them, R L For the E3 ligase ligand moiety, R T L1 is the target molecule portion, and L1 is the connector linking the A1 and P1 portions.

[0319] Preferably, R L R T The definitions of L1 and L1 are as described above.

[0320] In one specific embodiment, the conjugate provided by the present invention is suitable for further connection with a polypeptide element or target molecule T as shown in Formula IV.

[0321] R T -W 1 -L6-W 2 -R E3 (IV)

[0322] Among them, R T R E3 W 1 W 2 And L7 as defined above.

[0323] In one specific embodiment, the conjugates provided by the present invention that link a polypeptide element or target molecule T are shown in Formula V.

[0324] R T -W 1 -L7-W 2 -R E3 (V);

[0325] Among them, R T R E3 W 1 W 2 The definitions of L7 and L7 are as described above.

[0326] In one specific embodiment, the present invention also provides, for example, R T -W 1 -L5-W b -C≡CR E3 (1-1), R T -W 1 -L5-CO-R E3 (1-2) or R T -W 1 -L5-CONH-R E3 The coupling shown in (1-3);

[0327] Among them, W b The definition is the same as the definition of W; W 1 R T R E3 The definitions of L5 are as described above.

[0328] In another preferred embodiment, in equation 1-1, W 1 Selected from the following groups: NH, O; preferably, W is NH.

[0329] In another preferred embodiment, in equation 1-1, W b Selected from the following groups: None, -CH2-, -CH(OH)-, -C(=O)-.

[0330] In one specific embodiment, the present invention provides a coupling as shown in the following formula;

[0331]

[0332] Among them, W 1 R T R E3 The definitions of R are as described above; preferably, R is H, C1-6 alkyl (such as Me, Et, etc.);

[0333] m = 0, 1, 2, 3, etc. (preferably, m is not 0);

[0334] X 1 X 2 and X 3 Each is independently selected from: O, C 1-4 Alkylene

[0335] Preferably, W 1 Let W be a variable, and W be as defined above. More preferably, W... 1 It is NH.

[0336] In one specific embodiment, the present invention also provides a coupling as shown in the following formula;

[0337]

[0338] Among the various types,

[0339] R, R1, R T and R E3 As defined above;

[0340] Z 1 Z 2 and Z 3 Each is independently selected from: O, C 1-4 Alkylene, -CH(OH)-,

[0341] m = 0, 1, 2, 3, 4, etc.

[0342] In another specific implementation, the coupling agent is selected from the coupling agents of group 1:

[0343] Group 1

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350] Among them, R T R E3 R and R1 are as defined above; preferably, R and R 1 Each independently as -W 3 -L3-W 4 -(R P ) q Among them, W3 L3, W 4 R P And m as defined above.

[0351] In one specific embodiment, the present invention also provides, for example, R T -W 1 -L6-W b -C≡CR E3 (1a-1), R T -W 1 -L6-CO-R E3 (1a-2) or R T -W 1 -L6-CONH-R E3 The coupling shown in (Ia-3);

[0352] Among them, W b The definition is the same as the definition of W; W 1 R T R E3 The definitions of L5 are as described above.

[0353] In one specific embodiment, the present invention also provides, for example, R T -W a -L6-W b -C≡CR E3 The coupling shown; wherein, W a and W b The definition is the same as the definition of W; R T R E3 The definitions of L6 and L6 are as described above.

[0354] In another preferred embodiment, W a Selected from the following groups: NH, O; preferably, W is NH.

[0355] In another preferred embodiment, W b Selected from the following groups: None, -CH2-, -CH(OH)-, -C(=O)-.

[0356] In another specific embodiment, the coupling agent is selected from the coupling agents of group 1a:

[0357] Group 1a

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364] Among them, R T and R E3 As defined above.

[0365] In one specific implementation plan

[0366] The present invention also provides, for example, R T -W a -Cr 1 -W a -Cr 2 -L5-W 2 -R E3 (2) The coupling shown;

[0367] in,

[0368] W a The definition is the same as the definition of W;

[0369] Cr 1 It is none, or it was not replaced or was replaced by C. 1-4 C substituted by alkyl 4-7 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0370] Cr 2 For not replaced or by C 1-4 Alkyl groups substituted with 4 to 6 nitrogen-containing heterocyclic groups, and Cr 2 At least one nitrogen heteroatom is attached to L5;

[0371] W, R T R E3 W 2 The definitions of L5 are as described above.

[0372] In another preferred embodiment, W 2 Selected from the following group: W b -C≡C, C(=O), C(=O)NH.

[0373] In another specific embodiment, the present invention also provides, as R T -W a -Cr 1 -Cr 2 -L5-W b -C≡CR E3 The coupling shown;

[0374] Among them, W a and W b The definition is the same as the definition of W;

[0375] Cr 1 It is none, or it was not replaced or was replaced by C. 1-4 C substituted by alkyl 4-7 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0376] Cr 2 For not replaced or by C 1-4 Alkyl groups substituted with 4 to 6 nitrogen-containing heterocyclic groups, and Cr 2 At least one nitrogen heteroatom is attached to L5;

[0377] R T R E3 The definitions of L5 are as described above.

[0378] Preferably, W a Selected from the following groups: NH, O; preferably, W a It is NH.

[0379] Preferably, W b Selected from the following groups: None, -CH2-, -CH(OH)-, -C(=O)-.

[0380] Preferably, the coupling agent is selected from the group consisting of:

[0381] R T -NH-Cr 1 -Cr 2 -L5-CH2-C≡CR E3 ;

[0382] R T -NH-Cr 1 -Cr 2 -L5-C(=O)-C≡CR E3 ;

[0383] R T -NH-Cr 1 -Cr 2 -L5-CH(OH)-C≡CR E3 ;

[0384] R T -NH-Cr 1 -Cr 2 -L5-C≡CR E3 In each formula, R T R E3 Cr 1 Cr 2 The definitions of L5 are as described above.

[0385] Preferably, the coupling agent is selected from the group consisting of:

[0386] R T -NH-Cr 1 -Cr 2 -L8-C≡CR E3 ;

[0387] Among them, R T R E3 Cr 1 Cr 2 The definitions of L8 are as described above.

[0388] In another preferred embodiment, Cr 1 For none or Among them, Y 1 and Y 2 Each is independently selected from: CH and N; n1 = 0, 1 or 2; and n2 = 1 or 2.

[0389] In another preferred embodiment, Cr 2 for Where * represents the position connected to L5; Y 3 Selected from: CH and N, n3 = 0, 1 or 2; and n4 = 1 or 2.

[0390] In another preferred embodiment, Cr 1 Selected from the following group:

[0391] none,

[0392] In another preferred embodiment, Cr 2 Selected from the following group:

[0393]

[0394] In one specific embodiment, the present invention provides a coupling as shown in the following formula;

[0395]

[0396] in,

[0397] X 4 Selected from the following groups: CH2, O, NH, NR;

[0398] Y 1 and Y 3 Each is independently selected from the following groups: CH, N;

[0399] W a Selected from the following groups: NH, O;

[0400] m = 0, 1, 2, 3, etc. (preferably, m is not 0);

[0401] n = 0, 1, 2, 3, etc. (preferably, n is not 0);

[0402] R T R E3 The definitions of R are as described above; preferably, R is H, C1-6 alkyl (such as Me, Et, etc.), Ac, CHO, CONH2.

[0403] In another specific implementation, the coupling agent is selected from group 2:

[0404] Group 2

[0405]

[0406]

[0407] Among them, R T R E3 R and R1 are as defined above; preferably, R and R 1 Each independently as -W 3 -L3-W 4 -(R P ) q Among them, W 3 L3, W 4 R P And m as defined above.

[0408] In one specific embodiment, the present invention also provides, for example, R T -W a -Cr 1 -W a -Cr 2 -L6-W 2 -R E3 The coupling shown in (I-2a);

[0409] in,

[0410] W a The definition is the same as the definition of W;

[0411] Cr 1 It is none, or it was not replaced or was replaced by C. 1-4 C substituted by alkyl 4-7 Cycloalkyl or 4- to 6-membered heterocyclic groups;

[0412] Cr 2 For not replaced or by C 1-4 Alkyl groups substituted with 4 to 6 nitrogen-containing heterocyclic groups, and Cr 2 At least one nitrogen heteroatom is attached to L5;

[0413] W, R T RE3 W 2 The definitions of L5 are as described above.

[0414] In another preferred embodiment, W 2 Selected from the following group: W b -C≡C, C(=O), C(=O)NH.

[0415] In another specific embodiment, the present invention also provides, as R T -W a -Cr 1 -Cr 2 -L6-W b -C≡CR E3 The coupling shown; wherein, W a W b Cr 1 Cr 2 R T R E3 The definitions of L5 are as described above.

[0416] Preferably, the coupling agent is selected from the group consisting of:

[0417] R T -NH-Cr 1 -Cr 2 -L6-CH2-C≡CR E3 ;

[0418] R T -NH-Cr 1 -Cr 2 -L6-C(=O)-C≡CR E3 ;

[0419] R T -NH-Cr 1 -Cr 2 -L6-CH(OH)-C≡CR E3 ;

[0420] and R T -NH-Cr 1 -Cr 2 -L6-C≡CR E3 ;

[0421] In each formula, R T R E3 Cr 1 Cr 2 The definitions of L6 and L6 are as described above.

[0422] In another specific embodiment, the coupling agent is selected from group 2a:

[0423] Group 2a

[0424]

[0425]

[0426] In one specific implementation, the present invention provides, as R T -Ar1-L5-W 2 -R E (3) The coupling shown;

[0427] Among them, Ar1 is a -five- or six-membered nitrogen-containing heteroaryl group; L5, R T W2 and R E3 As defined above.

[0428] In another preferred embodiment, W2 is selected from: -CONH-, -CO-, -CONH-, -W b -C≡C-.

[0429] In one specific implementation, the present invention provides, as R T -Ar1-L5-CONH-R E3 R T -Ar1-L5-CO-R E3 Or R T- -Ar1-L5-W b -C≡CR E3 The coupling shown;

[0430] Among them, Ar1 is a -five- or six-membered nitrogen-containing heteroaryl group; L5, R T and R E3 As defined above.

[0431] In another preferred embodiment, Ar1 is Among them, V1, V2 and V4 are each independently selected from: -O-, -S-, -N=, -NH-, -CH=, -CH2-; V3 is selected from the following group: -N=, -CH=.

[0432] In one specific embodiment, the present invention provides a coupling as shown in the following formula;

[0433]

[0434] Among the various types,

[0435] V1, V2, and V4 are each independently selected from: -O-, -S-, -N=, -NH-, -CH=, -CH2-;

[0436] V3 is selected from the following groups: -N=, -CH=;

[0437] R, R1, R T and R E3 As defined above;

[0438] m = 0, 1, 2, 3, 4, etc. (ideally, m is not 0).

[0439] In one specific embodiment, the present invention provides a coupling as shown in the following formula;

[0440]

[0441] Among the various types,

[0442] R, R1, R T and R E3 As defined above;

[0443] m = 0, 1, 2, 3, 4, etc. (ideally, m is not 0).

[0444] In another specific implementation, the coupling agent is selected from group 3:

[0445] Group 3

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453] Among them, R T R E3 R and R1 are as defined above; preferably, R and R 1 Each independently as -W 3 -L3-W 4 -(R P ) q Among them, W 3 L3, W 4 R P And m as defined above.

[0454] In one specific embodiment, the present invention also provides, for example, R T -Ar1-L6-W2-R E The coupling shown;

[0455] Among them, Ar 1 L5, R T W 2 and R E3 As defined above.

[0456] In one specific implementation, the present invention provides, as R T -Ar 1 -L6-CONH-R E3 R T -Ar 1 -L6-CO-R E3 Or R T- -Ar 1 -L6-W b -C≡CR E3 The coupling shown; wherein, Ar 1 L6, R T and R E3 As defined above.

[0457] In another specific embodiment, the coupling agent is selected from group 3a-1 to group 3a-5;

[0458] Group 3a

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465] Among them, R T and R E3 As defined above.

[0466] ACTED

[0467] In this invention, when the target molecule is an antibody, a polypeptide, a cyclic peptide, a folic acid receptor ligand, an HSP90 ligand, or another extracellular target protein ligand, the conjugate of this invention may also be referred to simply as ACTED, ACTED molecule, or ACTED compound.

[0468] Some activated compounds are listed below:

[0469]

[0470] Wherein, TED refers to a monovalent group formed by the loss of the group on N in the coupling compound as shown in Formula I or the TED compound as shown in Formula VI.

[0471] R P L4 is defined as before.

[0472] In one specific embodiment, examples of the ACTED of the present invention include, but are not limited to, compounds or conjugates selected from the group consisting of:

[0473]

[0474] The main advantages of this invention include:

[0475] (a) The conjugate TED of the present invention has high activity on tumor cells, cell selectivity, and good safety.

[0476] (b) The conjugate TED of the present invention can exert an inhibitory effect on cell proliferation at catalytic levels. It can circulate within cells to degrade target proteins, thereby reducing the dosage and prolonging the dosing cycle, achieving a safe and effective anti-tumor effect.

[0477] (c) The conjugate TED of the present invention has an active site in the linker (L1) portion that can be linked to a drug delivery carrier (such as an antibody, peptide, or other small molecule ligand).

[0478] The present invention will be further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0479] Unless otherwise specified, the starting materials or compounds used in the examples are commercially available or can be prepared by methods known to those skilled in the art.

[0480] General Method 1:

[0481] Synthetic method of compound P1-Linker-Ligand A

[0482]

[0483] In the formula, A represents the structure shown in A1 or A2. Under N2 protection, compounds P1 (20 mg, 1 eq.), Linker-Ligand A (1 eq.), HATU (2 eq.), and DIEA (3 eq.) were dissolved in DMF (2 mL) and reacted at room temperature for 18 hours. The reaction solution was poured into 5 mL of water and extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 3), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the crude product was separated by thin-layer chromatography on silica gel plates (DCM / MeOH = 10 / 1) to obtain the target analyte.

[0484] The target compound was dissolved in DCM (3 mL), and 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. After concentration, the solution was washed with diethyl ether (5 mL * 3), and filtered to obtain the white solid target product P1-Linker-Ligand A.

[0485] General Method 2:

[0486] Synthetic method of compound P1–Linker g-Ligand A

[0487]

[0488] In the formula, A represents the structure shown in A1 or A2.

[0489] compound

[0490] (R)-8-cyclopentyl-7-ethyl-2-((4-ethynyl-2-methoxyphenyl)amino)-5-methyl-7,8-dihydropteridin-6(5H)-one (1 eq.), N3-linker-Ligand A (1 eq.), TBTA (1 eq.), [Cu(CH3CN)4]PF6 (Cat.) were dissolved in tert-butanol (5 mL) and water, and the mixture was reacted at room temperature for 16 hours to 4 days. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM = 10%) to give a white solid compound.

[0491] The target compound was dissolved in DCM (3 mL), and 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. After concentration, the solution was washed with diethyl ether (5 mL * 3), and filtered to obtain the white solid target product P1-Linker-Ligand A.

[0492] General Method 3:

[0493] Synthetic methods of compounds R1-Linker-Lig and A

[0494]

[0495] In the formula, A represents the structure shown in A1 or A2.

[0496] After the addition of compounds R1 / R2 (20 mg, 1 eq.), Linker-Lig and A (1 eq.), HATU (2 eq.), and DIEA (3 eq.), the reaction mixture was reacted at room temperature for 18 hours under nitrogen protection. The reaction solution was poured into 5 mL of water and extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 3), dried over anhydrous Na2SO4, and concentrated by rotary evaporation under reduced pressure to obtain a crude product. The crude product was then separated by thin-layer chromatography on silica gel plates (DCM / MeOH = 10 / 1) to obtain the target compound.

[0497] The target compound was dissolved in DCM (3 mL), and 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. After concentration, the solution was washed with diethyl ether (5 mL * 3), and filtered to obtain the white solid target product R1-Linker-Lig and A.

[0498] General Method 4:

[0499] Synthetic methods of compounds R2-Linker-Lig and A

[0500]

[0501] In the formula, A represents the structure shown in A1 or A2.

[0502] Compounds R1 / R2 (20 mg, 1 eq.), Linker-Lig and A (1 eq.), EDCI (2 eq.), and HOBT (2 eq.) were dissolved in DIEA (3 eq.) in 2 mL of DMF. After the addition of the reagents, the reaction mixture was reacted at room temperature under nitrogen protection for 18 hours. The reaction solution was poured into 5 mL of water and extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 3), dried over anhydrous Na2SO4, and concentrated by rotary evaporation under reduced pressure to obtain a crude product. The crude product was then separated by thin-layer chromatography on silica gel plates (DCM / MeOH = 10 / 1) to obtain the target compound.

[0503] The target compound was dissolved in DCM (3 mL), and 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. After concentration, the solution was washed with diethyl ether (5 mL * 3), and filtered to obtain the white solid target product R2-Linker-Lig and A.

[0504] General Method 5:

[0505] Synthetic methods of compounds R1 / R2–Linker-Lig and A

[0506]

[0507] In the formula, A represents the structure shown in A1 or A2.

[0508] Compounds R1 / R2 (1 eq.), N3-Linker-Lig and A (1 eq.), TBTA (1 eq.), and [Cu(CH3CN)4]PF6 (Cat.) were dissolved in t-BuOH (5 mL) and water (1 mL) and reacted at room temperature for 16 hours to 4 days. After the reaction was complete, the mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a white solid.

[0509] The target compound was dissolved in DCM (3 mL), and 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. After concentration, the solution was washed with diethyl ether (5 mL * 3), and filtered to obtain white solid target products R1 / R2–Linker-Lig and A.

[0510] General Method 6:

[0511] Synthetic methods of compounds M–Linker-Lig and A

[0512]

[0513] In the formula, A represents the structure shown in A1 or A2.

[0514] Compounds NH2-Linker-Lig and A (1 eq.) were dissolved in pyridine, and then di(p-nitrobenzene) carbonate (1 eq.) was added, and the mixture was reacted at room temperature for 2 hours. Then, M (1 eq.) and DIPEA were added to give a yellow reaction solution, which was then reacted at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography to give a white solid.

[0515] The target compound was dissolved in DCM (3 mL), and 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. After concentration, the solution was washed with diethyl ether (5 mL * 3), and filtered to obtain the white solid target products M–Linker-Lig and A.

[0516] General Method 7:

[0517] Synthetic method of compound R3-Linker-Ligand E

[0518]

[0519] In the formula, E represents the structure shown in A1, A2, or B1.

[0520] Compound R3 (20 mg, 1 eq.), Linker-Ligand E (2 eq.), and a catalytic amount of AcOH (1 drop) were dissolved in methanol / dichloromethane = 1 / 10 (10 mL) and reacted at room temperature for 18 hours. Then, NaCNBH3 (3 eq.) was added, and the reaction was continued at room temperature for another 3 hours. The reaction solution was concentrated, washed once with water (5 mL), extracted twice with ethyl acetate (10 mL), and the organic phase was concentrated to obtain the target product R3-Linker-Ligand E.

[0521] Example 1

[0522] Example 1.1 Synthesis of P1-connector b-A1:

[0523] Example 1.1.1 Synthesis of compound UBI-1289 (NH2-11b-A1)

[0524]

[0525] Step 1: Synthesis of UBI-1289b (V1179-123): UBI-1289a (7.2 g, 36.3 mmol) was reacted overnight in an ice bath with 4 M HCl / dioxane (25 mL). Diethyl ether (25 mL) was added, the mixture was stirred, filtered, and dried to obtain a white solid, UBI-1289b (4.4 g, 89% yield).

[0526] Step 2: Synthesis of UBI-1289d (V1179-126): UBI-1289b (4.2 g, 31.2 mmol) was dissolved in acetonitrile (150 mL), and K2CO3 (13 g, 93.6 mmol) and UBI-1289c (8.8 g, 31.2 mmol) were added. The mixture was heated to 80 °C and reacted overnight. The reaction solution was filtered, concentrated, and column filtered (dichloromethane / methanol = 0%–10%) to give a yellow oily product, UBI-1289d (5 g, yield 56%). LCMS [M+H] + =286.2.

[0527] Step 3: Synthesis of UBI-1289e (V1179-127): UBI-1289d (5g, 17.5mmol) was added to 4M HCl / dioxane (10mL) in an ice bath and reacted at room temperature for 1 hour. The reaction was concentrated to give a white solid product UBI-1289e (7.8g).

[0528] Step 4: UBI-1289g (V1179-130): UBI-1289e (7.2g, 16.2mmol) was dissolved in acetonitrile (100mL), and K2CO3 (4.5g, 32.4mmol) and UBI-1289f (3g, 17.9mmol) were added. The reaction mixture was allowed to react over the end of the week. The reaction solution was filtered, and the filtrate was concentrated and column filtered (dichloromethane / methanol = 0%–10%) to obtain a yellow oily product, UBI-1289g (1g, 23% yield). LCMS [M+H] + =272.3

[0529] Step 5: UBI-1289h (V1179-131): UBI-1289 g (1 g, 3.7 mmol) was dissolved in THF (20 mL), and NaHCO3 (621 mg, 7.4 mmol) and Boc2O (800 mg, 3.7 mmol) were added. The mixture was reacted at room temperature for 3 hours. The solution was filtered, concentrated, and column-coated (dichloromethane / methanol = 0%–3%) to obtain a yellow oily crude product, UBI-1289h (490 mg). LCMS [M+H] + =372.2

[0530] Step 6: UBI-1289i (V1179-138): UBI-1289h (490 mg, 1.32 mmol) was dissolved in ethanol (10 mL), and 2M NaOH (1.5 mL, 3 mmol) was added. The mixture was reacted overnight at room temperature. 15 mL of brine was added, and the mixture was extracted with ether (20 mL * 2). The aqueous layer was adjusted to pH ~5 with hydrochloric acid. The mixture was then extracted with ethyl acetate (40 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a colorless, oily crude product, UBI-1289i (300 mg). LCMS [MS + H₂] + =344.1

[0531] Step 7: UBI-1289j (V2111-001): UBI-1289i (240 mg, 0.69 mmol), Al (181 mg, 0.69 mmol), HATU (524 mg, 1.38 mmol), and DIPEA (0.5 mL) were dissolved in DMF (3 mL) and reacted overnight at room temperature. The reaction mixture was concentrated and column-secured (dichloromethane / methanol = 0%–30%) to give a yellow oily product UBI-1289j (V2111-001, 140 mg). LCMS [M+H] + =585.4

[0532] Step 8: UBI-1289 (V2111-002): UBI-1289j (140 mg, 0.24 mmol) was dissolved in THF (2 mL), and 1 MMe3P (0.36 mL, 0.36 mmol) was added. The mixture was reacted at room temperature for 1 hour. Water (0.5 mL) was added, and the reaction was continued for another hour. The reaction solution was concentrated and passed through a reverse-phase reactor (acetonitrile / water = 0%–30%) to obtain a yellow solid UBI-1289 (40 mg, yield 30%). LCMS [M+H] + =559.3

[0533] Example 1.2 Synthesis of P1-Connector c-A1

[0534] Example 1.2.1 Synthesis of compound UBI-1267

[0535]

[0536] Step 1: UBI-1267b (V879-078)

[0537] UBI1267a (10 g, 27.2 mmol) and TEA (8.4 mL, 60.94 mmol) were dissolved in THF (250 mL) and cooled to 0 °C. Then, MsCl (2.35 mL, 33.2 mmol) was added, and the mixture was reacted at 80 °C for 48 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under pressure to obtain an oily substance. Then, HCl (1 M) aqueous solution was added, and the mixture was extracted with dichloromethane (20 mL * 3). The organic phase was washed successively with saturated NaHCO3 aqueous solution, water, and saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude solid. The solid was recrystallized from 50 mL of petroleum ether / ethyl acetate (3 / 1). A white solid, UBI-1267b (4 g, yield 42%), was obtained.

[0538] 1 ¹H NMR (400MHz, chloroform-d) δ 7.54–7.41 (m, 5H), 7.36–7.09 (m, 10H), 3.76 (s, 3H), 2.26 (s, 1H), 1.91–1.82 (m, 1H), 1.47–1.33 (m, 1H).

[0539] Step 2: UBI-1267c (V907-082)

[0540] Compound UBI-1267b (2 g, 5.8 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (5 mL) was added at 0 °C. The reaction was then carried out at room temperature for 3 hours. The reaction solution was added with water (30 mL) and washed once with dichloromethane (20 mL). The aqueous phase was adjusted to pH > 8 with NaHCO3. A solution of acetic acid (150 mL) containing PNZCl (7.6 g, 0.04 mol) was slowly added dropwise to the aqueous phase at 0 °C. The reaction was then carried out at room temperature for 16 hours. The reaction solution was extracted twice with acetic acid (20 mL). The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain the crude product. The crude product was separated by column chromatography (petroleum ether / dichloromethane = 1 / 2) to give the white solid target product UBI-1267c (6.7 g, yield 61%). LCMS [M+H]+ = 101. 1 ¹H NMR (400MHz, chloroform-d) δ 8.37–8.03 (m, 2H), 7.74–7.43 (m, 2H), 5.46–4.94 (m, 2H), 3.76 (s, 3H), 3.16 (dd, J = 5.3, 3.2Hz, 1H), 2.64 (dd, J = 3.2, 1.3Hz, 1H), 2.52 (dd, J = 5.3, 1.3Hz, 1H).

[0541] Step 3: UBI-1267e (V1686-112)

[0542] Compounds UBI-1267c (3 g, 10.7 mmol) and UBI-1267d (30 mL) were cooled to 0 °C. Then, BF3 Et2O (456 mg, 3.2 mmol) was slowly added dropwise to the reaction solution, and the mixture was slowly brought to room temperature for 2 hours. The reaction solution was directly subjected to reversed-phase column chromatography (methanol / water = 5%–95%, 40 min) to give the pale yellow oily target product UBI-1267e (3.6 g, yield 84%). LCMS [M+H] + =225

[0543] 1 H NMR (400MHz, chloroform-d) δ8.45–8.09(m,2H),7.53(d,J=8.3Hz,2H),5.86(d,J=8.8Hz,1H),5.21(dd,J=13.3 ,4.3Hz,2H),4.47(d,J=8.6Hz,1H),4.00(dd,J=9.8,3.2Hz,2H),3.85–3.70(m,6H),3.68–3.55(m,5H).

[0544] Step 4: UBI-1267g (V1686-124)

[0545] Compound UBI-1267f (160 mg, 0.99 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of cesium carbonate (646 mg, 1.98 mmol), potassium iodide (247 mg, 1.49 mmol), and UBI-1267e (400 mg, 0.99 mmol). The mixture was then microwaved to 100 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. This crude product was subjected to reversed-phase column chromatography (methanol / water = 5%-95%, 40 min, 75% collection) to give the brown oily target product UBI-1267g (300 mg, yield 61%). LCMS [M+H] + =315. 1 H NMR (400MHz, chloroform-d) δ8.22(dd,J=9.3,2.6Hz,2H),7.67–7.38(m,2H),5.35–5.06(m,2H),4.60–4.34(m,1H),3.77( s,3H),3.69–3.54(m,7H),3.44(m,1H),2.85(d,J=12.9Hz,2H),2.63(s,2H),1.96(d,J=9.0Hz,3H),1.71(m,2H).

[0546] Step 5: UBI-1267h (V1686-137)

[0547] Compound UBI-1267 g (530 mg, 1.07 mmol) was dissolved in methanol (2 mL), tetrahydrofuran (6 mL), and water (2 mL), followed by the addition of lithium hydroxide (68 mg, 1.61 mmol) and reaction overnight. The reaction solution was washed once with ethyl acetate (20 mL), and the aqueous phase was adjusted to pH 6 with 3N dilute hydrochloric acid and concentrated to give 100 mg of the target product UBI-1267 h (450 mg, yield 87%) as a white solid. This crude product was used directly in the next reaction. LCMS [M+H] + =301

[0548] Step 6: UBI-1267i (V1686-139)

[0549] Compound UBI-1267h (100 mg, 0.21 mmol) and lenalidomide (54 mg, 0.21 mmol) were dissolved in dry pyridine (3 mL) and cooled to 0°C in an ice bath. Then, phosphorus oxychloride (319 mg, 2.1 mmol) was slowly added dropwise over 10 minutes (the color changed from brown to light yellow). The reaction was then allowed to proceed to room temperature for 10 minutes (the color turned black). The reaction solution was quenched with water and then concentrated directly to obtain the crude product. The crude product was subjected to reversed-phase column chromatography (methanol / water = 5%-95%, 40 minutes, 60% collection) to obtain the brown solid target product UBI-1267i (70 mg, yield 47%). LCMS [M+H] + =542. 1 H NMR (400MHz, DMSO-d6) δ11.02(t,J=5.6Hz,1H),8.24(d,J=8.4Hz,2H),7.79(s,2H),7.64(d,J=8.2Hz,2H),7.53(d,J=10. 3Hz,3H),5.26–5.00(m,3H),4.51(s,1H),4.20(m,5H),3.80–3.48(m,12H),3.17(s,2H),2.92(m,5H),2.12–1.64(m,8H).

[0550] Step 7: UBI-1267 (V1686-141)

[0551] Compound UBI-1267i (70 mg, 0.10 mmol) was dissolved in tetrahydrofuran (5 mL) and water (0.5 mL), followed by the addition of triphenylphosphine resin (100 mg, 0.15 mmol) and heating to 75 °C for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated to give the brown oily target product UBI-1267 (60 mg, 90% yield). LCMS [M+H] + =516

[0552] Example 1.2.2 Synthesis of compound UBI-1276 (P1-11c-COOH)

[0553]

[0554] Step 1: UBI-1276c (V1899-053)

[0555] 60% NaH (857 mg, 20.4 mmol) was added to anhydrous DMF in an ice bath, followed by UBI-1276a (2 g, 8.58 mmol), and the reaction was carried out for 15 minutes. Then, UBI-1276b (1.2 g, 10.7 mmol) was added, and the reaction was brought to room temperature and carried out for 2 hours. The reaction mixture was evaporated to dryness, and a small amount of diethyl ether and water were added to form a slurry. The upper organic phase was discarded, and the aqueous layer was adjusted to pH ~3 with hydrochloric acid. The mixture was then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was column-secreted (dichloromethane / methanol = 0%–20%) to give a yellow oily product UBI-1276c (1.148 g, yield 48%).

[0556] Step 2: UBI-1276d(V1685-061)

[0557] UBI-1276b (500 mg, 0.49 mmol) was dissolved in DCM and cooled to -78°C. Ozone gas was bubbled into the reaction solution for 20 minutes until the solution turned blue. N2 was then bubbled into the reaction solution for 20 minutes, followed by cooling to -78°C. Dimethyl sulfide was then added, and the solution was slowly raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain a crude product, which was directly used in the next reaction. LCMS [MH] + =260.1

[0558] Step 3: UBI-1276 (V1782-105)

[0559] UBI-1276d (115 mg, 0.44 mmol) was dissolved in methanol (4 mL). UBI-1284d (120 mg, 0.22 mmol) and NaOAc (18 mg, 0.22 mmol) were added, and the mixture was reacted for 15 minutes. Then, NaBH3CN (28 mg, 0.44 mmol) was added, and the mixture was reacted for another hour. The reaction solution was evaporated to dryness, and the crude product was passed through a column chromatography (dichloromethane / methanol = 0%–100%) to give a yellow oily product, UBI-1276 (170 mg, yield 34%). LC-MS [M+H] + =753.2.

[0560] 1H NMR (400MHz, DMSO-d6) δ8.44–8.37(m,1H),8.09(d,J=7.7Hz,1H),7.85(s,1H),7.59(s,1H),7.48(dq,J=4.7,1 .9Hz,2H),6.37(s,2H),4.36(t,J=8.1Hz,1H),4.23(dd,J=7.6,3.6Hz,1H),3.94(s,3H),3.76(d,J=7.1Hz,2H), 3.70(d,J=7.4Hz,2H),3.46(d,J=6.0Hz,2H),3.39(d,J=2.8Hz,2H),3.25(s,3H),2.93(d,J=11.2Hz,2H),2.14 –1.97(m,4H),1.89(d,J=3.0Hz,3H),1.81–1.71(m,7H),1.67–1.57(m,5H),1.37(s,9H),0.76(t,J=7.4Hz,3H).

[0561] Example 1.2.3 Synthesis of compound UBI-1287 (P1-10c-A1)

[0562]

[0563] Step 1: UBI-1287b (V1782-116)

[0564] 60% NaH (4.88 g, 122 mmol) was added to anhydrous DMF (30 mL) under ice bath conditions. UBI-1287a (10 g, 48.8 mmol) dissolved in anhydrous DMF (20 mL) was added dropwise to the above reaction solution. The reaction was allowed to proceed for half an hour, then UBI-1276b (5.3 mL, 61 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was evaporated to dryness, and a small amount of diethyl ether and water were added to form a slurry. The upper organic phase was discarded, and the aqueous layer was adjusted to pH ~3 with hydrochloric acid. The solution was then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was subjected to column chromatography (dichloromethane / methanol = 0%–10%) to give a colorless oily product UBI-1287b (10.5 g, yield 88%). LCMS [MH] + =244.3

[0565] 1H NMR (400MHz, DMSO-d6) δ12.67(s,1H),6.90(d,J=8.3Hz,1H),5.85(ddt,J=17.4,10.5,5.3Hz,1H),5.24(dq,J=17.3,1.8Hz,1H), 5.14(dq,J=10.4,1.5Hz,1H), 4.14(dt,J=8.4,5.5Hz,1H), 3.94(dq,J=5.3,1.7Hz,2H), 3.60(dt,J=6.5,3.8Hz,2H), 1.38(s,9H).

[0566] Step 2: UBI-1287c (V1782-134)

[0567] UBI-1287b (245 mg, 1 mmol), A1 (260 mg, 1 mmol), HATU (760 mg, 2 mmol), and DIPEA (390 mg, 3 mmol) were dissolved in DMF (5 mL) and reacted overnight at room temperature. The reaction mixture was concentrated and column filtered (dichloromethane / methanol = 0%–10%) to give a pale yellow solid product, UBI-1287c (400 mg, yield 82%). LCMS [M+H] + =487.1

[0568] Step 3: UBI-1287d (V1782-141)

[0569] UBI-1287c (200 mg, 0.4 mmol) was added to water (3 mL) and acetone (15 mL), followed by catalytic amounts of K₂O₄·2H₂O (cat.) and NaIO₄ (263 mg, 1.2 mmol). The mixture was reacted at room temperature for 2 hours. The mixture was filtered and concentrated, then extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was used directly in the next reaction. LCMS [M+H] + =489.3

[0570] Step 4: UBI-1287 (V1782-142)

[0571] UBI-1287d (V1782-141) and UBI-1284d (40 mg, 0.073 mmol) were dissolved in methanol (5 mL), and NaOAc (6 mg, 0.073 mmol) was added. The mixture was reacted at room temperature for 15 minutes. Then, NaBH3CN (9 mg, 0.15 mmol) was added, and the mixture was reacted at room temperature for 1 hour. The reaction was concentrated to obtain a white solid product, UBI-1287 (8 mg, yield 11%). LCMS [M+H] + =980.2.

[0572] Example 1.2.4 Synthesis of compound UBI-1288 (P1-12c-A1)

[0573]

[0574] Step 1: UBI-1288b (V1782-140)

[0575] UBI-1288a (500 mg, 1.83 mmol), A1 (473 mg, 1.83 mmol), HATU (1.39 g, 3.66 mmol), and DIPEA (715 mg, 5.49 mmol) were dissolved in DMF (5 mL) and reacted overnight at room temperature. The reaction mixture was concentrated and column filtered (dichloromethane / methanol = 0%–10%) to give a white solid UBI-1288b (320 mg, yield 34%). LCMS [M+H] + =515.2

[0576] Step 2: UBI-1288c (V1782-143)

[0577] UBI-1288b (150 mg, 0.3 mmol) was added to water (2 mL) and acetone (8 mL), followed by a catalytic amount of K₂O₄·2H₂O and reacted at room temperature for 2 hours. Then, NaIO₄ (192 mg, 0.9 mmol) was added and the reaction proceeded overnight at room temperature. The mixture was filtered and concentrated, then extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was used directly for the next reaction. LCMS [M+H] + =517.3

[0578] Step 3: UBI-1288 (V1782-145)

[0579] UBI-1288c and UBI-1284d (40 mg, 0.073 mmol) were dissolved in methanol (5 mL), and NaOAc (6 mg, 0.073 mmol) and a catalytic amount of HOAc were added. The reaction proceeded for 20 minutes. Then, NaBH3CN (9 mg, 0.15 mmol) was added, and the reaction proceeded at room temperature for 1 hour. The reaction solution yielded a white solid UBI-1288 (25 mg, yield 33%). LCMS [M+H] + =1008.2.

[0580] 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),9.94(s,1H),9.42(s,1H),8.39(d,J=7.1Hz,1H),8.10(s,1H),7.80( s,1H),7.74(t,J=9.3Hz,1H),7.52(m,4H),7.13(m,1H),5.17(m,1H),4.42–4.21(m,5H),4.13(m,1H),3.93 (s,3H),3.72(m,2H),3.28(m,2H),3.23(s,3H),3.13(m,2H),2.91(m,1H),2.61(m,2H),2.46–2.44(m,1H), 2.27(m,1H),2.02(m,6H),1.89–1.72(m,7H),1.63(m,5H),1.52(m,2H),1.39(s,9H),0.76(t,J=7.4Hz,3H).

[0581] Example 1.3 Synthesis Report of P1-Connector h-A1

[0582] Example 1.3.1 Synthesis of compound UBI-1268 (P1-13h)

[0583]

[0584] Step 1: UBI-1268b (V2037-023)

[0585] Compound UBI-1268a (2.1 g, 7.3 mmol) was dissolved in 50 mL of 3N dilute hydrochloric acid and reacted at room temperature for 2 hours. The reaction solution was extracted with 30 mL of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and used directly in the next reaction. LCMS [M+H] + =287

[0586] Step 2: UBI-1268d(V2037-024)

[0587] Compound UBI-1268c (600 mg, 2.46 mmol) was dissolved in methanol (30 mL), followed by the addition of sodium acetate (403 mg, 4.92 mmol) and UBI-1268b (1.56 g, 7.38 mmol). The mixture was reacted at 25 °C for 1 hour, followed by the addition of sodium cyanoborohydride (463 mg, 7.38 mol). The reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated, washed once with water (20 mL), extracted with ethyl acetate (30 mL), and the organic phase was concentrated and subjected to column chromatography (methanol / dichloromethane = 0-10%) to give the colorless oily target product UBI-1268d (790 mg, 25% yield). LCMS [M+H]+ =441. 1 H NMR (400MHz, chloroform-d) δ4.27(q,J=7.1Hz,2H),4.18(d,J=8.8Hz,2H),3.83(dd,J=12.0,6.9Hz,5H),3.63(t,J=5.0Hz,2H), 3.12(d,J=27.2Hz,6H),2.73(t,J=5.0Hz,2H),2.27(m,2H),1.94(d,J=14.0Hz,2H),1.45(s,9H),1.32(t,J=7.1Hz,3H).

[0588] Step 3: UBI-1268e (V2037-025)

[0589] Compound UBI-1268d (220 mg, 0.5 mmol) was dissolved in methanol (10 mL), one drop of acetic acid and paraformaldehyde (23 mg, 0.75 mmol) were added, and the mixture was reacted at 25 °C for 1 hour. Then, sodium cyanoborohydride (94 mg, 1.5 mol) was added. The reaction was allowed to proceed overnight at room temperature. The reaction solution was washed once with water (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was concentrated to give the colorless oily target product UBI-1268e (200 mg, 25% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =455

[0590] Step 4: UBI-1268f(V2037-027)

[0591] Compound UBI-1268e (220 mg, 0.48 mmol) was dissolved in ethanol (1 mL), tetrahydrofuran (3 mL), and water (1 mL), followed by the addition of lithium hydroxide (31 mg, 0.73 mmol) and reaction at room temperature overnight. The reaction solution was washed once with ethyl acetate (10 mL), and the aqueous phase was acidified to pH 6 with 3N HCl, then lyophilized to give the white solid target product UBI-1268f (250 mg, 100% yield) (containing salt). This crude product was used directly in the next reaction. LCMS [M+H] + =427.

[0592] Step 5: UBI-1268g (V2037-032)

[0593] Compound UBI-1268f (200 mg, 0.47 mmol) and lenalidomide (121 mg, 0.47 mmol) were dissolved in dry pyridine (5 mL) and cooled to 0 °C. Phosphorus oxychloride (718 mg, 4.69 mmol) was then slowly added dropwise over 10 minutes (the color changed from brown to pale yellow). The reaction was then carried out at room temperature for 10 minutes (the color turned black). The reaction solution was quenched with water (5 mL) and concentrated to obtain the crude product. This crude product was subjected to reversed-phase column chromatography (methanol / water = 5%-95%, 40 minutes, 60% collection) to give the target product UBI-1268g (100 mg, yield 32%) as a brown solid. LCMS [M+H] + =668

[0594] Step 6: UBI-1268 (V2037-033)

[0595] Compound UBI-1268 g (30 mg, 0.04 mmol) was dissolved in dichloromethane (8 mL) and methanol (2 mL), followed by the addition of a catalytic amount of Pd / C. The reaction solution was reacted at room temperature under hydrogen atmosphere for 4 hours. After filtration, the filtrate was concentrated to obtain the yellow oily target product UBI-1268 g (10 mg, yield 35%). This crude product was used directly in the next reaction. LCMS [M+H] + =642

[0596] Example 1.3.2 Synthesis of compound UBI-1269 (P1-13h)

[0597]

[0598] Step 1: UBI-1269c(V2037-041)

[0599] Compound 1269a (2 g, 11.4 mmol) was dissolved in dichloromethane (60 mL), cooled to 0 °C, and then ethyl trifluoroacetate (1.6 g, 11.4 mmol) was added. The reaction was carried out overnight at room temperature. The reaction solution was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1269c (1.5 g, yield 48%). LCMS [M+H] + =273. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.23 ​​(s, 1H), 3.72–3.53 (m, 8H), 3.52–3.43 (m, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.98–1.81 (m, 4H), 1.73 (p, J = 6.3 Hz, 2H).

[0600] Step 2: UBI-1269e (V2037-043)

[0601] Compound UBI-1269c (600 mg, 2.2 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (365 mg, 2.6 mmol) and UBI-1269d (293 mg, 2.2 mmol) were added. The reaction mixture was heated to 60 °C and reacted for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated by column chromatography (methanol / dichloromethane = 0-10%) to give the colorless oily target product UBI-1269e (240 mg, yield 34%). LCMS [M+H] + =325. 1 ¹H NMR (400MHz, chloroform-d) δ 7.91 (s, 1H), 3.69–3.62 (m, 2H), 3.62–3.55 (m, 5H), 3.54–3.43 (m, 4H), 2.83 (dt, J = 12.0, 6.6 Hz, 4H), 2.46 (td, J = 6.6, 2.7 Hz, 2H), 2.07–1.96 (m, 1H), 1.93–1.72 (m, 4H).

[0602] Step 3: UBI-1269f(V2037-044)

[0603] Compound UBI-1269e (250 mg, 0.77 mmol) was dissolved in tetrahydrofuran (15 mL), followed by the addition of sodium bicarbonate (97 mg, 1.16 mmol) and (Boc)₂O (200 mg, 0.93 mmol), and reacted at room temperature for 1 hour. The reaction solution was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 20) to give the colorless oily target product UBI-1269f (130 mg, yield 40%). LCMS [M+H] + =425

[0604] Step 4: UBI-1269g (V2037-047)

[0605] Compound UBI-1269f (150 mg, 2.9 mmol) was dissolved in methanol / tetrahydrofuran / water (5 / 5 / 3 mL), followed by the addition of sodium hydroxide (42 mg, 1.06 mmol), and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to give a colorless oily target product, UBI-1269 g (110 mg, 95% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =329

[0606] Step 5: UBI-1269 (V2037-049)

[0607] Compound P1 (149 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL), and HATU (266 mg, 0.70 mmol) and DIEA (136 mg, 1.05 mmol) were added. After reacting at room temperature for 20 minutes, UBI-1269 g (115 mg, 0.35 mmol) was added, and the reaction was continued at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted once with ethyl acetate (10 mL). The organic phase was concentrated and then separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1269 (150 mg, yield 58%) as a brown oil. LCMS [M+H] + =736

[0608] Example 1.3.3 Synthesis of compound UBI-1270 (P1-12h)

[0609]

[0610] Step 1: UBI-1270c (V2037-055)

[0611] Compound UBI-1270a (3 g, 17.1 mmol) was dissolved in UBI-1270b (10 mL) and 50% aq. NaOH (50 mL), and N(Bu)4HSO4 (11.7 g, 34.3 mmol) was added. The reaction was carried out at 40 °C for 16 hours. The reaction mixture was washed once with water (20 mL), extracted with dichloromethane (50 mL), and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 0-10%) to give the colorless oily target product UBI-1270c (4 g, yield 83%). LCMS [M+H] + =282

[0612] Step 2: UBI-1270d(V2037-057)

[0613] Compound UBI-1270c (5.5 g, 19.6 mmol) was reacted with N,N-dimethylformamide (50 mL) and sodium azide (1.9 g, 29.4 mmol) at 80 °C for 4 hours. The reaction mixture was then added to ice water (30 mL) and extracted twice with dichloromethane (20 mL). The organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 20) to give the colorless oily target product UBI-1270d (1.2 g, yield 21%). LCMS [M+H] + =289. 1H NMR (400MHz, chloroform-d) δ4.91(s,1H),3.72–3.63(m,5H),3.63–3.58(m,2H),3.58–3.51(m,2H) ),3.40(t,J=5.0Hz,2H),3.23(d,J=5.9Hz,2H),1.88–1.70(m,2H),1.44(d,J=0.8Hz,9H).

[0614] Step 3: UBI-1270e (V2037-063)

[0615] Compound UBI-1270d (1.2 g, 4.2 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of HCl / dioxane (15 mL) and reaction at room temperature for 2 hours. The reaction solution was concentrated to give the yellow oily target product UBI-1270e (1 g, 100% yield). LCMS [M+H] + =189

[0616] Step 4: UBI-1270g (V2037-065)

[0617] Compound UBI-1270e (500 mg, 2.2 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of potassium carbonate (676 mg, 4.9 mmol), potassium iodide as a catalyst, and UBI-1270f (499 mg, 2.2 mmol). The reaction mixture was reacted at 90 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1270 g (280 mg, yield 52%) as a yellow oil. LCMS [M+H] + =241. 1 ¹H NMR (400MHz, chloroform-d) δ 5.48 (s, 1H), 3.85–3.57 (m, 8H), 3.44 (dd, J = 5.5, 4.4 Hz, 2H), 3.04 (dt, J = 13.3, 6.4 Hz, 4H), 2.67 (td, J = 6.7, 2.7 Hz, 2H), 2.11 (t, J = 2.7 Hz, 1H), 2.02 (dq, J = 8.8, 6.0 Hz, 2H).

[0618] Step 5: UBI-1270h (V2037-067)

[0619] Compound UBI-1270 g (280 mg, 1.2 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), followed by the addition of (Boc)₂O (381 mg, 1.7 mmol) and sodium bicarbonate (196 mg, 2.3 mmol) and reacted at room temperature for 1 hour. The reaction solution was washed once with water (10 mL), extracted with ethyl acetate (15 mL), and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1270 h (270 mg, yield 68%). LCMS [M+H] + =341

[0620] Step 6: UBI-1270i (V2037-069)

[0621] Compound UBI-1270h (270 mg, 0.08 mmol) was dissolved in tetrahydrofuran (5 mL), and after adding trimethylphosphine (1.2 mL), the reaction was carried out at 45 °C for 1 hour. Water (1 mL) was then added, and the reaction was carried out at 45 °C for 1 hour. The reaction solution was concentrated to give the colorless oily target product UBI-1270i (250 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =315

[0622] Step 7: UBI-1270 (V2037-070)

[0623] Compound P1 (338 mg, 0.80 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of HATU (363 mg, 0.96 mmol) and DIEA (308 mg, 2.39 mmol). After reacting at room temperature for 20 minutes, UBI-1270i (250 mg, 0.80 mmol) was added. The reaction was then allowed to proceed overnight at room temperature. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the pale yellow oily target product UBI-1270 (400 mg, 70% yield). LCMS [M+H] + =722. 1H NMR (400MHz, DMSO-d6) δ8.47–8.30(m,2H),7.85(s,1H),7.60(s,1H),7.49(d,J=8.0Hz,2H),4.41–4.30(m,1H),4.2 4(dd,J=7.6,3.6Hz,1H),3.93(s,3H),3.59–3.51(m,4H),3.49(dd,J=6.1,3.7Hz,2H),3.42(q,J=5.9Hz,2H),3.36(t ,J=6.2Hz,2H),3.24(d,J=4.0Hz,4H),3.21(d,J=5.3Hz,1H),3.20–3.15(m,2H),2.81(s,1H),2.33(s,2H),1.89(d, J=8.5Hz,2H),1.77(ddd,J=14.6,7.8,3.7Hz,4H),1.64(dt,J=14.4,4.7Hz,5H),1.37(s,9H),0.76(t,J=7.5Hz,3H).

[0624] Example 1.3.4 Synthesis of compound UBI-1271 (P1-13h)

[0625]

[0626] Step 1: UBI-1271c(V)

[0627] Compound UBI-1271a (10 g, 64.6 mmol) was dissolved in dioxane (25 mL) and 60% potassium hydroxide (10 mL), followed by the addition of UBI-1271b (15 g, 129.3 mmol), and the reaction was carried out at 25 °C for 18 hours. The reaction solution was concentrated and extracted three times with dichloromethane (30 mL). The organic phase was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 0-100%) to give the colorless oily target product UBI-1271c (8 g, yield 43%). LCMS [M+H] + =290. 1 H NMR (400MHz, DMSO-d6) δ6.81–6.58(m,1H),3.56(t,J=6.2Hz,2H),3.35(t,J=6. 1Hz, 2H), 3.04 (q, J = 6.0Hz, 2H), 2.41 (t, J = 6.2Hz, 2H), 1.38 (d, J = 11.9Hz, 18H).

[0628] Step 2: UBI-1271d(V2037-056)

[0629] Compound UBI-1271c (8 g, 28 mmol) was dissolved in tetrahydrofuran (80 mL) and cooled to 0 °C. LiAlH4 / THF (30.4 mL) was then added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (150 mL), and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1271d (4.6 g, 75% yield). LCMS [M+H] + =220. 1 ¹H NMR (400 MHz, chloroform-d) δ 4.84 (s, 1H), 3.76 (t, J = 5.7 Hz, 2H), 3.63 (t, J = 5.8 Hz, 2H), 3.54–3.42 (m, 2H), 3.31 (t, J = 5.2 Hz, 2H), 2.12 (s, 1H), 1.83 (p, J = 5.8 Hz, 2H), 1.45 (s, 9H).

[0630] Step 3: UBI-1271e (V2037-060)

[0631] Compound UBI-1271d (1 g, 4.6 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (553 mg, 5.5 mmol). Then, methanesulfonyl chloride (680 mg, 5.9 mmol) dissolved in dichloromethane (10 mL) was slowly added dropwise to the reaction mixture. The reaction was carried out at room temperature for 2 hours, followed by extraction with water (10 mL) and dichloromethane (20 mL). The organic phase was concentrated to give the target product UBI-1271e (1.2 g, 88% yield) as a yellow oil. This crude product was used directly in the next reaction. LCMS [M+H] + =298

[0632] Step 4: UBI-1271g (V2037-061)

[0633] Compound UBI-1271f (742 mg, 4.6 mmol) was dissolved in acetonitrile (15 mL), followed by the addition of potassium carbonate (1.4 g, 10.0 mmol) and UBI-1271e (1.4 g, 4.6 mmol), and the mixture was heated to 60 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 0-10%) to give the colorless oily target product UBI-1271g (1.2 g, yield 60%). LCMS [M+H] + =328

[0634] 1¹H NMR (400 MHz, chloroform-d) δ 5.04 (s, 1H), 3.85–3.69 (m, 2H), 3.58 (m, 2H), 3.51 (q, J = 6.3, 5.7 Hz, 2H), 3.30 (q, J = 5.3 Hz, 2H), 2.92 (m, 4H), 1.93–1.79 (m, 2H), 1.57 (m, 4H), 1.45 (s, 9H).

[0635] Step 5: UBI-1271h (V2037-064)

[0636] Compound UBI-1271 g (1.6 g, 4.9 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of HCl / dioxane (15 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the yellow oily target product UBI-1271h (1.2 g, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =228

[0637] Step 6: UBI-1271j(V2037-066)

[0638] Compound UBI-1271h (600 mg, 2.3 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of potassium carbonate (691 mg, 5.0 mmol), potassium iodide as a catalyst, and UBI-1271i (510 mg, 2.3 mmol). The reaction mixture was heated to 90 °C and reacted for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1271j (230 mg, yield 36%) as a yellow oil. LCMS [M+H] + =280. 1 ¹H NMR (400MHz, chloroform-d) δ 4.05 (t, J = 5.1 Hz, 3H), 3.81–3.51 (m, 5H), 3.41–2.92 (m, 8H), 2.59 (m, 2H), 2.28–1.91 (m, 5H).

[0639] Step 7: UBI-1271k (V2037-068)

[0640] Compound UBI-1271j (120 mg, 0.43 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), followed by the addition of (Boc)₂O (141 mg, 0.65 mmol) and sodium bicarbonate (72 mg, 0.86 mmol), and reacted at room temperature for 1 hour. The reaction mixture was then extracted with ethyl acetate (15 mL) after adding water (10 mL). The organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1271k (110 mg, yield 67%). LCMS [M+H] + =380

[0641] Step 8: UBI-1271l(V2037-072)

[0642] Compound UBI-1271k (230 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of trimethylphosphine (0.73 mL) and heating at 45 °C for 1 hour. Water (1 mL) was then added, and the reaction proceeded for another hour. The reaction mixture was concentrated to give the colorless oily target product UBI-1271l (210 mg, 100% yield). This crude product was used directly in the next reaction step. LCMS [M+H] + =354

[0643] Step 9: UBI-1271 (V2037-073)

[0644] Compound P1 (253 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of HATU (271 mg, 0.71 mmol) and DIEA (230 mg, 1.78 mmol) and reacted at room temperature for 20 minutes. Then, UBI-1271l (210 mg, 0.59 mmol) was added and reacted at room temperature for 16 hours. The reaction mixture was then diluted with water (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the pale yellow oily target product UBI-1271 (360 mg, 80% yield). LCMS [M+H] + =761

[0645] Example 1.3.5 Synthesis of compound UBI-1272 (P1-14h)

[0646]

[0647] Step 1: UBI-1272b (V2128-008)

[0648] Compound UBI-1272a (5 g, 28.5 mmol) and triethylamine (3.5 g, 34.2 mmol) were reacted with methanesulfonyl chloride (4.2 g, 37.1 mmol) in a solution of dry dichloromethane (50 mL). The reaction mixture was stirred at 0 °C for 30 min and then allowed to rise to room temperature for 5 h. The reaction mixture was then diluted with water (10 mL) and extracted three times with dichloromethane (10 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the colorless oily target product UBI-1272b (7.2 g, 100% yield).

[0649] Step 2: UBI-1272d(V2128-009)

[0650] At 0 °C, a solution of compound UBI-1272c (12.6 g, 165.8 mmol) in N,N-dimethylformamide (80 mL) was added to a solution of 60% sodium hydride (2.2 g, 55.3 mmol). After 30 minutes at room temperature, a solution of UBI-1272b (7 g, 27.6 mmol) in N,N-dimethylformamide (20 mL) was slowly added, and the reaction was allowed to proceed for 12 hours at room temperature. The reaction was quenched with saturated ammonium chloride solution at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with brine and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 33% ethyl acetate in petroleum ether to give the pale yellow oily target product UBI-1272d (2.6 g, 40% yield).

[0651] 1 H NMR (400MHz, DMSO-d6) δ6.75(s,1H),4.36(t,J=5.2Hz,1H),3.52–3.33(m,6H),2.98–2.92(m,2H),1.60(dt,J=17.0,6.6Hz,4H),1.37(s,9H).

[0652] Step 3: UBI-1272e (V2037-076)

[0653] Compound UBI-1272d (1.5 g, 6.4 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (780 mg, 7.7 mmol) and methanesulfonyl chloride (958 mg, 8.4 mmol) dissolved in dichloromethane (10 mL) were added dropwise to the reaction solution, and the mixture was reacted at room temperature for 2 hours. The reaction solution was then extracted with water (10 mL) and dichloromethane (15 mL). After rotary evaporation of the organic phase, a pale yellow oily target product, UBI-1272e (2.0 g, 100% yield), was obtained. This crude product was used directly in the next reaction. LCMS [M+H] + =312

[0654] Step 4: UBI-1272g (V2037-079)

[0655] Compound UBI-1272f (1.0 g, 6.4 mmol) was dissolved in acetonitrile (50 mL), followed by the addition of potassium carbonate (2.0 g, 14.2 mmol), potassium iodide (catalyst), and UBI-1272e (2.0 g, 6.4 mmol). The mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1272 g (550 mg, yield 26%) as a yellow oil. LCMS [M+H] + =342. 1 ¹H NMR (400 MHz, chloroform-d) δ 4.90 (s, 1H), 3.47 (dd, J = 11.7, 5.8 Hz, 6H), 3.22 (q, J = 6.3 Hz, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.34 (m, 1H), 2.02 (m, 2H), 1.89–1.62 (m, 6H), 1.44 (s, 9H).

[0656] Step 5: UBI-1272h (V2037-080)

[0657] Compound UBI-1272 g (550 mg, 1.61 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of HCl / dioxane (3 mL) and reacted at room temperature for 2 hours. The reaction solution was evaporated to dryness to give a yellow, oily crude product UBI-1272 h (500 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =242

[0658] Step 6: UBI-1272j(V2037-081)

[0659] Compound UBI-1272h (570 mg, 2.0 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of potassium carbonate (621 mg, 4.5 mmol), potassium iodide (458 mg, 2.0 mmol), and UBI-1272i (458 mg, 2.0 mmol). The mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness and then separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1272j (470 mg, 78% yield) as a yellow oil. LCMS [M+H] + =294

[0660] Step 7: UBI-1272k(V2037-082)

[0661] Compound UBI-1272j (470 mg, 1.6 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), followed by the addition of (Boc)₂O (525 mg, 2.4 mmol) and sodium bicarbonate (269 mg, 3.2 mmol), and reacted at room temperature for 1 hour. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic phase was evaporated to dryness and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1272k (250 mg, yield 40%). LCMS [M+H] + =394. 1 ¹H NMR (400MHz, chloroform-d) δ 3.50–3.22 (m, 9H), 2.79 (m, 2H), 2.42 (m, 4H), 2.28–2.10 (m, 2H), 2.05–1.86 (m, 3H), 1.77 (tt, J = 14.2, 6.7 Hz, 6H), 1.46 (s, 9H).

[0662] Step 8: UBI-1272l(V2037-083)

[0663] Compound UBI-1272k (250 mg, 0.64 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of trimethylphosphine (0.95 mL) and heating to 45 °C for 1 hour. Water (1 mL) was then added, and the reaction was continued at 45 °C for another hour. The reaction mixture was evaporated to dryness to obtain the colorless oily target product UBI-1272l (230 mg, 99% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =368

[0664] Step 9: UBI-1272 (V2037-084)

[0665] Compound P1 (266 mg, 0.63 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of HATU (286 mg, 0.75 mmol) and DIEA (243 mg, 1.88 mmol). After reacting at room temperature for 20 minutes, UBI-1272 (230 mg, 0.63 mmol) was added, and the reaction proceeded to room temperature for another 16 hours. The reaction mixture was then diluted with water (10 mL), extracted with ethyl acetate (20 mL), and the organic phase was evaporated to dryness before separation by column chromatography (methanol / dichloromethane = 1 / 10) to obtain the yellow oily target product UBI-1272 (380 mg, 78% yield). LCMS [M+H] + =775

[0666] Example 1.3.6 Synthesis of compound UBI-1273 (P1-15h)

[0667]

[0668] Step 1: UBI-1273b (V2037-087)

[0669] Compound UBI-1272h (570 mg, 2.1 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of potassium carbonate (621 mg, 4.5 mmol), potassium iodide as a catalyst, and UBI-1273a (333 mg, 2.1 mmol). The mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness and then separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1273b (400 mg, yield 19%) as a yellow oil.

[0670] LCMS[M+H] + =308

[0671] Step 2: UBI-1273c(V2037-089)

[0672] Compound UBI-1273b (500 mg, 1.6 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), followed by the addition of (Boc)₂O (532 mg, 2.4 mmol) and sodium bicarbonate (274 mg, 3.3 mmol), and reacted at room temperature for 1 hour. The reaction mixture was extracted with water (10 mL) and ethyl acetate (20 mL), and the organic phase was evaporated to dryness and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1273c (250 mg, yield 38%).

[0673] LCMS[M+H] + =408

[0674] 1 ¹H NMR (400MHz, chloroform-d) δ 3.57–3.36 (m, 5H), 3.27 (m, 4H), 2.80 (s, 2H), 2.45 (s, 2H), 2.19 (td, J = 7.1, 2.7Hz, 3H), 1.96 (t, J = 2.7Hz, 3H), 1.86–1.54 (m, 8H), 1.45 (s, 9H).

[0675] Step 3: UBI-1273d(V2037-091)

[0676] Compound UBI-1273c (250 mg, 0.61 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of trimethylphosphine (0.92 mL) and heating to 45 °C for 1 hour. Water (1 mL) was then added, and the reaction continued at 45 °C for another hour. The reaction mixture was evaporated to dryness to obtain the colorless oily target product UBI-1273d (230 mg, 100% yield). This target product was used directly in the next reaction step.

[0677] LCMS[M+H] + =382

[0678] Step 4: UBI-1273 (V2037-093)

[0679] Compound P1 (257 mg, 0.60 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of HATU (275 mg, 0.72 mmol) and DIEA (234 mg, 1.81 mmol). After reacting at room temperature for 20 minutes, UBI-1273d (230 mg, 0.60 mmol) was added, and the reaction was continued at room temperature for 16 hours. The reaction solution was extracted with water (10 mL) and ethyl acetate (20 mL). The organic phase was evaporated to dryness and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the pale yellow oily target product UBI-1273 (330 mg, yield 69%).

[0680] LCMS[M+H] + =790

[0681] Example 1.3.7 Synthesis of compound UBI-1275 (P1-13h)

[0682]

[0683] Step 1: UBI-1275a(V2037-109)

[0684] Compound UBI-1272d (600 mg, 2.6 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of HCl / dioxane (5 mL) and reacted at room temperature for 2 hours. The reaction solution was evaporated to dryness to obtain the yellow oily target product UBI-1275a (500 mg, 100% yield). This crude product was used directly in the next reaction step.

[0685] LCMS[M+H] + =134

[0686] Step 2: UBI-1275c (V2037-110)

[0687] Compound UBI-1275a (436 mg, 2.6 mmol) was dissolved in acetonitrile (40 mL), followed by the addition of potassium carbonate (782 mg, 5.7 mmol), potassium iodide (577 mg, 2.6 mmol), and UBI-1275b (577 mg, 2.6 mmol). The mixture was heated to 90 °C and reacted for 16 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness and then separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1275c (400 mg, yield 86%) as a yellow oil.

[0688] LCMS[M+H] + =186

[0689] Step 3: UBI-1275d (V2037-111)

[0690] Compound UBI-1275c (600 mg, 3.2 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), followed by the addition of (Boc)₂O (1.1 g, 4.9 mmol) and sodium bicarbonate (545 mg, 6.5 mmol), and reacted at room temperature for 1 hour. The reaction mixture was extracted with water (10 mL) and ethyl acetate (20 mL), and the organic phase was evaporated to dryness and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the colorless oily target product UBI-1275d (260 mg, yield 28%).

[0691] LCMS[M+H] + =286

[0692] Step 4: UBI-1275e (V2128-054)

[0693] Compound UBI-1275d (245 mg, 0.86 mmol) was dissolved in dichloromethane (8 ml), and then Dysmartin reagent (546 mg, 1.3 mmol) was added and reacted at room temperature for 1 hour. The reaction solution was filtered and used directly in the next step.

[0694] LCMS[M+1] + =284.

[0695] Step 5: UBI-1275 (V2128-056)

[0696] Compounds UBI-1275e (220 mg, 0.78 mmol) and UBI-1275f (280 mg, 0.54 mmol) were dissolved in dichloromethane / methanol = 10 / 1 (16 mL), and sodium acetate (106 mg, 0.78 mmol) was added. The reaction was continued at room temperature for 1 hour, followed by the addition of sodium cyanoborohydride (49 mg, 0.78 mmol), and the reaction was continued at room temperature for 3 hours. The reaction solution was diluted with water and extracted three times with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (methanol / dichloromethane = 0-10%) to give the target product UBI-1275 (55 mg, 9% yield) as a yellow solid.

[0697] LCMS[M+H]+=747.

[0698] Example 1.3.8 Synthesis of compound UBI-1274 (NH2-10h-A1)

[0699]

[0700] Step 1: UBI-1274c (V2127-034)

[0701] Compounds UBI-1274a (900 mg, 3.18 mmol), DIEA (410 mg, 3.18 mmol), and UBI-1274b (411 mg, 4.77 mmol) were dissolved in acetonitrile (30 mL) and reacted at 80 °C for 18 hours. The reaction solution was evaporated to dryness and then separated by column chromatography (petroleum ether / ethyl acetate = 50%–100% for 20 min, then methanol / dichloromethane = 0%–10% for 40 min) to give the target product UBI-1274c (1.0 g, yield 86%) as a white solid.

[0702] Step 2: UBI-1274d (V2037-116)

[0703] Compound UBI-1274c (260 mg, 0.70 mmol) was dissolved in methanol (2 mL), tetrahydrofuran (6 mL), and water (2 mL), followed by the addition of lithium hydroxide (36 mg, 0.85 mmol) and reaction at room temperature for 1 hour. The reaction solution was washed once with ethyl acetate (15 mL), and the aqueous phase was acidified to pH 6 with 3N HCl and concentrated to give the target product UBI-1274d (330 mg, 100% yield) as a white solid.

[0704] LCMS[M+H] + =356

[0705] Step 3: UBI-1274e (V2037-113)

[0706] Compound UBI-1274d (250 mg, 0.70 mmol) was dissolved in N,N-dimethylformamide (6 mL), followed by the addition of HATU (321 mg, 0.85 mmol) and DIEA (273 mg, 2.11 mmol). After reacting at room temperature for 20 minutes, lenalidomide (182 mg, 0.70 mmol) was added, and the reaction was continued at room temperature for 16 hours. The reaction solution was extracted with water (10 mL) and ethyl acetate (20 mL). The organic phase was evaporated to dryness and separated by preparative chromatography (methanol / dichloromethane = 1 / 10) to give the yellow oily target product UBI-1274e (18 mg, yield 4%).

[0707] LCMS[M+H] + =597

[0708] Step 4: UBI-1274 (V2037-114)

[0709] Compound UBI-1274e (20 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of HCl / dioxane (0.3 mL), and reacted at room temperature for 2 hours. The reaction solution was evaporated to dryness to give the target product UBI-1274 (15 mg, 100% yield) as a yellow oil. This crude product was used directly in the next reaction step.

[0710] LCMS[M+H] + =497

[0711] Example 1.3.9 Synthesis of compound UBI-1278 (9h-A1)

[0712]

[0713] Step 1: UBI-1278b (V1661-133)

[0714] UBI-1278a (4.197 g, 20.5 mmol) was dissolved in anhydrous DMF (60 mL), cooled to 0 °C, and sodium hydride (1.64 g, 41 mmol) was added to the solution. The reaction mixture was stirred at 0 °C for 30 min. Bromopropyne (80% toluene solution, 2.2 mL, 20.5 mmol) was slowly added dropwise to the system (15 min), and the reaction was continued at 0 °C for 2 h until complete. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The reaction mixture was concentrated and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give UBI-1278b (4.86 g, 98% yield). LC-MS: [M-56] + =188.2

[0715] Step 2: UBI-1278d (V1661-136)

[0716] UBI-1278b (1 g, 6.94 mmol) and triethylamine (1.1 mL, 7.8 mmol) were dissolved in tetrahydrofuran (20 mL) and cooled to -10 °C. UBI-1278c (1.0 mL, 7.8 mmol) was added dropwise, and the mixture was stirred at -10 °C for 1 hour. The reaction system was heated to 0 °C. A mixture of NaBH4 (0.78 g, 20.8 mmol) dissolved in tetrahydrofuran (10 mL) and water (2 mL) was added dropwise to the above system. The mixture was stirred at 0 °C for 1 hour. The mixture was poured into a 20% aqueous solution of citric acid. Extraction was performed with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried (MgSO4), and filtered. After concentration, the mixture was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give UBI-1278d (0.9 g, 100% yield). LC-MS: [M-56] + =174.2

[0717] Step 3: UBI-1278e (V2031-017)

[0718] Under nitrogen protection, UBI-1278d (300 mg, 1.3 mmol), UBI-1237 (480 mg, 1.3 mmol), PdCl2(PPh3)2 (46 mg, 0.06 mmol), copper iodide (25 mg), and triethylamine (400 mg) were added to anhydrous DMF (10 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours. After cooling to room temperature, the mixture was added to water, extracted with dichloromethane, washed with water, dried over sodium sulfate, filtered, and the reaction solution was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain UBI-1278e (200 mg, yield 32.4%). LC-MS: [M+H] + =472.5

[0719] Step 4: UBI-1278f(V2031-018)

[0720] Desmartin reagent (555 mg, 1.31 mmol) was added to a solution of UBI-1278e (200 mg, 0.87 mmol) in 10 mL of dichloromethane and stirred at 0 °C for 1 hour. The mixture was quenched with saturated sodium thiosulfate solution and extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, brine, and water, and dried over sodium sulfate. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain a yellow solid UBI-1278f (110 mg, yield 55.3%). LC-MS: [M+H] +=580.2

[0721] Step 5: UBI-1278h (V2031-027)

[0722] UBI-1278f (40 mg, 0.24 mmol), UBI-1278g (113 mg, 0.24 mmol), and acetic acid (10 mg) were added to methanol (2 mL) and stirred for one hour. Then, sodium cyanoborohydride (30 mg, 0.48 mmol) was added, and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, 5 mL of the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and the reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain compound UBI-1278h (40 mg, yield 81%). LC-MS: [M+H] + =580.2

[0723] Step 6: UBI-1278 (V2031-035)

[0724] PMe3 (1 mL) was added to 5 mL of tetrahydrofuran in UBI-1278h (40 mg, 0.07 mmol). The system was stirred at 45 °C for 1 h, then water (0.5 mL) was added, and the system was stirred at 20 °C for 16 h. The mixture was then concentrated under reduced pressure to obtain the colorless oily target product UBI-1278 (38 mg, 100% yield). LCMS: [M+H] + =554.3

[0725] Example 1.3.10 Synthesis of compound UBI-1279 (P1-9h)

[0726]

[0727] Step 1: UBI-1279c(V2031-047)

[0728] Under argon protection, UBI-1279a (500 mg, 7.14 mmol) was added to anhydrous DMF (10 mL), and sodium hydride (571 mg, 14.3 mmol) was added in portions. After stirring the reaction mixture for 30 minutes, UBI-1279b (2.11 g, 10.7 mmol) was added. The reaction mixture was then stirred at 0 °C for 2 hours until complete conversion (TLC analysis, ethyl acetate:petroleum ether = 1:10). The reaction mixture was quenched with water (20 mL) and the solvent was removed under reduced pressure. Extraction was performed with ethyl acetate (30 mL × 3), dried over sodium sulfate, and the concentrated solution was separated by silica gel column chromatography (0%–20% ethyl acetate:petroleum ether) to give a colorless oil, UBI-1279c (0.72 g, 54.1% yield). LCMS: [M+H]+ =187.2

[0729] 1 ¹H NMR (400MHz, chloroform-d) δ 4.63 (t, J = 5.1 Hz, 1H), 3.72–3.57 (m, 6H), 3.53 (d, J = 5.2 Hz, 2H), 2.48 (td, J = 7.0, 2.7 Hz, 2H), 1.97 (t, J = 2.7 Hz, 1H), 1.22 (dd, J = 7.1, 1.4 Hz, 6H).

[0730] Step 2: UBI-1279d(V2031-062)

[0731] UBI-1279c (0.72 g, 3.87 mmol) was added to a 1 N HCl (20 mL) aqueous solution. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with dichloromethane (30 mL × 2), dried over sodium sulfate, filtered, and concentrated to obtain UBI-1279d (430 mg, 100% yield). LCMS: [M+H] + =113.1

[0732] Step 3: UBI-1205f(V2031-062)

[0733] UBI-1279d (50 mg, 0.45 mmol), UBI-1279e (230 mg, 0.45 mmol), and acetic acid (50 mg) were added to methanol (5 mL), and the reaction mixture was stirred for one hour. Then, sodium cyanoborohydride (56 mg, 0.89 mmol) was added, and the reaction mixture was stirred at 20 °C for 16 hours. After the reaction was complete, the mixture was quenched in water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over sodium sulfate, filtered, and the reaction mixture was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 0–10%) to give a white solid UBI-1279f (115 mg, yield 44.6%). LCMS: [M+H] + =578.3

[0734] Step 4: UBI-1279 (V2031-063)

[0735] UBI-1279f (100 mg, 0.48 mmol), di-tert-butyl dicarbonate (57 mg, 0.26 mmol), sodium bicarbonate (43 mg), and water (2 mL) were added to tetrahydrofuran (5 mL). The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 0–10%), yielding a yellow oily substance UBI-1279 (50 mg, 42.6% yield). LCMS: [M+H]+ =678.3

[0736] Example 1.3.11 Synthesis of compound UBI-1280 (P1-11h)

[0737]

[0738] Step 1: UBI-1280b (V2031-075)

[0739] UBI-1279d (250 mg, 2.23 mmol), UBI-1280a (290 mg, 2.23 mmol), and acetic acid (50 mg) were added to methanol (5 mL), and the reaction mixture was stirred for 1 hour. Sodium cyanoborohydride (281.3 mg, 4.46 mmol) was then added to the mixture, and the mixture was stirred at 20 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 0–20%) to give a yellow oily substance, UBI-1280b (200 mg, yield 39.6%). LCMS: [M+H] + =227.2

[0740] Step 2: UBI-1280c(V2031-078)

[0741] UBI-1280b (200 mg, 0.88 mmol), di-tert-butyl dicarbonate (290 mg, 1.33 mmol), sodium bicarbonate (223 mg), and water (2 mL) were added to tetrahydrofuran (5 mL). The reaction was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow oil UBI-1280c (200 mg, yield 69.3%). LCMS: [M+H] + =327.2

[0742] Step 3: UBI-1280d(V2031-080)

[0743] At room temperature, 1 mL of 1 M trimethylphosphine (tetrahydrofuran solution) was added to UBI-1280c (200 mg), 5 mL of tetrahydrofuran, and 0.1 mL of water. The reaction mixture was stirred overnight. After the reaction was complete, the solution was dried under vacuum to obtain UBI-1280d (170 mg, yield 95.9%), which was used directly in the next step without purification. LCMS: [M+H] + =301.2

[0744] Step 4: UBI-1280 (V2031-086)

[0745] P1 (170 mg, 0.4 mmol), UBI-1280d (150 mg, 0.5 mol), HATU (285 mg, 0.75 mmol), and diisopropylethylamine (193.5 mg, 1.5 mol) were dissolved in DMF (10 mL) and stirred at room temperature for 18 hours. After the reaction was complete, the mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL × 3). The synthesized organic layer was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10%) to give a yellow solid UBI-1280 (100 mg, yield 35.4%). LCMS: [M+H] + =708.4

[0746] Example 1.3.12 Synthesis of compound UBI-1281 (P1-12h)

[0747]

[0748] Step 1: UBI-1281b (V2031-076)

[0749] UBI-1281a (2.0 g, 28.57 mmol), tetrabutylammonium bisulfate (0.97 g, 2.86 mmol), and bis(2-chloroethyl) ether (12.2 g, 85.7 mmol) were added to 12 mL of 50% sodium hydroxide aqueous solution. The reaction mixture was stirred vigorously at 40 °C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was added to a mixture of 80 mL of water and 80 mL of dichloromethane and extracted with dichloromethane. The organic phases were combined and dried over sodium sulfate. The reaction mixture was concentrated and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a colorless oil, UBI-1281b (3.5 g, yield 69.4%). LCMS: [M+H] + =177.1

[0750] 1 ¹H NMR (400MHz, chloroform-d) δ 3.80–3.75 (m, 2H), 3.68–3.62 (m, 8H), 2.49 (d, J = 2.6 Hz, 2H), 1.98 (s, 1H).

[0751] Step 2: UBI-1281c(V2031-079)

[0752] UBI-1281b (200 mg, 1.13 mmol), 3-azidopropylamine (97.7 mg, 1.13 mmol), potassium iodide (188.6 mg, 1.13 mmol), and potassium carbonate (313.6 mg, 2.27 mmol) were added to acetonitrile (5 mL), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain a colorless oily substance UBI-1281c (200 mg, yield 73.5%).

[0753] LCMS:[M+H] + =241.2 1 H NMR (400MHz, chloroform-d) δ3.98–3.87(m,2H),3.74–3.67(m,4H),3.64(t,J=6.7Hz,2H),3.57(t,J=6.3Hz,2H),3.2 8–3.21(m,2H),3.18(t,J=7.3Hz,2H),2.50(td,J=6.7,2.7Hz,2H),2.21–2.11(m,2H),2.06(t,J=2.7Hz,1H).

[0754] Step 3: UBI-1281d(V2031-078)

[0755] UBI-1281c (200 mg, 0.88 mmol), di-tert-butyl dicarbonate (290 mg, 1.33 mmol), sodium bicarbonate (223 mg), and water (2 mL) were added to tetrahydrofuran (5 mL). The reaction system was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to give a yellow oily substance UBI-1281d (200 mg, yield 70.6%). LCMS: [M+H] + =341.2

[0756] Step 4: UBI-1281e (V2031-081)

[0757] At room temperature, 0.88 mL of 1 M trimethylphosphine (tetrahydrofuran) was added to a reaction mixture of 5 mL tetrahydrofuran and 0.1 mL water for UBI-1281d (200 mg, 0.59 mmol) and stirred overnight at room temperature. After the reaction was complete, the mixture was pumped dry to obtain UBI-1281e (150 mg, yield 81.2%). LCMS: [M+H] + =314.2

[0758] Step 5: UBI-1281 (V2031-082)

[0759] P1 (162 mg, 0.38 mmol), UBI-1281e (150 mg, 0.48 mmol), HATU (272 mg, 0.72 mmol), and diisopropylethylamine (185 mg, 1.43 mmol) were dissolved in DMF (10 mL) and stirred overnight at room temperature. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to give a yellow solid UBI-1281 (100 mg, yield 36.4%). LCMS: [M+H] + =722.4

[0760] Example 1.3.13 Synthesis of compound UBI-1282 (P1-10h)

[0761]

[0762] Step 1: UBI-1282c(V2031-48)

[0763] UBI-1282a (500 mg, 5.94 mmol) was dissolved in anhydrous DMF (10 mL), and sodium hydroxide (356.6 mg, 8.92 mmol) was added in portions. After stirring the reaction system for 30 minutes, UBI-1282b (1.76 g, 8.92 mmol) was added. The reaction system was then stirred at 0 °C for 2 hours until complete conversion (TLC analysis, ethyl acetate:petroleum ether = 1:10). After the reaction was complete, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3) and dried over sodium sulfate. The organic phases were combined, and the filtrate was concentrated after drying with sodium sulfate and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain UBI-1282c (0.9 g, yield 75.6%).

[0764] LCMS:[M+H] + =201.2

[0765] 1 H NMR (400MHz, chloroform-d) δ4.62(t,J=5.2Hz,1H),3.70(dq,J=9.4,7.0Hz,2H),3.62–3.53(m,4H),3.49(d,J=5.3Hz ,2H),2.29(td,J=7.0,2.6Hz,2H),1.94(t,J=2.7Hz,1H),1.80(tt,J=7.1,6.2Hz,2H),1.22(t,J=7.1Hz,6H).

[0766] Step 2: UBI-1282d(V2031-062)

[0767] UBI-1282c (0.8 g, 4 mmol) was added to 1N HCl (20 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with dichloromethane (30 mL × 2), dried over sodium sulfate, filtered, and concentrated to obtain UBI-1282d (350 mg, yield 69.4%). This crude product was used directly in the next step. LCMS: [M+H] + =127.1

[0768] Step 3: UBI-1282 (V2031-090)

[0769] UBI-1282d (50 mg, 0.45 mmol), UBI-1282e (113 mg, 0.22 mmol), and acetic acid (10 mg) were added to methanol (5 mL) and stirred at room temperature for one hour. Then, sodium cyanoborohydride (56 mg, 0.89 mmol) was added and the mixture was stirred at 20°C for 16 hours. The reaction solution was concentrated and separated by silica gel column chromatography to obtain a yellow solid UBI-1282 (55 mg, yield 40%).

[0770] LCMS:[M+H] + =618.4

[0771] Example 1.3.14 Synthesis of compound UBI-1254 (P1-14h)

[0772]

[0773] Step 1: UBI-1254c (V2118-034)

[0774] UBI-1254a (1.0 g, 12 mmol) was dissolved in DMF (30 mL), and NaH (60%, 576 mg, 24 mmol) was added at 0°C. The mixture was then heated to room temperature and reacted for one hour. UBI-1254b (3 g, 12 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for another 6 hours. After the reaction was complete, the reaction solution was poured into ice water and extracted three times with EA. The EA layers were combined, washed twice with water and once with saline solution. The mixture was dried, filtered, and purified by column chromatography (PE / EA) to obtain a colorless oily product, UBI-1254c (1 g, 33% yield).

[0775] 1H NMR (400MHz, CDCl3) δ3.64(t,J=6.2Hz,2H),3.45(td,J=6.3,1.2Hz,4H),2.23(td,J=7.1,2.7 Hz,2H),1.89(t,J=2.7Hz,1H),1.73(pd,J=6.6,4.8Hz,4H),0.91–0.75(m,9H),0.05-0(m,6H).

[0776] Step 2: UBI-1254d (V2118-035)

[0777] UBI-1254b (1 g, 4 mmol) was dissolved in 30 mL of THF, and 10 mL of TBAF in THF (1 M) was added. The reaction was allowed to proceed overnight (approximately 16 hours) at room temperature. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, and THF was removed by rotary evaporation. The mixture was extracted three times with EA, the organic layers were combined, dried, filtered, and purified by column chromatography (PE / EA) to obtain a colorless oily product, UBI-1254d (480 mg, yield: 85%). LC-MS: [M+H] + =143

[0778] Step 3: UBI-1254e (V2118-036)

[0779] UBI-1254d (110 mg, 0.77 mmol) was dissolved in DCM (10 mL), and TEA (157 mg, 1.55 mmol) was added. MsCl (106 mg, 0.92 mmol) was slowly added dropwise at 0°C. After the addition was complete, the mixture was reacted at room temperature for one hour, and the reaction was monitored by TLC. Saturated NaHCO3 solution was added to the solution, and the mixture was extracted twice with DCM (20 mL * 2). The organic layers were combined, dried, filtered, and purified by column chromatography (PE / EA) to obtain a yellow oily product, UBI-1254e (160 mg, 94% yield). LC-MS: [M+H] + =221

[0780] Step 4: UBI-1254g (V2118-037)

[0781] UBI-1254e (160 mg, 0.72 mmol), UBI-1254f (450 mg, 0.82 mmol), and K₂CO₃ (113 mg, 0.82 mmol) were added to ACN (50 mL), and the mixture was reacted at 80 °C for 16 hours. The solid was removed by filtration after cooling. Water was added to the filtrate, and the mixture was extracted three times with DCM (50 mL x 3). The organic layers were combined, dried, filtered, and purified by slurry (DCM / MeOH) to give a yellow solid product, UBI-1254g (160 mg, 75% purity).

[0782] LC-MS:[M+H] + =675

[0783] Step 5: UBI-1254h (V2118-038)

[0784] UBI-1254 g (160 mg, 0.24 mmol) was dissolved in 10 mL of THF, and Boc2O (110 mg, 0.5 mmol) and saturated NaHCO3 (84 mg, 1 mmol in 10 mL H2O) solution were added. The mixture was reacted at room temperature for 2 hours. After the reaction was completed, water was added, and the mixture was extracted three times with DCM:MeOH = 10:1 (10 mL * 3). The organic layers were combined, dried, filtered, and purified by TCM / MeOH to give a yellow solid product UBI-1254 h (120 mg). The two-step yield was 25%.

[0785] LC-MS:[M+H] + =775

[0786] Example 1.3.15 Synthesis of compound UBI-1251 (P1-15h)

[0787]

[0788] Step 1: UBI-1251b (V2118-044)

[0789] UBI-1254e (250 mg, 1.14 mmol), UBI-1251a (670 mg, 1.19 mmol), and K₂CO₃ (164 mg, 1.19 mmol) were added to DMF (20 mL), and the mixture was reacted at 80 °C for 16 hours (overnight reaction). After cooling, excess solids were removed by filtration. 50 mL of water was added to the filtrate, and the mixture was extracted twice with DCM (50 mL * 2). The organic layers were combined, dried over Na₂SO₄, filtered, and purified by column chromatography (DCM / MeOH) with silica gel. The final product was a yellow solid, UBI-1251b (140 mg, 65% purity). The purity was not high, and some starting material and byproducts were present, which were removed in the next purification step.

[0790] LC-MS:[M+H] + =689

[0791] Step 5: UBI-1251b (V2118-045)

[0792] UBI-1251a (140 mg, 0.2 mmol) was dissolved in 10 mL of THF, and Boc₂O (87 mg, 0.4 mmol) and NaHCO₃ solution (84 mg, 1 mmol in 10 mL H₂O) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was monitored by TLC to ensure complete reaction, the mixture was extracted three times with DCM:MeOH at a ratio of 10:1 (10 mL * 3). The organic layers were combined, dried over Na₂SO₄, filtered, and purified by column chromatography (DCM / MeOH) to obtain the final product UBI-1251b (85 mg, two-step yield 9.5%) as a yellow solid.

[0793] LC-MS:[M+H] + =789

[0794] Example 1.3.16 Synthesis of compound UBI-1252 (P1-10h)

[0795]

[0796] Step 1: UBI-1252b (V2118-007)

[0797] UBI-1252a (20 g, 149 mmol) was dissolved in DCM (200 mL). TsCl (85 g, 447 mmol), TEA (124 mL, 894 mmol), and DMAP (1.8 g, 14.9 mmol) were added at 0°C, and the mixture was reacted at room temperature for 8 hours. The solid was removed by filtration, and the filtrate was purified by column chromatography (PE / EA) using PE and EA as the mobile phase. The final product, UBI-1252b (39 g, 88.2 mmol, yield 59%), was obtained as a yellow oily liquid.

[0798] 1 H NMR (400MHz, CDCl3) δ7.90–7.67(m,4H),7.44–7.28(m,4H),4.72–4.47(m,1H), 3.94–3.65(m,3H),3.64–3.25(m,3H),2.45(d,J=4.3Hz,6H),1.08–0.92(m,3H).

[0799] LCMS[M+H] + =443

[0800] Step 2: UBI-1252c (V2118-008)

[0801] UBI-1252b (39 g, 88 mmol) was dissolved in 200 mL of LDM and gently stirred. NaN3 (17 g, 264 mmol) was carefully added to the solution, and the reaction was carried out overnight (16 hours) at 80 °C. TLC monitoring (PE / EA = 10 / 1, 1 / 1) showed that the product disappeared and a new spot formed. Excess NaN3 was removed by filtration, and then 200 mL of water was added, followed by two extractions with EA (200 mL * 2). The EA layers were combined, washed twice with 200 mL of water and once with 100 mL of saturated brine, then dried over Na2SO4, filtered, and evaporated to dryness to obtain a yellow oily product UBI-1252c (15 g, 94% yield).

[0802] LCMS[M+H] + =185

[0803] Step 3: UBI-1252d(V2118-009)

[0804] At 0°C, UBI-1252c (15 g, 82 mmol) and 1M HCl solution (123 mL, 123 mmol) were added to a solution of Et2O (100 mL) / EtOAc (200 mL) / THF (50 mL) and stirred. PPh3 (21.5 g, 82 mmol) was dissolved in EtOAc (150 mL) / Et2O (50 mL) and slowly added dropwise to the above mixture, completing the addition over one hour. The reaction was carried out at room temperature for three hours. The aqueous layer was washed twice with EA (100 mL), and the EA was discarded. 2M NaOH solution was added dropwise to the aqueous layer until the pH reached approximately 10, and then extracted twice with DCM (200 mL * 2). The DCM layers were combined, dried over sodium sulfate, filtered, and evaporated to dryness to obtain a yellow oily crude product UBI-1252d (12 g, yield 92%).

[0805] LCMS[M+H] + =159

[0806] Step 4: UBI-1252f(V2118-010)

[0807] UBI-1252d (1 g, 6.3 mmol), UBI-1252e (1.4 g, 6.3 mmol), and K2CO3 (2.6 g, 19 mmol) were added to 150 mL of ACN and reacted at 60 °C overnight (approximately 16 hours). The solids were removed by cooling and filtration, and the filtrate was evaporated to dryness and purified by column chromatography (DCM / MeOH = 0–10%) to obtain a yellow oily product, UBI-1252f (820 mg, yield 62%).

[0808] LCMS[M+H] + =211

[0809] Step 5: UBI-1252g (V2118-011)

[0810] UBI-1252f (820 mg, 3.9 mmol) was dissolved in 10 mL of THF, and NaHCO3 solution (983 mg, 11.7 mmol dissolved in 10 mL of H2O) and Boc2O (1.27 g, 5.85 mmol) were added. The reaction was carried out at 20 °C for two hours. After the reaction was completed, EA (20 mL * 2) was added for extraction twice. The organic layers were combined, dried, filtered, and purified by column chromatography (DCM / MeOH = 0–10%) to obtain a yellow oily product UBI-1252 g (850 mg, yield 70%).

[0811] 1 H NMR (400MHz, CDCl3) δ3.77–3.00(m,8H),2.43(s,2H),1.96(s,1H),1.52–1.38(m,9H),1.24–1.06(m,6H).

[0812] LCMS[M+H] + =311

[0813] Step 6: UBI-1252h (V2118-054)

[0814] UBI-1252g (200mg, 0.64mmol) was dissolved in 10mL THF, and PMe3 (98mg, 1.28mmol) was added. The reaction was carried out at room temperature for three hours. The reaction was monitored by TLC to determine when it was complete. The product UBI-1252h (272mg) was obtained by rotary evaporation and used directly in the next step.

[0815] LCMS[M+H] + =285

[0816] Step 7: UBI-1252j(V2118-055)

[0817] UBI-1252h (272 mg, 0.64 mmol) and UBI-1252i (183 mg, 0.64 mmol) were dissolved in 20 mL of DCM, and HATU (243 mg, 0.64 mmol) and DIPEA (248 mg, 1.92 mmol) were added. The reaction was carried out at room temperature for one hour. The reaction was monitored by TLC. The sample was evaporated to dryness and passed through a column (DCM / MeOH = 10:1) to give 105 mg of yellow solid product UBI-1252j, with a two-step yield of 23.5%.

[0818] LCMS[M+H] + =692.

[0819] Example 1.3.17 Synthesis of compound UBI-1253 (P1-11h)

[0820]

[0821] Step 1: UBI-1253a(V2118-029)

[0822] UBI-1253a (1 g, 5.3 mmol) was dissolved in DCM (50 mL), and TEA (1.6 g, 15.9 mmol) was added. The mixture was then cooled to 0°C, and MsCl (736 mg, 6.4 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for one hour. The reaction was quenched with saturated NaHCO3 solution, and the mixture was extracted twice with DCM (50 mL * 2). The organic layers were combined, dried, filtered, and purified by column chromatography (PE / EA) to give a yellow oily product UBI-1253b (1.2 g, 86% yield).

[0823] LC-MS:[M+H] + =268

[0824] Step 2: UBI-1253d (V2118-030)

[0825] UBI-1253b (1.2 g, 4.5 mmol), UBI-1253c (566 mg, 4.5 mmol), and K₂CO₃ (1.2 g, 9 mmol) were added to ACN (50 mL), and the mixture was reacted at 60 °C for 16 hours. The mixture was cooled and filtered, and the filtrate was evaporated to dryness to remove acetonitrile. Then, 50 mL of water was added, and the mixture was extracted twice with DCM. The organic layers were combined, dried, filtered, and purified by column chromatography (DCM / MeOH) to give a yellow oily product, UBI-1253d (1.2 g, 89% yield).

[0826] 1 H NMR(400MHz, CDCl3)δ5.39(s,1H),3.37(dd,J=47.0,13.8Hz,2H),3.20–3.03(m,2H),2.83–2.63(m,2H),2.34( t,J=6.8Hz,2H),2.15(s,2H),1.99–1.76(m,3H),1.76–1.60(m,2H),1.59–1.48(m,3H),1.45(d,J=8.0Hz,9H).

[0827] LC-MS:[M+H] + =298

[0828] Step 3: UBI-1253e (V2118-031)

[0829] UBI-1253d (1.2 g, 4 mmol) was dissolved in DCM (20 mL), and 4 M HCl in dioxane (2 mL) was added. The mixture was reacted at room temperature for one hour. The supernatant was discarded after standing. The solid was washed twice with Et2O, and the Et2O was discarded. The remaining solid was dried by pumping to obtain the yellow solid product UBI-1253e (HCl salt) (900 mg, yield 96%).

[0830] LCMS[M+H] + =198

[0831] Step 4: UBI-1253g (V2118-032)

[0832] UBI-1253e (900 mg, 4.7 mmol), UBI-1253f (1 g, 4.7 mmol), and K₂CO₃ (1.3 g, 9.4 mmol) were added to 100 mL of LCN and reacted overnight at 60 °C (approximately 16 hours). The mixture was cooled and filtered, and the filtrate was evaporated to dryness and purified by column chromatography (DCM:MeOH = 0–10%) to obtain a yellow oily product, UBI-1253g (530 mg, purity 75%). The purity was not high, containing some raw materials and byproducts, which were removed in the next purification step.

[0833] LCMS[M+H] + =250

[0834] Step 5: UBI-1253h (V2118-033)

[0835] UBI-1253 g (530 mg, 2 mmol) was dissolved in 30 mL of THF, and NaHCO3 solution (504 mg, 6 mmol, in 10 mL H2O) and Boc2O (872 mg, 4 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water was added and the mixture was extracted twice with DCM (50 mL * 2). The organic layers were combined, dried, filtered, and evaporated to dryness. The residue was purified by column chromatography (DCM / MeOH) to give a yellow oily product UBI-1253 h (510 mg), with a two-step yield of 36%.

[0836] LCMS[M+H] + =350

[0837] Step 6: UBI-1253i (V2118-042)

[0838] UBI-1253h (510 mg, 1.46 mmol) was dissolved in 20 mL of THF and PMe3 (222 mg, 2.9 mmol) was added. The mixture was reacted at room temperature for three hours and then evaporated to dryness to obtain product UBI-1253i (324 mg, yield: 69%), which was directly used in the next step of the reaction.

[0839] LCMS[M+H] + =324

[0840] Step 7: UBI-1253k (V2118-043)

[0841] UBI-1253i (324 mg, 1 mmol), UBI-1253j (292 mg, 1 mmol), and HATU (456 mg, 1.2 mmol) were successively added to DMF (15 mL), followed by DIPEA (387 mg, 3 mmol). The reaction was carried out at room temperature for 2 hours. The product was purified directly by column chromatography (DCM / MeOH) to give a white solid product UBI-1253k (70 mg, yield 9.6%).

[0842] LCMS[M+H] + =731

[0843] Example 1.3.18 Synthesis of compound UBI-1277 (NH2-12h-A1)

[0844]

[0845] Step 1: UBI-1277b (V1782-093)

[0846] UBI-1277a (600 mg, 3.27 mmol) was dissolved in methanol (12 mL). NaBH4 (247 mg, 6.55 mmol) was added under ice bath conditions. The reaction was slowly brought to room temperature and carried out for 2 hours. The reaction was quenched with saturated NH4Cl (30 mL), followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give a yellow oily product (580 mg, 100% yield). LC-MS [M-100] + =86.3

[0847] Step 2: UBI-1277c(V1782-096)

[0848] UBI-1277b (580 mg, 2.7 mmol), UBI-1237 (500 mg, 1.35 mmol), Pd(PPh3)2Cl2 (95 mg, 0.135 mmol), CuI (51 mg, 0.27 mmol), and TEA (136 mg, 1.35 mmol) were dissolved in anhydrous DMF (12 mL). The mixture was heated to 80 °C and reacted under N2 protection for 1.5 hours. After cooling to room temperature, the crude product was evaporated to dryness and subjected to column chromatography (petroleum ether / ethyl acetate = 0%–100%) to give a brown oily product, UBI-1277c (500 mg). LC-MS [M+H] + =428.2

[0849] Step 3: UBI-1277d (V1782-121)

[0850] UBI-1277c (400 mg, 0.94 mmol) was dissolved in DCM (5 mL), and 4 M HCl / dioxane (5 mL) was added. The mixture was reacted overnight at room temperature. The solvent was evaporated to dryness, and the crude product was mixed with diethyl ether and slurryed. The mixture was filtered, and the solid was dried to give a brown solid product, UBI-1277d (340 mg). LC-MS [M+H] + =328.4

[0851] Step 4: UBI-1277e (V1782-127)

[0852] UBI-1277d (300 mg, 0.82 mmol) was dissolved in methanol (20 mL), and UBI-1301 (600 mg, 2.47 mmol) and NaOAc (130 mg, 1.64 mmol) were added. The reaction proceeded for 1 hour. Then, NaBH3CN (77 mg, 1.23 mmol) was added, and the reaction proceeded for another hour. The reaction was quenched with saturated brine, and the organic phase was extracted with dichloromethane, dried, and filtered. The filtrate was used directly in the next step. LC-MS [M+H] + =524.2.

[0853] Step 5: UBI-1277f(V1782-130)

[0854] UBI-1277e (500 mg, crude) was dissolved in THF (5 mL) and Boc₂O (1 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was evaporated to dryness and passed through a column chromatography (dichloromethane / methanol = 0%–10%) to give a colorless oily product UBI-1277f (100 mg). LC-MS [MS+H] + =624.3

[0855] Step 6: UBI-1277 (V1782-131)

[0856] UBI-1277f (100 mg, 0.16 mmol) was dissolved in THF (5 mL) and added to triphenylphosphine resin (200 mg). The mixture was reacted at 40 °C for 48 hours. After filtration and rotary evaporation, a yellow solid product, UBI-1277f (40 mg, yield 42%), was obtained. LCMS [M+H] + =598.4.

[0857] Example 1.3.19 Synthesis of compound UBI-1290 (P1-10h)

[0858]

[0859] Step 1: UBI-1290a(V2111-014)

[0860] UBI-1279d (200 mg, 0.38 mmol) was dissolved in methanol (3 mL). UBI-1295 (72 mg, 0.57 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 1 hour. Then, NaBH3CN (48 mg, 0.76 mmol) was added, and the reaction was carried out for 10 minutes. Water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was used directly in the next reaction step.

[0861] Step 2: UBI-1290 (V2111-015)

[0862] UBI-1290a was dissolved in THF (3 mL), and Boc₂O (0.5 mL) and saturated NaHCO₃ (0.5 mL) were added. The mixture was reacted at room temperature for 1 hour. Water (5 mL) was added, and the mixture was extracted with DCM (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The crude product was passed through a column (dichloromethane / methanol = 0%–10%) to give a yellow oily UBI-1290 (120 mg). LCMS [M+H] + =692.3

[0863] Synthetic method of compound UBI-1291 (P1-2h)

[0864]

[0865] Step 1: UBI-1291 (V2111-049)

[0866] P1 (37 mg, 0.35 mmol), UBI-1291a (100 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol), and DIPEA (89 mg, 0.69 mmol) were dissolved in DMF (3 mL) and reacted at room temperature for 3 hours. The reaction solution was filtered, evaporated to dryness, and column chromatography (dichloromethane / methanol = 0%–10%) to give a yellow solid UBI-1291 (130 mg, 100% yield). LCMS [M+H] + =477.4

[0867] 1 H NMR(400MHz,DMSO-d6)δ8.52(t,J=5.8Hz,1H),8.43(d,J=8.3Hz,1H),7.85(s,1H),7 .62(s,1H),7.48(d,J=8.0Hz,2H),4.42–4.31(m,1H),4.24(m,1H),3.94(s,3H),3.6 2(m,2H),3.41–3.35(m,2H),3.25(s,3H),3.14(m,2H),2.85(m,1H),2.42(m,2H),2. 04(m,1H),1.89(m,2H),1.84–1.73(m,4H),1.65–1.59(m,2H),0.76(t,J=7.5Hz,3H).

[0868] Synthetic method of compound UBI-1292 (NH2-13h-A1)

[0869]

[0870] Step 1: UBI-1292c (V2111-035)

[0871] UBI-1292b (2.7 g, 16.7 mmol), UBI-1292a (37 g, 83.6 mmol), Bu4NHSO4 (12.4 g, 36.6 mmol), and 60% KOH (30 mL) were reacted overnight at 40 °C. Water was added, and the mixture was extracted with DCM (50 mL * 3). The organic phase was concentrated and evaporated to dryness. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 0%–100%) to give a colorless, oily product, UBI-1292c (2 g, yield 27%). LCMS [M-100] + =332.3

[0872] Step 2: UBI-1292d(V2111-034)

[0873] UBI-1292c (700 mg, 1.6 mmol) was dissolved in anhydrous DMF (10 mL), and NaN3 (320 mg, 4.8 mmol) was added. The mixture was reacted at 80 °C for 5 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was concentrated, evaporated to dryness, and column chromatography (petroleum ether / ethyl acetate = 0%–100%) to give a colorless oily product UBI-1292d (430 mg, yield 89%). LCMS [M-100] + =203.2

[0874] Step 3: UBI-1292e (V2111-036)

[0875] UBI-1292d (430 mg, 1.42 mmol) was dissolved in dichloromethane (3 mL), and HCl / dioxane (7 mL, 28 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to give a yellow oily product, UBI-1292e (300 mg). LCMS [M+H] + =203.3

[0876] Step 4: UBI-1292g (V2111-037)

[0877] UBI-1292e (340 mg, 1.42 mmol) was dissolved in acetonitrile (7 mL), and UBI-1292f (318 mg, 1.42 mmol) and K₂CO₃ (390 mg, 2.84 mmol) were added. The reaction mixture was reacted at 70 °C overnight. After cooling, the mixture was filtered, and the filtrate was used directly for the next step. LCMS [M+H] + =255.4

[0878] Step 5: UBI-1292h (V2111-039)

[0879] UBI-1292 g was dissolved in THF (6 mL), and Boc₂O (0.5 mL) and NaHCO₃ (300 mg) were added. The mixture was reacted at room temperature for 1 hour. Water (5 mL) was added, and the mixture was concentrated with dichloromethane (15 mL) to an organic phase. The solution was dried, filtered, evaporated to dryness, and column chromatography (petroleum ether / ethyl acetate = 0%–100%) to give a yellow oily product, UBI-1292 h (200 mg). LCMS [M-100] + =255.4

[0880] Step 6: UBI-1292i (V2111-045)

[0881] UBI-1292h (130 mg, 0.36 mmol), UBI-1237 (120 mg, 0.32 mmol), Pd(PPh3)2Cl2 (60 mg, 0.085 mmol), CuI (40 mg, 0.21 mmol), and TEA (3 drops) were dissolved in anhydrous DMF (5 mL) and reacted at 40 °C for 1 hour under N2 protection. The reaction mixture was evaporated to dryness and passed through a column (dichloromethane / methanol = 0%–10%) to give a yellow oily product UBI-1292i (200 mg mixture).

[0882] Step 7: UBI-1292 (V2111-047)

[0883] UBI-1292i (15 mg crude) was dissolved in THF (2 mL), and 1 M Me3P (1 mL) was added. The mixture was reacted at room temperature for 1 hour. Water (0.5 mL) was added, and the reaction was continued for another hour. The reaction solution was concentrated and then subjected to reverse-phase chromatography (acetonitrile / water = 0%–100%) to give a red solid (V2111-047, 20 mg). LCMS [M+H] + =571.5

[0884] 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=7.6Hz,1H),7.63(d,J=7.5Hz,1H),7.53(t,J=7.5Hz,1H),5.16(m,1H),4.45(m,1H),4.30(m,1H),3.62(m,1H) ,3.56–3.37(m,10H),2.99–2.90(m,1H),2.69(m,2H),2.60(m,2H),2.44 (m,2H),2.02(m,1H),1.90(m,2H),1.43–1.35(m,9H),1.09–0.96(m,6H).

[0885] Example 1.3.20 Synthesis of compound UBI-1293 (P1-13h)

[0886]

[0887] Step 1: UBI-1293b (V2111-063)

[0888] UBI-1293a (1.5 g, 6.83 mmol) and TEA (1.5 mL, 10.8 mmol) were dissolved in anhydrous dichloromethane (15 mL). MsCl (1.5 mL, 18.9 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness to give a yellow oily product, UBI-1293b (1.78 g, 87% yield), which was used directly in the next reaction. LCMS [M-100] + =198.2

[0889] Step 2: UBI-1293c (V2111-063)

[0890] UBI-1293b (1.78 g, 6 mmol) was dissolved in acetonitrile (50 mL), and UBI-1238 (1.07 g, 6.6 mmol) and K₂CO₃ (1.65 g, 12 mmol) were added. The mixture was reacted overnight at 80 °C. The reaction solution was filtered, concentrated, and column chromatography (acetonitrile / water = 0%–30%) to give a yellow oily product, UBI-1293c (400 mg, yield 20%). LCMS [M+H] + =328

[0891] Step 3: UBI-1293d(V2111-064)

[0892] UBI-1293c (0.4 g, 1.2 mmol) was added to 4 M HCl / dioxane (4 mL, 20 mmol) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give a yellow oily product UBI-1293d (0.3 g, 100% yield). LCMS [M+H] + =228

[0893] Step 4: UBI-1293e (V2111-069)

[0894] UBI-1293d (724 mg, 2.75 mmol) was dissolved in acetonitrile (70 mL), and UBI-1292f (616 mg, 2.75 mmol), K₂CO₃ (760 mg, 5.5 mmol), and KI (228 mg, 1.37 mmol) were added. The mixture was reacted overnight at 80 °C. The reaction solution was cooled and filtered. The filtrate was used directly for the next reaction. LCMS [M+H] + =280.2

[0895] Step 5: UBI-1293f(V2111-070)

[0896] UBI-1293e was dissolved in THF (6 mL), and Boc₂O (2 mL, 8.25 mmol) and NaHCO₃ (700 mg, 8.25 mmol) were added. The mixture was reacted at room temperature for 1 hour. Water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and column filtered (dichloromethane / methanol = 0%–100%) to give a colorless oily product, UBI-1293f (350 mg mixture). LCMS [M+H] + =380.2

[0897] Step 6: UBI-1293g (V2111-073)

[0898] UBI-1293f (350 mg, 0.46 mmol) was dissolved in THF (2 mL), and 1 M Me3P (3 mL, 3 mmol) was added. The mixture was reacted at 50 °C for 1 hour. Water (0.5 mL) was added, and the mixture was reacted again at 50 °C for 1 hour. The concentrated reaction mixture was used directly for the next reaction. LCMS [M+H] + =354.3

[0899] Step 7: UBI-1293 (V2111-072)

[0900] UBI-1293 g (60 mg, 0.17 mmol), P1 (50 mg, 0.11 mmol), HATU (130 mg, 0.34 mmol), and DIPEA (66 mg, 0.51 mmol) were dissolved in DMF (1 mL) and reacted at room temperature for 3 hours. Water was added, followed by extraction with ethyl acetate (10 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by rotary evaporation using a liquid chromatography-tandem chromatography (dichloromethane / methanol = 0%–10%) to give a white solid product UBI-1293 (25 mg, 20% yield). LCMS [M+H] + =761.5

[0901] 1H NMR (400MHz, DMSO-d6) δ8.43(d,J=8.3Hz,1H),8.30(s,1H),7.85(s,1H),7.62(s,1H),7.49(d, J=11.2Hz,2H),4.35(m,1H),4.24(m,1H),4.05(d,J=7.1Hz,1H),3.94(s,3H),3.71(m,2H),3.5 5(m,2H),3.44(m,3H),3.29(m,2H),3.27(m,2H),3.25(s,3H),3.17–3.07(m,2H),2.85(m,1H), 2.37(m,2H),2.02(m,3H),1.93–1.71(m,10H),1.65(m,4H),1.40(s,9H),0.77(t,J=7.4Hz,3H).

[0902] Example 1.3.21 Synthesis of compound UBI-1294 (P1-14h)

[0903]

[0904] Step 1: UBI-1294b (V2111-077)

[0905] UBI-1293d (443 mg, 1.68 mmol) was dissolved in acetonitrile (70 mL), and then UBI-1294a (272 mg, 1.68 mmol) and K₂CO₃ (464 mg, 3.36 mmol) were added. The mixture was reacted overnight at 80 °C. After cooling, the mixture was filtered, and the filtrate was used directly for the next reaction. LCMS [M+H] + =294.3

[0906] Step 2: UBI-1294c (V2111-079)

[0907] UBI-1294b was dissolved in THF (6 mL), and Boc₂O (2 mL, 9.17 mmol) and saturated NaHCO₃ (2 mL) were added. The mixture was reacted overnight at room temperature. Water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography (dichloromethane / methanol = 0%–100%) to give a yellow oily product, UBI-1294c (400 mg mixture). LCMS [M+H] + =394.2

[0908] Step 3: UBI-1294e (V2111-081)

[0909] UBI-1294d (400 mg, 1 mmol) was dissolved in THF (2 mL), and 1 M Me3P (1.5 mL, 1.5 mmol) was added. The mixture was reacted at 50 °C for 1 hour. Water (0.5 mL) was added, and the mixture was reacted again at 50 °C for 1 hour. The solvent was concentrated and evaporated to dryness for use in the next step. LCMS [M+H] + =368

[0910] Step 4: UBI-1294 (V2111-083)

[0911] UBI-1294d (360 mg, 1 mmol), P1 (300 mg, 0.7 mmol), HATU (760 mg, 2 mmol), and DIPEA (390 mg, 3 mmol) were dissolved in DMF (5 mL) and reacted overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, concentrated, and column-secred (dichloromethane / methanol = 0%–10%) to give a white solid product, UBI-1294 (230 mg, 30% yield). LCMS [M+H] + =775.3 1 H NMR (400MHz, DMSO-d6) δ8.42(d,J=8.2Hz,1H),8.29(d,J=7.3Hz,1H),7.84(s,1H),7.63(m,1 H),7.53–7.45(m,2H),4.42–4.32(m,1H),4.31–4.23(m,1H),3.95(m,4H),3.70(m,3H),3.55 (m,2H),3.45(m,3H),3.25(s,3H),3.20(m,5H),2.81(m,1H),2.16–2.12(m,2H),2.10–1.98( m,4H),1.88(m,2H),1.76(m,8H),1.63(m,5H),1.40(d,J=1.6Hz,9H),0.77(t,J=7.4Hz,3H).

[0912] Example 1.3.22 Synthesis method of compound UBI-1260 (P1-11h):

[0913]

[0914] Step 1: UBI-1260a(V1685-067)

[0915] UBI-1143c (40 g, 247 mmol) and K₂CO₃ (68.2 g, 494 mmol) were dissolved in acetonitrile, and bromoethanol (21 g, 494 mmol) was added. The mixture was reacted at 80°C for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography (dichloromethane / methanol = 50 / 1) to give the colorless, transparent oily target product UBI-1260a (23 g, yield 27.3%).

[0916] 1 ¹H NMR (400MHz, chloroform-d) δ 3.65–3.56 (m, 2H), 3.49–3.40 (m, 1H), 2.84–2.78 (m, 2H), 2.53 (t, 2H), 2.32–2.21 (m, 2H), 1.98–1.88 (m, 2H), 1.74–1.62 (m, 2H)

[0917] Step 2: UBI-1260c (V1685-068)

[0918] UBI-1260a (15 g, 88 mmol) was dissolved in THF (300 mL) and cooled to 0 °C. NaH (4.2 g, 105.6 mmol) was added. The reaction was carried out at 50 °C for 1 hour. Then, UBI-1260b (22.5 g, 114 mmol) was added, and the reaction was carried out at 70 °C for 16 hours. The reaction solution was cooled, and HCl (2 M) was added until pH = 8. The crude product was concentrated by rotary evaporation under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the colorless, transparent oily target product UBI-1260c (11 g, yield 44%).

[0919] 1 H NMR (400MHz, chloroform-d) δ4.63(t,J=5.3Hz,1H),3.79–3.52(m,6H),3.50(d,J=5.3Hz,2H),3.39(q,J=5.1,4.5Hz,1H),2.82(dd,J=11.2,5. 6Hz,2H),2.58(t,J=5.8Hz,2H),2.23(t,J=10.0Hz,2H),1.97–1.85(m,2H),1.68(dtd,J=13.2,9.6,3.7Hz,2H),1.22(t,J=7.1Hz,6H).

[0920] Step 3: UBI-1260d (V1685-082)

[0921] UBI-1260c (1 g, 3.5 mmol) was dissolved in methanol (20 mL) and reacted at room temperature under N2 protection for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product, which was used directly in the next step. LC-MS: [M+H] + =261.2

[0922] Step 4: UBI-1260d (V1685-094)

[0923] UBI-1260d (1 g, 3.8 mmol), P1 (1.6 g, 3.8 mmol), and HATU (2.9 g, 7.7 mmol) were dissolved in DIPEA (1.4 mL, 7.7 mmol) and DMF (10 mL), and reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was separated by reverse-phase column chromatography (water / methanol = 5% / 95% for 45 min). A white solid UBI-1260d (1.5 g, 60% yield) was given. LC-MS: [M+H] + =:668.2

[0924] Step 5: UBI-1260f(V1685-095)

[0925] UBI-1260d (1.5 g, 2.25 mmol) was reacted with hydrochloric acid (3 mL) and water (12 mL) at room temperature for 16 hours. After the reaction was complete, a saturated NaHCO3 aqueous solution was added to adjust the pH to 7. Extraction was performed with dichloromethane (5 mL x 3). The organic phase was dried over Na2SO4 and concentrated to obtain the crude product UBI-1260f (1 g, yield 76.9%). This was used directly in the next step. LC-MS: [M+H] + =:594.2

[0926] Step 6: UBI-1260g (V1685-096)

[0927] Proprynne (24 mg, 0.26 mmol) was dissolved in MeOH (10 mL), and UBI-1260f (300 mg, 0.51 mmol) and one drop of acetic acid were added. The reaction was carried out at room temperature for 1 hour. Then, NaBH3CN (36 mg, 0.51 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with saturated NaHCO3 aqueous solution and concentrated to obtain the crude product. The crude product was dissolved in THF, filtered, and the filtrate was used directly for the next step. LC-MS: [M+H] + =633.2.

[0928] Step 7: UBI-1260 (V1685-098)

[0929] UBI-1260 g (200 mg, 0.31 mmol), (Boc)₂O (200 mg, 0.93 mmol), and NaHCO₃ (78 mg, 0.93 mmol) were dissolved in THF and reacted at room temperature for 1 hour. The reaction solution was concentrated and separated by Pre-TLC (dichloromethane / methanol = 10 / 1). A white solid, UBI-1260 (40 mg, yield 17.6%), was given. LC-MS: [M+H] + =733.4

[0930] Example 1.3.23 Synthesis method of compound UBI-1261 (P1-12h):

[0931]

[0932] Step 1: UBI-1261b (V1685-097)

[0933] Butyryl-3-yn-1-amine (34 mg, 0.26 mmol) was dissolved in methanol (10 mL), and UBI-1260f (300 mg, 0.51 mmol) and one drop of acetic acid were added. The reaction was carried out at room temperature for 1 hour. Then, NaBH3CN (36 mg, 0.51 mmol) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with saturated NaHCO3 aqueous solution and concentrated to obtain the crude product. The crude product was dissolved in THF, filtered, and the filtrate was used directly for the next step. LC-MS: [M+H] + =647.2

[0934] Step 2: UBI-1261 (V1685-099)

[0935] UBI-1261b (200 mg, 0.31 mmol), (Boc)₂O (200 mg, 0.93 mmol), and NaHCO₃ (78 mg, 0.93 mmol) were dissolved in THF and reacted at room temperature for 1 hour. The reaction solution was concentrated and separated by Pre-TLC (dichloromethane / methanol = 10 / 1). A white solid, UBI-1260 (40 mg, yield 17.6%), was given. LC-MS: [M+H] + =747.4

[0936] Example 1.3.24 Synthesis method of compound UBI-1262 (P1-9h):

[0937]

[0938] Step 1: UBI-1262a(V1685-111)

[0939] UBI-1285g (1.38g, 6.45mmol) and K2CO3 (890mg, 6.45mmol) were dissolved in acetonitrile (100mL), and 4-bromobutyne (681mg, 5.16mmol) was added. The mixture was reacted at 70℃ for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the target product UBI-1262a (370mg, yield 28.4%) as a yellow, transparent oil. LC-MS: [M+H] + =267.2.

[0940] Step 2: UBI-1262b (V1685-112)

[0941] UBI-1262a (370 mg, 1.4 mmol), (Boc)₂O (606 mg, 2.8 mmol), and NaHCO₃ (176 mg, 2.1 mmol) were dissolved in THF (10 mL) and reacted at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (10 mL * 3). The organic phase was dried over Na₂SO₄.

[0942] The crude product was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 100%) to give the target product UBI-1262b (337 mg, yield 65.8%) as a white solid.

[0943] 1 ¹H NMR (400MHz, chloroform-d) δ 3.67–3.29 (m, 10H), 2.43 (dt, J = 8.5, 4.1 Hz, 2H), 1.98 (t, J = 2.7 Hz, 1H), 1.84 (s, 2H), 1.46 (s, 9H).

[0944] Step 3: UBI-1262c (V1685-113)

[0945] UBI-1262b (337 mg, 0.92 mmol) was dissolved in H₂O (1 mL) and THF (10 mL), and then NaOH (73 mg, 1.8 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction solution was concentrated to obtain a crude product, which was used directly in the next step. LC-MS: [M+H] + =267.2.

[0946] Step 4: UBI-1262 (V1685-114)

[0947] UBI-1262c (400 mg, 1.48 mmol), P1 (630 mg, 1.48 mmol), and HATU (1.1 g, 2.96 mmol) were dissolved in DIPEA (545 μL, 2.96 mmol) and DMF (10 mL). The reaction was carried out at room temperature for 2 hours. After the reaction was complete, the reaction solution was separated by reversed-phase column chromatography (water / methanol = 5% / 95% for 45 min). A white solid UBI-1262 (100 mg, 10% yield) was obtained.

[0948] 1H NMR (400MHz, DMSO-d6) δ8.41 (d, J = 8.4Hz, 1H), 8.36–8.32 (m, 1H), 7.84 (s, 1H), 7.60 (s, 1H), 7. 48(d,J=7.8Hz,2H),4.45–4.29(m,1H),4.24(dd,J=7.6,3.6Hz,1H),3.94(s,3H),3.45(t,J=5.8 Hz,4H),3.38–3.27(m,6H),3.25(s,4H),2.82(d,J=3.5Hz,1H),2.37(d,J=7.6Hz,3H),2.06–1. 98(m,1H),1.95–1.72(m,8H),1.63(dd,J=14.2,7.1Hz,3H),1.39(s,9H),0.76(t,J=7.4Hz,3H).

[0949] Example 1.3.25 Synthesis of compound UBI-1263 (P1-13h):

[0950]

[0951] Step 1: UBI-1263b (V1685-121)

[0952] UBI-1263b (5 g, 71.4 mmol) was dissolved in DMF (200 mL) and cooled to 0 °C. NaH (3.4 g, 85.7 mmol) was added. The reaction was carried out at 0 °C for 1 hour. UBI-1263a (21.6 g, 85.7 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 16 hours. Saturated NH4Cl aqueous solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phase was dried over Na2SO4, concentrated to obtain a crude product, and separated by silica gel column chromatography (petroleum ether / dichloromethane = 3 / 1) to obtain a colored oily product UBI-1263b (5 g, yield 29%).

[0953] 1¹H NMR (400MHz, chloroform-d) δ 3.65 (t, J = 6.1 Hz, 2H), 3.50 (td, J = 6.6, 3.4 Hz, 4H), 2.41 (t, J = 7.0, 2.7 Hz, 2H), 1.92 (t, J = 2.7 Hz, 1H), 1.73 (p, J = 6.2 Hz, 2H), 0.84 (s, 9H), 0.00 (s, 6H).

[0954] Step 2: UBI-1263c (V1685-123)

[0955] UBI-1263b (3g, 12.4mmol) was dissolved in THF (100mL) and TBAF (4.85g, 18.6mmol) was added. The reaction mixture was reacted at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50mL x 3). The organic phase was dried over Na₂SO₄, concentrated to obtain a crude product, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give a colored oily substance, UBI-1263c (1.3g, yield 82.2%).

[0956] 1 ¹H NMR (400MHz, chloroform-d) δ 3.82–3.75 (m, 2H), 3.67 (t, J = 5.8 Hz, 2H), 3.58 (t, J = 6.7 Hz, 2H), 2.47 (td, J = 6.7, 2.7 Hz, 2H), 2.34 (s, 1H), 2.00 (t, J = 2.6 Hz, 1H), 1.85 (p, J = 5.7 Hz, 2H).

[0957] Step 3: UBI-1263d (V1685-129)

[0958] UBI-1263c (128 mg, 1 mmol) was dissolved in DCM (10 mL), followed by the addition of TEA (88 μL, 2 mmol) and MsCl (155 μL, 2 mmol). The reaction mixture was allowed to react at room temperature for 16 hours. Water was then added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was dried over Na₂SO₄ and concentrated to obtain a crude product, which was used directly in the next step.

[0959] Step 4: UBI-1263f (V1685-130)

[0960] UBI-1263e (213 mg, 0.388 mmol), UBI-1263d (214 mg, 0.388 mmol), and K₂CO₃ (160 mg, 1.16 mmol) were dissolved in DMF (10 mL) and reacted at 70 °C for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL * 3). The organic phase was dried over Na₂SO₄, concentrated to obtain the crude product, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1). The silica gel column was then washed with MeOH / NH₃·H₂O = 1 / 1 to obtain the crude product UBI-1263f (200 mg, yield 78.1%). LC-MS: [M+H] + =661.2

[0961] Step 5: UBI-1263 (V1685-131)

[0962] UBI-1263f (200 mg, 0.3 mmol), (Boc)₂O (327 mg, 1.5 mmol), and NaHCO₃ (80 mg, 0.9 mmol) were dissolved in THF. The reaction mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried over Na₂SO₄, concentrated to obtain a crude product, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1–100%) to give the white solid target product UBI-1263 (80 mg, yield 34.7%). LC-MS: [M+H] + =761.5

[0963] Example 1.3.26 Synthesis of compound UBI-1264 (P1-14h):

[0964]

[0965] Step 1: UBI-1264a (V1899-108)

[0966] P1 (1.43 g, 8.22 mmol), N-tert-butoxycarbonyl-1,3-propanediamine (3.5 g, 8.22 mmol), and HATU (4.7 g, 16.44 mmol) were dissolved in DIPEA (3.2 g, 24.66 mmol) and DMF (40 mL). The reaction was carried out at room temperature for 18 hours. The reaction solution was added to 100 mL of water, and a solid appeared. The solid was filtered to give the yellow target compound UBI-1264a (3.5 g, 73% yield).

[0967] 1H NMR (400MHz, DMSO-d6) δ8.43(d,J=8.3Hz,1H),8.31(t,J=5.8Hz,1H),7.85(s,1H),7.61(s,1H),7.5 1–7.43(m,2H),6.82(t,J=5.8Hz,1H),4.35(t,J=8.2Hz,1H),4.24(dd,J=7.6,3.6Hz,1H),3.94(s,3 H),3.33(s,1H),3.25(s,4H),2.98(q,J=6.6Hz,2H),2.06–1.97(m,1H),1.90(td,J=7.9,2.5Hz,2H) ,1.78(qd,J=6.8,4.3,3.5Hz,4H),1.68–1.55(m,5H),1.38(s,9H),0.76(t,J=7.4Hz,3H).LCMS[M+H] + =582

[0968] Step 2: UBI-1264b (V1899-110)

[0969] UBI-1264a (300 mg, 0.52 mmol) was cooled to 0°C, and then 4M HCl / dioxane (0.6 mL) was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction solution was concentrated to give a yellow oily substance, UBI-1264b (200 mg, 85% yield). LCMS [M+H] + =482

[0970] Step 3: UBI-1264c (V1685-134)

[0971] UBI-1264b (600 mg, 1 mmol), UBI-1263d (206 mg, 1 mmol), and K₂CO₃ (414 mg, 3 mmol) were dissolved in DMF and reacted at 70 °C for 16 hours. After the reaction was complete, the reaction solution was directly separated by reversed-phase column chromatography (water / methanol = 5% / 95% for 45 minutes). A white solid crude product, UBI-1264c (200 mg, yield 29.6%), was obtained. LC-MS: [M+H] + =675.5

[0972] Step 2: UBI-1264 (V1685-135)

[0973] UBI-1264c (200 mg, 0.3 mmol), (Boc)₂O (327 mg, 1.5 mmol), and NaHCO₃ (80 mg, 0.9 mmol) solution in THF were reacted at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was dried over Na₂SO₄, concentrated to obtain the crude product, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1–100%) to give the white solid target product UBI-1264 (80 mg, yield 34.5%). LC-MS: [M+H] + =774.5

[0974] Example 1.3.27 Synthesis of compound UBI-1265 (P1-10h):

[0975]

[0976] Step 1: UBI-1265a (V1685-144)

[0977] UBI-1264b (200 mg, 0.41 mmol), UBI-1263d (85 mg, 0.41 mmol), and K₂CO₃ (113 mg, 0.82 mmol) were dissolved in DMF and reacted at 70 °C for 16 hours. The reaction solution was then separated by direct reverse-phase column chromatography (water / methanol = 5% / 95% for 45 min). A white solid crude product, UBI-1265a (200 mg, yield 82.6%), was given. LC-MS: [M+H] + =592.2

[0978] Step 2: UBI-1265 (V1685-148)

[0979] UBI-1265a (200 mg, 0.3 mmol), (Boc)₂O (327 mg, 1.5 mmol), and NaHCO₃ (80 mg, 0.9 mmol) were dissolved in THF and reacted at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phase was dried over Na₂SO₄, concentrated to obtain a crude product, and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1–100%) to give the white solid target product UBI-1265 (90 mg, yield 34.5%). LC-MS: [M+H] + =692.5

[0980] Example 1.3.28 Synthesis of compound UBI-1258 (P1-14h)

[0981]

[0982] Step 1: UBI-1258b (V2126-010)

[0983] Compound UBI-1258a (0.5 g, 2.28 mmol) and compound TEA (0.7 g, 6.84 mmol) were dissolved in DCM (20 mL). MsCl (0.4 g, 3.42 mmol) was added dropwise to the reaction solution at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction solution was washed with water, the organic phase was dried, and evaporated to dryness to give a colorless oily crude product UBI-1097c (670 mg, 100% yield). LCMS [M+H] + =298.2

[0984] Step 2: UBI-1258c (V2126-011)

[0985] Compounds UBI-1258b (670 mg, 2.28 mmol), UBI-1238 (400 mg, 2.46 mmol), K₂CO₃ (690 mg, 5 mmol), and KI (40 mg, 0.23 mmol) were dissolved in CH₃CN (20 mL) and reacted at 90 °C for 16 hours. The reaction mixture was washed with water (50 mL) and extracted with dichloromethane (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure by rotary evaporation to obtain the crude product. The crude product was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the white solid target product UBI-1258c (600 mg, yield 80%). LCMS [M+H] + =328.3

[0986] Step 3: UBI-1258d (V2126-012)

[0987] Compound UBI-1258c (600 mg, 1.83 mmol) was dissolved in 4N HCl / dioxane (10 mL), and then reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the target product UBI-1258d (500 mg, 90% yield) as a white solid. LCMS [M+H] + =228.3

[0988] Step 4: UBI-1258f(V2126-017)

[0989] Compounds UBI-1258d (400 mg, 1.33 mmol), UBI-1258e (215 mg, 1.33 mmol), K₂CO₃ (550 mg, 4 mmol), and KI (25 mg, 0.13 mmol) were dissolved in CH₃CN (20 mL) and reacted at 90 °C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was separated by reversed-phase C18 column chromatography and lyophilized to obtain the colorless oily target product UBI-1258f (350 mg, yield 90%, purity 50%). LCMS [M+H] + =294.2

[0990] Step 5: UBI-1258g (V2126-022)

[0991] Compound UBI-1258f (350 mg, 1.2 mmol), compound di-tert-butyl carbonate (392 mg, 1.8 mmol), and NaHCO3 (300 mg, 3.6 mmol) were dissolved in THF (10 mL), and the mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product, which was then separated by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to give a white solid UBI-1258 g (200 mg, yield 42%). LCMS [M+H] + =394.3

[0992] Step 6: UBI-1258h (V2126-024)

[0993] Compound UBI-1258 g (200 mg, 0.51 mL) was dissolved in 1 mL (1 mmol) of a tetrahydrofuran solution of 1N trimethylphosphine in CH3CN (10 mL), and the reaction was carried out at room temperature for 1 hour. Water (1 mL) was added to the reaction solution, and the reaction was carried out at 40 °C for 2 hours. The reaction solution was concentrated by rotary evaporation under reduced pressure to give the white solid target product UBI-1258 h (180 mg, 100% yield). LCMS [M+H] + =368.3

[0994] Step 7: UBI-1258 (V2126-025)

[0995] Compound UBI-1258h (180 mg, 0.5 mmol), compound P1 (210 mg, 0.50 mmol), HATU (230 mg, 0.6 mmol), and diisopropylethylamine (190 mg, 1.5 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated by rotary evaporation under reduced pressure to obtain a crude product, which was diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane:methanol = 0:1) to give a white solid UBI-1258 (300 mg, yield 78%). LCMS [M+H] + =775.5

[0996] Example 1.3.29 Synthesis of compound UBI-1257 (P1-12h)

[0997]

[0998] Step 1: UBI-1257b (V2126-015)

[0999] Compound UBI-1257a (4 g, 21 mmol) and triethylamine (6.4 g, 63 mmol) were dissolved in dichloromethane (200 mL). Methylsulfonyl chloride (3.6 g, 31.5 mmol) was added dropwise to the reaction solution at 0 °C, and the reaction was carried out at room temperature for 1 hour. The reaction solution was washed with water, the organic phase was dried over anhydrous sodium sulfate, and concentrated by rotary evaporation under reduced pressure to give a colorless oily crude product UBI-1257b (5.6 g, 100% yield). LCMS [M+H] + =268.2

[1000] Step 2: UBI-1257c (V2126-016)

[1001] Compounds UBI-1257b (5.6 g, 21 mmol), UBI-1238 (3.4 g, 21 mmol), K₂CO₃ (5.8 g, 42 mmol), and KI (400 mg, 2.1 mmol) were dissolved in CH₃CN (200 mL) and reacted at 90 °C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product, which was then separated by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the white solid target product UBI-1257c (4.5 g, yield 72%). LCMS [M+H] + =298.3

[1002] Step 3: UBI-1257d (V2126-020)

[1003] Compound UBI-1257c (1.5 g, 5 mmol) was dissolved in 4N HCl / dioxane (30 mL), and then reacted at room temperature for 1 hour. The reaction solution was concentrated by rotary evaporation under reduced pressure to give crude UBI-1257d (1.3 g, 95% yield). LCMS [M+H] + =198.3

[1004] Step 4: UBI-1257f(V2126-023)

[1005] Compounds UBI-1257d (800 mg, 2.96 mmol), UBI-1257e (480 mg, 2.96 mmol), K₂CO₃ (1.25 g, 8.88 mmol), and KI (60 mg, 0.3 mmol) were dissolved in CH₃CN (30 mL) and reacted at 90 °C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then separated by reversed-phase C18 column chromatography and lyophilized to obtain the colorless oily target product UBI-1257f (500 mg, yield 60%, purity 50%). LCMS [M+H] + =264.3

[1006] Step 5: UBI-1257g (V2126-026)

[1007] Compound UBI-1257f (500 mg, 1.9 mmol), compound di-tert-butyl carbonate (620 mg, 2.8 mmol), and NaHCO3 (480 mg, 5.7 mmol) were dissolved in THF (20 mL), and the mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated by rotary evaporation under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to give the white solid target product UBI-1257g (250 mg, 36% yield). LCMS [M+H] + =364.3

[1008] Step 6: UBI-1257h (V2126-028)

[1009] Compound UBI-1257 g (250 mg, 0.69 mL) was dissolved in 1N trimethylphosphine in tetrahydrofuran solution (1.4 mL, 1.4 mmol) in THF (10 mL), and then reacted at room temperature for 1 hour. Water (1 mL) was added to the reaction solution, and the reaction was carried out at 40 °C for 2 hours. The reaction solution was concentrated by rotary evaporation under reduced pressure to give the white solid target product UBI-1257 h (230 mg, 100% yield). LCMS [M+H] + =338.4

[1010] Step 7: UBI-1257 (V2126-029)

[1011] Compound UBI-1257h (230 mg, 0.69 mmol), compound P1 (290 mg, 0.69 mmol), HATU (315 mg, 0.83 mmol), and diisopropylethylamine (270 mg, 2.1 mmol) were dissolved in DMF (5 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated by rotary evaporation under reduced pressure to obtain a crude product, which was diluted with dichloromethane and washed with water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane:methanol = 10:1) to give a white solid UBI-1257 (400 mg, yield 78%). LCMS [M+H] + =745.5

[1012] Example 1.4 Synthesis of Compound Connector b-A1

[1013] Example 1.4.1 Synthesis of compound UBI-1302 (NH2-12e-Al)

[1014]

[1015] Step 1: UBI-1302b (V1895-009)

[1016] Compound UBI-1302a (660 mg, 2.11 mmol) and HCl / dioxane (10 mL, 4 N) were added to tetrahydrofuran (10 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated by rotary evaporation under reduced pressure to obtain compound UBI-1302b (525 mg, 100% yield).

[1017] Step 2: UBI-1302c(V1895-015)

[1018] Compound UBI-1302b (525 mg, 2.11 mmol) and tert-butyl 3-oxozyrazobutane-1-carboxylic acid (361 mg, 2.11 mmol) were added to dichloromethane (10 mL), followed by sodium triacetoxyborohydride (530 mg, 2.51 mmol). After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure by rotary evaporation. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound UBI-1302c (240 mg) as a white solid. Yield: 31%.

[1019] Step 3: UBI-1302d(V1895-017)

[1020] UBI-1302c (240 mg, 0.65 mmol), benzyl chloroformate (144 mg, 0.85 mmol), and sodium bicarbonate (771 mg, 9.18 mmol) were added to tetrahydrofuran (20 mL). After reacting at room temperature for 12 h, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated to give product UBI-1302d (198 mg, yield 77%).

[1021] Step 4: UBI-1302e (V1895-018)

[1022] UBI-1302d (198 mg, 0.39 mmol) and dioxane hydrochloride (10 mL, 4 N) were added to tetrahydrofuran (10 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound UBI-1302e (159 mg, 100% yield).

[1023] Step 5: UBI-1302f(V1895-019)

[1024] UBI-1302e (159 mg, 0.39 mmol), DIEA (50 mg, 0.39 mmol), and 2-(2,6-dioxadiazine-3-yl)-4-fluoroisoindole-1,3-dione (107 mg, 0.39 mmol) were added to DMF (30 mL) and reacted at 80 °C for 18 h. The mixture was then separated by silica gel column chromatography to obtain compound UBI-1302f (80 mg, yield 31%).

[1025] Step 6: UBI-1302 (V1895-020)

[1026] UBI-180857f (41 mg, 0.06 mmol) and 10% palladium on carbon (20 mg) were added to a methanol / dichloromethane (1 mL / 10 mL) mixed solvent and reacted at room temperature under hydrogen atmosphere for 2 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was washed with cold diethyl ether (10 mL * 3) and dried to obtain compound UBI-1302 (19 mg, yield 49%).

[1027] Example 1.4.2 Synthesis of compound UBI-1303 (NH2-12e-Al)

[1028]

[1029] Step 1: UBI-1303b (V1895-025)

[1030] 1-(tert-Butoxycarbonyl)cyclopropanecarboxylic acid (500 mg, 2.49 mmol), lenalidomide (644 mg, 2.49 mmol), HATU (1015 mg, 2.67 mmol), and DIPEA (0.3 mL) were added to DMF (3 mL), stirred at room temperature for 16 h, and purified by reverse-phase column chromatography (MeOH / H2O = 5%–95%, 45 min). The product UBI-1303b (846 mg, 77% yield) was obtained.

[1031] Step 2: UBI-1303c (V1895-028)

[1032] UBI-1303b (846 mg, 1.91 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and then HCl / dioxane (0.5 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to give the crude product target compound UBI-1303c (654 mg, 100% yield) (76 mg, 100% yield).

[1033] Step 3: UBI-1303d (V1895-059)

[1034] Compounds UBI-1303c (305 mg, 1.44 mmol) and UBI-1301 (492 mg, 1.44 mmol) were added to dichloromethane (10 mL), followed by sodium triacetoxyborohydride (530 mg, 2.51 mmol). After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure by rotary evaporation. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound UBI-1303d (240 mg) as a white solid. Yield: 31%.

[1035] Step 4: UBI-1303e (V1895-061)

[1036] UBI-1303d (240 mg, 0.45 mmol) and di-tert-butyl dicarbonate (146 mg, 0.67 mmol) were added to dioxane (30 mL) and reacted at room temperature for 2 h. The mixture was then concentrated and extracted with ethyl acetate (10 mL * 3). The solution was filtered and concentrated to obtain the desired compound UBI-1303e (233 mg, yield 82%).

[1037] Step 5: UBI-1303 (V1895-062)

[1038] UBI-1303e (233 mg, 0.37 mmol) and 10% palladium on carbon (20 mg) were added to a methanol / dichloromethane (1 mL / 10 mL) mixed solvent and reacted at room temperature under hydrogen atmosphere for 2 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was washed with cold diethyl ether (10 mL * 3) and dried to obtain compound UBI-1303 (221 mg, 100% yield).

[1039] LCMS:(M+H) + =613.3

[1040] Example 1.4.3 Synthesis of compound UBI-1304 (NH2-12e-Al)

[1041]

[1042] Step 1: UBI-1304b (V1685-046)

[1043] Lenalidomide (1 g, 3.8 mmol) was dissolved in AcOH (20 mL), and then N-Boc-3-hydroxyazacyclobutane (1.31 g, 7.7 mmol) was added. The reaction mixture was reacted at 80 °C for 1 h. The reaction solution was cooled to 30 °C, and NaBH(OAc)3 was added, followed by reaction at room temperature for 16 h. The reaction solution was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give the target compound UBI-1304b (1.15 g, yield 73.2%) as a white solid. LC-MS: (M+H) + =415.1

[1044] Step 2: UBI-1304c (V1685-047)

[1045] UBI-1304b (100 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and then HCl / dioxane (0.5 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to give the crude product of the target compound (76 mg, 100% yield), which was used directly in the next reaction step.

[1046] Step 3: UBI-1304d(V1895-065)

[1047] UBI-1304c (300 mg, 1.42 mmol) and UBI-1301 (452 ​​mg, 1.44 mmol) were added to dichloromethane (10 mL), followed by sodium triacetoxyborohydride (530 mg, 2.51 mmol). After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure by rotary evaporation. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound UBI-1304d (215 mg) as a white solid. Yield: 30%.

[1048] Step 4: UBI-1304e (V1895-066)

[1049] UBI-1304d (215 mg, 0.42 mmol) and 10% palladium on carbon (20 mg) were added to a methanol / dichloromethane (1 mL / 10 mL) mixed solvent and reacted at room temperature under hydrogen atmosphere for 16 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was washed with cold diethyl ether (10 mL * 3) and dried to obtain compound UBI-1304e (139 mg, yield 71%).

[1050] LCMS:(M+H) + =485.1

[1051] Example 1.4.3 Synthesis of compound UBI-13045 (NH2-12e-Al)

[1052]

[1053] Step 1: UBI-1305b (V1895-026)

[1054] 1-Boc-L-azacyclobutane-2-carboxylic acid (500 mg, 2.49 mmol), lenalidomide (644 mg, 2.49 mmol), HATU (1015 mg, 2.67 mmol), and DIPEA (0.3 mL) were added to DMF (3 mL), stirred at room temperature for 16 h, and purified by reverse-phase column chromatography (MeOH / H2O = 5%–95%, 45 min). The product UBI-1305b (846 mg, 77% yield) was obtained.

[1055] Step 2: UBI-1305c (V1895-027)

[1056] UBI-1303b (846 mg, 1.91 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and then HCl / dioxane (0.5 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to give the crude product target compound UBI-1303c (654 mg, 100% yield) (76 mg, 100% yield).

[1057] Step 3: UBI-1305d (V1895-029)

[1058] Compounds UBI-1305c (352 mg, 1.42 mmol) and UBI-1301 (485 mg, 1.42 mmol) were added to dichloromethane (10 mL), followed by sodium triacetoxyborohydride (530 mg, 2.51 mmol). After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure by rotary evaporation. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound UBI-1305d (229 mg) as a white solid. Yield: 30%.

[1059] Step 4: UBI-1305 (V1895-070)

[1060] UBI-1305d (229 mg, 0.43 mmol) and 10% palladium on carbon (20 mg) were added to a methanol / dichloromethane (1 mL / 10 mL) mixed solvent and reacted at room temperature under hydrogen atmosphere for 16 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was washed with cold diethyl ether (10 mL * 3) and dried to obtain compound UBI-1305 (139 mg, yield 71%).

[1061] LCMS:(M+H) + =513.1

[1062] Example 1.4.4 Synthesis of compound UBI-1306 (NH2-12e-Al)

[1063]

[1064] Step 1: UBI-1306b (V1895-057)

[1065] 1-Boc-R-azacyclobutane-2-carboxylic acid (500 mg, 2.49 mmol), lenalidomide (644 mg, 2.49 mmol), HATU (1015 mg, 2.67 mmol), and DIPEA (0.3 mL) were added to DMF (3 mL), stirred at room temperature for 16 h, and purified by reverse-phase column chromatography (MeOH / H2O = 5%–95%, 45 min). The product UBI-1306b (840 mg, 76% yield) was obtained.

[1066] Step 2: UBI-1306c (V1895-058)

[1067] UBI-1306b (840 mg, 1.91 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and then HCl / dioxane (0.5 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to give the crude product target compound UBI-1306c (650 mg, 100% yield) (76 mg, 100% yield).

[1068] Step 3: UBI-1306d(V1895-072)

[1069] UBI-1301 (352 mg, 1.42 mmol) and UBI-1306c (485 mg, 1.42 mmol) were added to dichloromethane (10 mL), followed by sodium triacetoxyborohydride (530 mg, 2.51 mmol). After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound UBI-1306d (229 mg) as a white solid. Yield: 30%

[1070] Step 4: UBI-1306 (V1895-073)

[1071] UBI-1306d (229 mg, 0.43 mmol) and 10% palladium on carbon (20 mg) were added to a methanol / dichloromethane (1 mL / 10 mL) mixed solvent and reacted at room temperature under hydrogen atmosphere for 16 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was washed with cold diethyl ether (10 mL * 3) and dried to obtain compound UBI-1306 (154 mg, yield 71%).

[1072] LCMS:(M+H) + =513.1

[1073] Example 1.4.5 Synthesis of compound UBI-1307 (NH2-12e-Al)

[1074]

[1075] Step 1: UBI-1307b (V1895-057)

[1076] 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazabutane-3-carboxylic acid (500 mg, 2.49 mmol), lenalidomide (644 mg, 2.49 mmol), HATU (1015 mg, 2.67 mmol), and DIPEA (0.3 mL) were added to DMF (3 mL), stirred at room temperature for 16 h, and purified by reverse-phase column chromatography (MeOH / H2O = 5%–95%, 45 min). The product UBI-1307b (840 mg, 76% yield) was obtained.

[1077] Step 2: UBI-1307c (V1895-061)

[1078] UBI-1307b (840 mg, 1.91 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and then HCl / dioxane (0.5 mL) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to give the crude product, the target compound UBI-1307c (650 mg, 100% yield).

[1079] Step 3: UBI-1307d (V1895-075)

[1080] Compounds UBI-1307c (352 mg, 1.42 mmol) and UBI-1301 (485 mg, 1.42 mmol) were added to dichloromethane (10 mL), followed by sodium triacetoxyborohydride (530 mg, 2.51 mmol). After the reaction was complete, 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure by rotary evaporation. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound UBI-1307d (230 mg) as a white solid. Yield: 30%

[1081] Step 4: UBI-1307 (V1895-076)

[1082] UBI-1307d (229 mg, 0.43 mmol) and 10% palladium on carbon (20 mg) were added to a methanol / dichloromethane (1 mL / 10 mL) mixed solvent and reacted at room temperature under hydrogen atmosphere for 16 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was washed with cold diethyl ether (10 mL * 3) and dried to obtain compound UBI-1307 (154 mg, yield 71%).

[1083] LCMS:(M+H) + =513.1

[1084] Example 1.4.6 Synthesis of compound UBI-1308 (NH2-12e-Al)

[1085]

[1086] Step 1: UBI-1308b (V1895-091)

[1087] UBI-1308a (1.0 g, 4.67 mmol), UBI-1308a-1 (2.6 g, 4.67 mmol), and N,N-diisopropylethylamine (1.8 g, 14.01 mmol) were added to acetonitrile (20 mL) and reacted at 80 °C for 18 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product. Purification was performed by rapid chromatography (DCM / MeOH = 0%–10% for 20 min) to give compound UBI-1308b (1.5 g, 72% yield).

[1088] Step 2: UBI-1308c (V1895-092)

[1089] UBI-1308b (1.1 g, 2.5 mmol) was dissolved in MeOH (500 mL), and magnesium filings (5.6 g, 2.3 mmol) were added. The mixture was reacted overnight at 65 °C. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. This crude product was purified by rapid chromatography (eluting with DCM / MeOH = 0%–10%) to give product UBI-1308c (0.29 g) as a white solid. Yield: 41%.

[1090] Step 3: UBI-180889d(V1895-093)

[1091] UBI-180889c (500 mg, 1.77 mmol) and 4-bromo-1-yne (280 mg, 2.12 mmol) were added to acetonitrile (10 mL), and potassium carbonate (733 mg, 5.31 mmol) was added under N2. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the crude product, which was purified by rapid chromatography (DCM / MeOH = 0%–10%, elution for 20 minutes) to give a white solid UBI-180889d (473 mg, yield 80%).

[1092] Step 4: UBI-1308d (V1895-094)

[1093] Compound UBI-1308c (400 mg, 1.49 mmol) was dissolved in DMF (10 mL), and palladium dichlorodi(triphenylphosphine) (104 mg, 0.149 mmol), cuprous iodide (57 mg, 0.07 mmol), and triethylamine (150 mg, 1.49 mmol) were added. The mixture was reacted overnight at 80 °C under nitrogen. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. This crude product was purified by rapid chromatography (eluting with DCM / MeOH = 0%–20% for 30 min) to give product UBI-1308d (260 mg) as a white solid. Yield: 38%.

[1094] Step 5: UBI-1308e (V1895-095)

[1095] UBI-1308c (900 mg, 3.15 mmol) and dioxane hydrochloride (10 mL, 4 N) were added to tetrahydrofuran (10 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound UBI-1308 (215 mg, 100% yield).

[1096] Example 1.4.7 Synthesis of compound UBI-1309 (NH2-12e-Al)

[1097]

[1098] Step 1: UBI-1309b (V2127-011)

[1099] UBI-1309a (20.7 g, 100 mmol) and triethylamine (17.1 g, 150 mmol) were dissolved in DCM (60 mL), and methanesulfonyl chloride (12.5 g, 110 mmol) was slowly added. After reacting at room temperature for 1 hour, the mixture was extracted with dichloromethane (50 mL × 3), and the combined organic layers were washed with brine (50 mL). The organic phase was dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by rapid chromatography (DCM:MeOH = 10:1) to obtain UBI-1309b (26.5 g, 93% yield), a colorless oil.

[1100] Step 2: UBI-1309c (V2127-013)

[1101] UBI-1309b (285 mg, 1.00 mmol), tert-butylpiperidin-4-ylcarbamate (200 mg, 1.00 mmol), and potassium carbonate (414 mg, 3.00 mmol) were dissolved in DMF (9 mL) and reacted in a microwave oven at 120 °C for 1 hour. The crude product was purified by rapid chromatography (petroleum ether / ethyl acetate = 80%–100%, 20 min; dichloromethane / methanol = 0%–10%, 20 min) to obtain a colorless oily substance UBI-1309c (110 mg, yield 28%).

[1102] Step 3: UBI-1309d(V2127-014)

[1103] UBI-1309c (110 mg, 27.3 mmol) and 10% palladium on carbon (581 mg, 5.46 mmol) were added to methanol (20 mL) and reacted at room temperature in a hydrogen atmosphere for 12 h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to give UBI-1309d (72 mg, 100% yield) as a white solid.

[1104] Step 4: UBI-1309f(V2127-024)

[1105] UBI-1309d (500 mg, 1.35 mmol), 3-butyn-1-ol (94 mg, 1.35 mmol), Pd(PPh3)2Cl2 (94 mg, 0.135 mmol), and cuprous iodide (51 mg, 0.27 mmol) were added to DMF (2 mL) and reacted at 80 °C under N2 protection for 16 hours. The mixture was purified by reversed-phase chromatography (MeOH / H2O = 5% 95% 45 min), and 60% was collected. Compound UBI-1309f (215 mg, 54% yield) was given as a white solid.

[1106] Step 5: UBI-1309g (V2127-026)

[1107] Compound UBI-1309f (312 mg, 1.00 mmol) and triethylamine (171 mg, 1.50 mmol) were added to dichloromethane (60 mL), and methanesulfonyl chloride (125 mg, 1.10 mmol) was slowly added dropwise. After reacting at room temperature for 1 hour, the reaction mixture was extracted with DCM (50 mL × 3), the combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to give compound UBI-1309g (171 mg, 99% yield) as a white solid.

[1108] Step 6: UBI-1309h (V2127-027)

[1109] Compound UBI-1309g (78 mg, 0.20 mmol), N,N-diisopropylethylamine (50 mg, 0.39 mmol), and compound UBI-1309d (51 mg, 0.20 mmol) were added to acetonitrile (30 mL) and reacted at 80 °C for 18 h. The crude product was concentrated and then purified by silica gel chromatography (PE / EtOAc = 70%–100% for 20 min, MeOH / DCM = 0%–10% for 40 min) to obtain compound UBI-1309h (51 mg, yield 46%).

[1110] Step 7: UBI-1309 (V2127-029)

[1111] UBI-1309h (51 mg, 0.09 mmol) and dioxane hydrochloride (10 mL, 4 N) were added to tetrahydrofuran (10 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound UBI-1309 (41 mg, 100% yield).

[1112] Example 1.5 Synthesis of compound P1-connector h-A1

[1113]

[1114] Step 1: UBI-1237 (V1782-042)

[1115] Al (5.2 g, 20 mmol) and NaNO2 (4.15 g, 60 mmol) were added to 200 mL of water. Diluted H2SO4 (20 mL concentrated sulfuric acid plus 50 mL water) was slowly added dropwise over an ice bath, completing the addition over approximately 75 minutes. The mixture was then reacted at room temperature for 30 minutes. Next, 100 mL of an aqueous solution of KI (16.6 g, 100 mmol) was added dropwise over an ice bath, and the reaction was continued at 80 °C for 3 hours, followed by cooling. The filter cake was filtered and washed repeatedly with petroleum ether and water. The solid was then recrystallized from ethanol to give a brownish-yellow solid product, UBI-1237 (5.4 g, 72% yield). LCMS [M+H] + =371 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.04(d,J=7.7Hz,1H),7.77(t,J=5.6Hz,1H),7.35(t,J=7.6Hz,1H),5.15(m,1 H),4.29(d,J=17.5Hz,1H),4.14(d,J=17.5Hz,1H),2.91(m,1H),2.66–2.55(m,1H),2.49–2.42(m,1H),2.02(m,1H).

[1116] Step 2: P1 - Connector h - A1

[1117] Compound P1-linker h (20 mg, 1 eq.), UBI-1237 (1 eq.), Pd(PPh3)2Cl2 (0.2 eq.), CuI (0.2 eq.), and TEA (1 eq.) were dissolved in anhydrous DMF (4 mL) and reacted at room temperature to 100 °C for 1 to 16 hours under N2 protection. After cooling, 5 mL of water was added, followed by extraction with ethyl acetate (5 mL * 3). The organic phase was washed successively with saturated brine, dried over Na2SO4, and concentrated to obtain the crude product. The crude product was separated into the target compound by preP1-TLC (DCM / MeOH = 10 / 1).

[1118] The target compound was dissolved in dichloromethane (3 mL), and then 0.5 mL of HCl / dioxane 4 M was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated by rotary evaporation under reduced pressure to obtain a crude product, which was washed with anhydrous diethyl ether (5 mL * 3), filtered, and dried under vacuum to obtain the target compound P1-connector h-A11.

[1119] Synthesis method of compound UB-180925

[1120]

[1121] Step 1: UB-180925b(V2031-110)

[1122] Cbz-Cl (361 mg, 2.12 mmol) was added to UB-180925a (400 mg, 1.41 mmol) and TEA (285 mg, 2.83 mmol) in 10 mL of dichloromethane. The reaction mixture was stirred at 0 °C for 3 hours. After the reaction was complete, the mixture was concentrated and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain a yellow oily substance UB-180925b (380 mg, yield 64%). LCMS: [M+H] + =418.2

[1123] Step 2: UB-180925c(V2031-111)

[1124] 4N dioxane hydrochloride (2 mL) was added to UB-180925b (380 mg, 0.91 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at 20 °C for 4 hours. After the reaction was complete, the mixture was concentrated to give a white solid UB-180925c (250 mg, 86.5% yield). LCMS: [M+H] + =318.2

[1125] Step 3: UB-180925d(V2031-112)

[1126] P1 (268 mg, 0.63 mmol), UB-180925c (250 mg, 0.79 mol), HATU (450 mg, 1.18 mmol), and diisopropylethylamine (305 mg, 2.37 mmol) were dissolved in anhydrous DMF (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was poured into water (20 mL) and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to give a yellow solid UB-180925d (250 mg, yield 54.8%). LCMS: [M+H] + =725.4

[1127] 1 H NMR (400MHz, chloroform-d) δ11.22(s,2H),8.65–8.52(m,1H),8.28(dd,J=31.2,8.4Hz,3H),7.59(s,1H),7.46(d,J=1.8 Hz,1H),7.35(qd,J=6.4,5.5,1.9Hz,5H),6.62(d,J=7.8Hz,1H),5.30(s,1H),5.14(s,2H),4.46(q,J=8.1Hz,1H) ,4.27(dd,J=7.7,3.5Hz,1H),3.98(s,7H),3.66(pd,J=6.6,3.1Hz,7H),3.49(s,2H),3.31(s,3H),3.09(qd,J=7. 5,3.5Hz,8H),2.29(dd,J=32.4,11.8Hz,4H),2.13(d,J=11.6Hz,1H),2.01–1.62(m,10H),0.87(t,J=7.5Hz,3H).

[1128] Step 4: UB-180925e (V2031-113)

[1129] 10% palladium on carbon (30 mg) was added to a methanol (5 mL) solution of UB-180925d (200 mg, 0.28 mol). The reaction mixture was stirred under H2 bulb for 4 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with methanol. The filtrate was concentrated to give a white solid UB-180925e (110 mg, yield 67.5%). LCMS: [M+H] + =591.4

[1130] Step 5: UB-180925f(V2031-119)

[1131] UB-180925e (250 mg, 0.42 mmol), UBI-1282 (125 mg, 0.635 mmol), potassium iodide (70.3 mg, 0.42 mmol), and potassium carbonate (117 mg, 0.85 mmol) were added to an acetonitrile (5 mL) solution. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, water (5 mL) was added to separate the organic matter, which was then dried (using sodium sulfate), filtered, and the reaction solution was concentrated. The solution was then separated by silica gel column chromatography (dichloromethane / methanol = 10%) to give a yellow solid UB-180925f (200 mg, yield 66.9%). LCMS: [M+H] + =707.4

[1132] 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.41(d,J=8.6Hz,1H),8.10(s,1H),7.84(s,1H),7.60(s,1H ),7.51–7.43(m,2H),4.60(s,1H),4.35(q,J=8.1Hz,1H),4.24(dd,J=7.8,3.6Hz,1H),3.94(s,3H ),3.75(s,1H),3.60(t,J=8.2Hz,2H),3.48(t,J=8.3Hz,3H),3.06(s,2H),2.18–1.71(m,12H),1. 63(dd,J=14.7,7.2Hz,4H),1.40(d,J=13.2Hz,2H),1.12(t,J=7.0Hz,6H),0.76(t,J=7.4Hz,3H).

[1133] Step 6: UB-180925g (V2031-122)

[1134] UB-180925f (150 mg, 0.21 mmol) was added to 1N HCl (10 mL). The reaction system was reacted at 30 °C for 4 hours. After the reaction was complete, the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated by filtration to obtain UB-180925 g (110 mg). LCMS: [M+H] + =633.4

[1135] Step 7: UB-180925i(V2031-121)

[1136] UBI-1237 (400 mg, 1.08 mmol), UB-180925h (274 mg, 1.62 mmol), PdCl2(PPh3)2 (38 mg, 0.05 mmol), copper iodide (21 mg), and triethylamine (491 mg) were added to anhydrous DMF (5 mL). The reaction mixture was stirred at 80 °C for 2 hours, and then cooled to room temperature after the reaction was complete. The mixture was added to water, extracted with dichloromethane, dried over brine (30 mL) and sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to give a yellow solid UB-180925i (250 mg, yield 56.2%).

[1137] LCMS:[M+H] + =412.2 1 H NMR (400MHz, DMSO-d6) δ11.01 (s, 1H), 7.71 (dd, J = 7.6, 1.1Hz,

[1138] 1H),7.64(dt,J=8.1,1.9Hz,1H),7.51(d,J=7.6Hz,1H),7.11–6.97(m,1H),5 .15(dd,J=13.3,5.1Hz,1H),3.18(q,J=6.6Hz,2H),3.04(q,J=6.6Hz,1H),2. 98–2.89(m,1H),2.62(s,1H),2.61–2.54(m,2H),2.45(dd,J=13.1,4.4Hz,1H ), 2.39 (t, J = 6.7Hz, 1H), 2.02 (dd, J = 8.9, 3.6Hz, 1H), 1.37 (d, J = 4.7Hz, 9H).

[1139] Step 8: UB-180925j(V2031-123)

[1140] 1 mL of 4N dioxane hydrochloride solution was added to 5 mL of dichloromethane containing 150 mg (0.21 mmol) of UB-180925i. The reaction mixture was stirred at 20 °C for 4 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated to obtain UB-180925j (110 mg, yield 97%). LCMS: [M+H] + =312.1

[1141] Step 9: UB-180925 (V2031-125)

[1142] UBI-180925 (50 mg, 0.17 mmol), UBI-180925j (35.7 mg, 0.17 mmol), and acetic acid (10 mg) were added to methanol (2 mL). After stirring the reaction mixture for one hour, sodium cyanoborohydride (15 mg, 0.24 mmol) was added, and the mixture was stirred at 60 °C for another 3 hours. After the reaction was complete, a white solid UBI-180925 (2.6 mg, yield 3.6%) was obtained. LCMS: [M+H] + =928.5

[1143] Synthesis method of compound UB-180933

[1144]

[1145] Step 1: UB-180933b(V2031-124)

[1146] UB-180933a (115 mg, 0.635 mmol), potassium iodide (70.3 mg, 0.42 mmol), and potassium carbonate (117 mg, 0.85 mmol) were added to acetonitrile (5 mL), and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, water (5 mL) was added, and the mixture was extracted with ethyl acetate, dried (sodium sulfate), filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol = 10%) to obtain a yellow solid UB-180933b (150 mg, yield 51.3%). LCMS: [M+H] + =691.4

[1147] Step 2: UB-180933c(V2031-126)

[1148] UB-180933b (150 mg, 0.22 mmol) was added to 5 mL of 4N dioxane hydrochloride. The reaction mixture was incubated at 30 °C for 4 hours. After the reaction was complete, 10 mL of water was added, the mixture was extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated to obtain UB-180933c (113 mg, yield 80.5%). LCMS: [M+H] + =647.4

[1149] Step 3: UB-180933 (V2031-133)

[1150] UBI-180925j (50 mg, 0.45 mmol), UBI-180933c (113 mg, 0.22 mmol), and acetic acid (10 mg) were added to methanol (5 mL). The system was stirred at room temperature for 1 hour, then sodium cyanoborohydride (56 mg, 0.89 mmol) was added, and stirring continued overnight. After the reaction was complete, UBI-180933 (5 mg, yield 3.1%) was prepared. LCMS: [M+H] + =942.5

[1151] 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),11.01(s,1H),9.69(s,1H),8.38(d,J=7.8Hz,1H),7.82(t,J=4.1Hz,2H),7.74( ddd,J=14.9,7.7,1.1Hz,2H),7.65–7.51(m,3H),5.17(dd,J=13.3,5.1Hz,1H),4.63–4.29(m,3H),4.17(p,J=8.7Hz,1 H),3.91(s,3H),3.58(d,J=12.0Hz,4H),3.45(s,2H),3.31(s,1H),3.21(s,3H),3.10(s,2H),3.01–2.86(m,1H),2.63 (s,1H),2.19(d,J=9.2Hz,2H),2.08–1.74(m,10H),1.66(t,J=11.9Hz,2H),1.57–1.34(m,6H),0.75(t,J=7.4Hz,3H).

[1152] In this article, the compound number UB-18XXXX can also be simplified to the number XXXX, for example UB-180925 is compound 925 (0925).

[1153] Other compounds shown in Table A1 were prepared using a similar method.

[1154] Table A1

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175] Synthesis method of compound M5:

[1176]

[1177] Step 1: M5-c(V2591-149)

[1178] M5-b (243 mg, 1.3 mmol) and 1 mL of DIPEA were added to M5-a (200 mg, 1.3 mmol) in a 10 mL solution of tert-butanol. The mixture was then stirred at 90 °C for 18 hours, and the mixture was concentrated under vacuum to obtain a solid. Diethyl ether was added and the mixture was sonicated for 10 minutes, then filtered to obtain the desired product M5-c (270 mg, 69% yield), which was a yellow solid.

[1179] LCMS[M+1] + =298.2.

[1180] Step 2: M5 (V2876-001)

[1181] M5-d (228 mg, 0.8 mmol) was added to M5-c (245 mg, 0.8 mmol) in a solution of n-butanol (10 ml), followed by the addition of hydrochloric acid (1 ml). The mixture was then stirred at 80 °C. The mixture was heated in a microwave at 150 °C for 2 hours under nitrogen protection. The reaction mixture was then added to ether and filtered to obtain M5 (385 mg) as a yellow solid.

[1182] 1 H NMR (400MHz, DMSO) δ12.49(s,1H),9.39(s,2H),9.28–9.09(m,3H),8.36–8.16(m,2H),7.52(d,J=8.6Hz,3H),6.98(d,J= 8.8Hz,2H),3.40–3.36(m,2H),3.23(s,2H),2.85(d,J=4.8Hz,3H),1.40–1.26(m,2H),0.86(t,J=7.2Hz,2H).LCMS[M+1] + =439.4

[1183] Synthesis of compound UB-180961

[1184]

[1185] Step 1: UB-180961c(V2407-041)

[1186] Compound UB-180961a (20 g, 71.1 mmol) was dissolved in dry DMF (80 mL) and cooled to 0 °C. NaH (16.8 g, 107 mmol) was then added to the reaction solution. Half an hour later, UB-180961b (21.1 g, 107 mmol) was dissolved in dry DMF (20 mL) and added dropwise to the reaction solution. The reaction was allowed to proceed overnight at room temperature. Ice water (100 mL) was added to the reaction solution, and the mixture was extracted three times with EtOAc (60 mL). The combined organic phases were separated by column chromatography (PE / EtOAc = 0-100%) to obtain the colorless oily target product UB-180961c (25 g, 47% yield).

[1187] 1 H NMR (400MHz, CDCl3) δ4.63(t,J=5.2Hz,1H),3.72–3.52(m,8H),2.47(td,J=7.0,2.6Hz,2H),1.98(t,J=2.7Hz,1H),1.28-1.21(m,6H).

[1188] Step 2: UB-180961d(V2407-042)

[1189] Compound UB-180961c (15 g, 285.4 mmol) was dissolved in water (40 mL), followed by the addition of concentrated HCl (10 mL) and reacted overnight at room temperature. The reaction solution was extracted three times with DCM (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the colorless oily target product UB-180961d (7.6 g). This crude product was used directly in the next reaction step.

[1190] 1 H NMR (400MHz, CDCl3) δ9.74(d,J=0.8Hz,1H),4.15(d,J=0.8Hz,2H),3.72–3.67(m,2H),2.54(t,J=2.7Hz,2H),2.02(t,J=3.4Hz,1H).

[1191] Step 3: UB-180961f(V2407-044)

[1192] Compounds UB-180961d (7.8 g, 68 mmol) and UB-180961e (7.6 g, 68 mmol) were dissolved in DCE (100 mL) and reacted at room temperature for 1 hour. Then, NaBH(OAc)3 (29.6 g, 136 mmol) was added and the reaction was continued at room temperature overnight. TEA (5 mL, sat) and Boc2O (6 g, 23.8 mmol) were added to the reaction solution and the reaction was continued at room temperature for 18 hours. The reaction solution was extracted twice with EtOAc (15 mL). The organic phase was dried with anhydrous Na2SO4 and separated by column chromatography (PE / EtOAc = 0-100%) to give the yellow oily target product UB-180961f (4.6 g, 57% yield).

[1193] 1 H NMR (400MHz, CDCl3) δ4.14(ddd,J=28.9,14.7,7.4Hz,5H),2.67(t,J=11.7Hz,2H),1.82(dd,J=14.1,7 .0Hz,2H),1.70(d,J=12.3Hz,2H),1.59(d,J=18.5Hz,4H),1.46(s,9H),1.19(dd,J=12.2,4.0Hz,2H).

[1194] Step 4: UB-180961g (V2407-047)

[1195] Compound UB-180961f (4.6 g, 15 mmol), along with Al-I (3.7 g, 10 mmol), Pd(PPh3)2Cl2 (701 mg, 1 mmol), CuI (190 mg, 1 mmol), and TEA (4.2 mL, 30 mmol), were dissolved in dry DMF (120 mL) and reacted overnight at 80 °C. The reaction solution was extracted twice with EtOAc (15 mL), and the organic phase was dried over anhydrous Na2SO4 and separated by column chromatography (PE / EtOAc = 0-100%) to give the target product UB-180961g (3.6 g, 57% yield) as a yellow solid. 1 H NMR (400MHz, DMSO) δ11.00(s,1H),7.72(d,J=6.9Hz,1H),7.63(d,J=7.2Hz,1H),7.53(t,J=7.6Hz,1H),5.15(dd,J=13.3 ,5.1Hz,1H),4.46(dd,J=18.0,11.1Hz,2H),4.30(d,J=17.7Hz,1H),3.62(t,J=6.6Hz,2H),3.47(t,J=6.5Hz,2H),3.30–

[1196] 3.15(m,3H),2.98–2.87(m,1H),2.71(t,J=6.7Hz,2H),2.59(d,J=18.0Hz,1H),2.44(dd,J=13.1,4.4H z,1H),2.07–1.98(m,1H),1.79-1.77(d,J=11.1Hz,2H),1.53(s,4H),1.37(s,9H),1.21–1.08(m,2H).

[1197] Step 5: UB-180961h(V2407-048)

[1198] Compound UB-180961 g (3.6 g, 33.8 mmol), TEA (10.3 g, 10.2 mmol), and DMAP (12.4 g, 10.2 mmol) were dissolved in dry DMF (140 mL), and TsCl (14.6 g, 7.7 mmol) was added at 0 °C. The reaction mixture was heated to 30 °C and reacted for 15 hours. The reaction mixture was extracted twice with DCM (50 mL), and the organic phase was concentrated and separated by column chromatography (PE / EtOAc = 0-100%) to give the white solid target product UB-180961 h (3.6 g, 86% yield).

[1199] 1H NMR (400MHz, DMSO) δ11.01(s,1H),7.78(d,J=8.3Hz,2H),7.73(dd,J=7.5,0.8Hz,1H),7.63–7.59(m,1H),7.52 (t,J=7.6Hz,1H),7.46(d,J=8.0Hz,2H),5.16(dd,J=13.3,5.1Hz,1H),4.37(dt,J=41.1,17.7Hz,3H),3.60(t,J =6.6Hz,2H),3.44(t,J=6.5Hz,2H),3.19(s,2H),2.91(d,J=12.3Hz,1H),2.70(t,J=6.6Hz,2H),2.59(d,J=16.2 Hz,1H),2.46–2.37(m,4H),2.05–2.00(m,1H),1.78(d,J=8.3Hz,2H),1.64–1.43(m,6H),1.36(d,J=5.1Hz,9H).

[1200] Step 6: UB-180961i(V2407-049)

[1201] Compound V2407-048 (3.6 g, 5.1 mmol) and NaN3 (667 mg, 10.2 mmol) were dissolved in DMF (10 mL) and reacted overnight at 80 °C. The reaction solution was extracted twice with EtOAc (100 mL), and the organic phase was dried and separated by column chromatography (PE / EtOAc = 0-100%) to give the white solid target product UB-180961i (2.4 g, 68% yield).

[1202] 1 H NMR (400MHz, DMSO) δ11.00(s,1H),7.72(d,J=7.4Hz,1H),7.63(d,J=7.3Hz,1H),7.52(t,J=7.6H z,1H),5.15(dd,J=13.3,5.1Hz,1H),4.44(d,J=17.7Hz,1H),4.31(d,J=17.7Hz,1H),3.92(s,1H ),3.63(t,J=6.6Hz,2H),3.49(t,J=6.3Hz,2H),3.24(s,2H),3.00–2.85(m,1H),2.73(t,J=6.6H z,2H),2.61(s,1H),2.46–2.37(m,1H),2.02(d,J=5.5Hz,1H),1.93–1.44(m,8H),1.38(s,10H).

[1203] Step 7: The method is similar to General Method 2.

[1204] UB-180961(V2240-090)

[1205] LCMS[M+H] + =884.6

[1206] 1 H NMR(400MHz,DMSO-d6)δ13.08(s,1H),11.01(s,1H),9.62(s,1H),8.96(m,3H),7.76–7.68(m,3H),7.66–7.61(m,2H) ,7.56–7.49(m,2H),5.16(dd,J=13.3,5.1Hz,1H),4.71(m,1H),4.51–4.44(m,2H),4.32(d,J=17.8Hz,1H),3.91(s,3 H),3.80(t,J=5.3Hz,2H),3.69(t,J=6.7Hz,2H),3.32(m,1H),3.21(s,3H),3.16(m,2H),2.97–2.89(m,1H),2.79(t, J=6.7Hz,2H),2.59(m,1H),2.44(m,1H),2.05–1.73(m,14H),1.46(m,2H),1.41–1.33(m,2H),0.75(t,J=7.4Hz,3H).

[1207] Synthesis of compound UB-180937

[1208]

[1209] The method is similar to General Method 1

[1210] UB-180937(V2768-119)

[1211] 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.70(s,1H),8.98(s,2H),7.95(d,J=5.4Hz,1H),7.87–7.80(m,2H),7.73(dd,J=7.6,1.1H z,1H),7.68–7.58(m,3H),7.53(t,J=7.6Hz,1H),5.16(dd,J=13.3,5.1Hz,1H),4.51–4.45(m,2H),4.33(s,1H),4.17(d,J=8.8Hz, 1H),3.94(s,4H),3.81(t,J=5.3Hz,2H),3.70(t,J=6.7Hz,2H),3.18(d,J=26.3Hz,6H),2.99–2.88(m,1H),2.80(t,J=6.7Hz,2H), 2.59(d,J=17.8Hz,1H),2.46(dd,J=13.1,4.2Hz,1H),2.09–1.73(m,13H),1.63–1.39(m,6H),0.76(t,J=7.4Hz,3H).LCMS[M / 2+1] + =431.1

[1212] Synthesis method of compound UB-180934

[1213]

[1214] The method is similar to General Method 1

[1215] LCMS[M+1] + =899.7

[1216] 1H NMR(400MHz,)δ11.02(s,1H),8.41(d,J=8.5Hz,1H),7.84(d,J=12.8Hz,2H),7.69(t,J=14.8Hz,2H),7.57–7 .51(m,2H),7.51–7.44(m,2H),5.17(dd,J=13.2,5.2Hz,1H),4.46(d,J=17.7Hz,1H),4.39–4.28(m,2H),4.2 5(dd,J=7.7,3.6Hz,1H),3.95(d,J=7.9Hz,4H),3.25(s,3H),2.96(d,J=18.8Hz,2H),2.72–2.63(m,2H),2.5 9(s,1H),2.43(s,1H),2.06(d,J=18.5Hz,7H),1.94–1.71(m,11H),1.71–1.50(m,9H),0.77(t,J=7.4Hz,3H).

[1217] Synthesis method of compound UB-181010

[1218]

[1219] Step 1: UB-181010c (V2141-112)

[1220] Compound UB-181010a (700 mg, 10 mmol) was dissolved in DMF (10 mL), cooled to 0 °C, and then NaH (400 mg, 10 mmol) was added. After reacting at room temperature for 16 hours, the reaction solution was quenched with water and extracted with ethyl acetate (30 mL * 3). The combined organic phases were dried, concentrated, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give the white solid target product UB-181010c (650 mg, 18% yield). 1 H NMR (400MHz, Chloroform-d) δ7.80(d,J=8.4Hz,2H),7.41–7.31(m,2H),3.66(d,J=4Hz,4H),3.61(d,J=11.8Hz,10H),2.51–2.43(m,3H).

[1221] Step 2: UB-181010e(V2141-114)

[1222] Compound UB-181010c (500 mg, 1.4 mmol) was dissolved in CH3CN (10 mL), followed by the addition of K2CO3 (390 mg, 2.8 mmol) and UB-181010d (200 mg, 1.4 mmol). The reaction was carried out at 80 °C for 16 hours. After filtration, the filtrate was concentrated to obtain the crude product, which was then purified by silica gel column chromatography to yield the target product UB-181010e (300 mg, 65.9% yield) as an oily substance. LC-MS: [M+H] + =324.3

[1223] Step 3: UB-181010f(V2141-115)

[1224] Compound UB-181010e (300 mg, 0.92 mmol) was dissolved in THF (10 mL), and (BOC)₂O (400 mg, 1.85 mmol) and NaHCO₃ (155 mg, 1.85 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried, and the crude product (390 mg, 99% yield) was concentrated and used directly for the next step LC-MS: [M+H₂]₂. + =425.4

[1225] Step 4: UB-181010h (V2141-117)

[1226] Under N2 protection, compounds UB-181010f (300 mg, 0.7 mmol), UB-181010g (260 mg, 0.7 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), and CuI (266 mg, 1.4 mmol) were dissolved in TEA (200 μL) and DMF (10 mL) and reacted at 80 °C for 2 hours. The reaction solution was filtered and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the white solid target product UB-181010h (230 mg, 49% yield). LC-MS: [M+H] + =666.7

[1227] Step 4: UB-181010 (V2141-124)

[1228] The method is similar to General Method 3

[1229] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.03(s,1H),9.00(s,2H),8.80(s,1H),8.70(s,1H),8.31(d,J=8.5Hz,1H),7.97–7.7 7(m,5H),7.69(d,J=7.8Hz,1H),7.62(s,1H),7.59–7.47(m,2H),7.34(d,J=2.3Hz,2H),7.18(t,J=8.8Hz,2H),5.11(dd,J=13 .3,5.0Hz,1H),4.70(s,1H),4.52–4.28(m,2H),3.96–3.90(m,9H),3.75(t,J=5.4Hz,2H),3.62(t,J=6.7Hz,2H),3.30(s,1H) ,3.12(p,J=5.5Hz,2H),2.91(m,1H),2.72(t,J=6.7Hz,2H),2.62–2.56(m,1H),2.37(m,1H),2.06–1.78(m,6H).LC-MS:[M+H] + =903,452

[1230] Synthetic method of compound UB-181011

[1231]

[1232] Step 1: UB-181011c(V2141-128)

[1233] Compound UB-181011a (5 g, 26 mmol) was dissolved in UB-181011b (10 mL), and Bu4NHSO4 (17.7 g, 52 mmol) and 50% NaOH (50 mL) were added. The reaction mixture was reacted at 50 °C for 16 hours. The reaction solution was then diluted with water and extracted with dichloromethane (30 mL x 3). The combined organic phases were dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give the colorless oily target product UB-181011c (4.4 g, 60% yield). LC-MS: [M+H] + =280.3

[1234] Step 2: UB-181011d(V2141-129)

[1235] Compound UB-181011c (4.4 g, 15.7 mmol) was dissolved in acetone (200 mL), and NaI (23.5 g, 15.7 mmol) was added. The mixture was reacted at 80 °C for 2 days. The reaction solution was concentrated, water was added, and the mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried and concentrated to give the crude product UB-181011d (5.2 g, 90% yield), which was used directly in the next step. LC-MS: [M+H] + =372.3

[1236] Step 3: UB-181011e (V2141-130)

[1237] Compound UB-181011d (5.2 g, 14 mmol) and NaN3 (1.82 g, 28 mmol) were dissolved in DMF (50 mL) and reacted at 80 °C for 16 hours. The reaction mixture was then extracted with water and ethyl acetate (20 mL * 3). The combined organic phases were dried and concentrated to give the crude product UB-181011e (4.2 g, 100% yield). LC-MS: [M + H] + =286.3

[1238] Step 4: UB-181011f(V2141-131)

[1239] Compound UB-181011e (4.2 g, 14.6 mmol) was dissolved in HCl / dioxane (50 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give crude product UB-181011f (4 g, 100% yield), which was directly used in the next step LC-MS: [M+H] + =186.3

[1240] Step 5: UB-181011g (V2141-132)

[1241] Compound UB-181011f (2.5 g, 13.4 mmol) was dissolved in CH3CN (200 mL), and K2CO3 (3.7 g, 26.8 mmol) and ethyl 2-bromoacetate (2.23 g, 13.4 mmol) were added. The reaction mixture was reacted at room temperature for 16 h. The reaction solution was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give UB-181011g (820 mg, 22.7% yield). LC-MS: [M+H] + =272.3

[1242] Step 6: UB-181011h (V2141-133)

[1243] Compound UB-181011 g (820 mg, 3 mmol) was dissolved in THF (50 mL), and (BOC)₂O (241 mg, 6 mmol) and NaHCO₃ (504 mg, 6 mmol) were added. The reaction mixture was reacted at room temperature for 2 h. The reaction solution was then extracted with ethyl acetate (20 mL * 3). The combined organic phases were dried and concentrated to give the crude product UB-181011 h (800 mg, 73.2% yield), which was directly used in the next step LC-MS: [M + H₂]₂. + =372.3

[1244] Step 7: UB-181011i (V2141-134)

[1245] Compound UB-181011h (800 mg, 2.15 mmol), NaOH (344 mg, 8.6 mmol), was dissolved in THF (20 mL), methanol (20 mL), and water (2 mL). The reaction mixture was reacted at 50 °C for 2 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The pH of the aqueous phase was adjusted to 3 with 1 M HCl aqueous solution. Then, the mixture was extracted with dichloromethane (20 mL x 3). The dichloromethane organic phases were combined, dried, and concentrated to give the crude product UB-181011i (600 mg, 81% yield), which was used directly in the next step. LC-MS: [M+H] + =345.3

[1246] Step 8: UB-181011j(V2141-135)

[1247] Compounds UB-181011i (300 mg, 0.87 mmol), A3 (226 mg, 0.87 mmol), and HATU (661 mg, 1.74 mmol) were dissolved in DMF (5 mL) and DIPEA (1 mL) and reacted at room temperature for 2 hours. The reaction mixture was then extracted with water and ethyl acetate (20 mL x 3). The combined organic phases were dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give UB-181011j (270 mg, 53% yield). LC-MS: [M+H] + =587.3

[1248] Step 9: UB-181011 (V2141-138)

[1249] The method is similar to General Method 3

[1250] 1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.98(s,1H),10.01(s,1H),9.16(s,2H),8.69(s,1H),8.51(s,1H),8.30(d,J =8.5Hz,1H),7.96–7.87(m,3H),7.80(d,J=8.4Hz,2H),7.71(s,2H),7.59–7.44(m,1H),7.34(d,J=2.2Hz,1H),7.17(t ,J=8.8Hz,2H),5.09(dd,J=13.3,5.1Hz,1H),4.50–4.27(m,4H),4.02(t,J=5.7Hz,2H),3.44–3.34(m,4H),3.08–2.86 (m,3H),2.71–2.59(m,1H),2.42–2.32(m,1H),2.05–1.87(m,3H),1.76–1.67(m,2H),1.58–1.44(m,4H).LC-MS:[M+H] + =942.8

[1251] Synthetic method of compound UB-181013

[1252]

[1253] Step 1: UB-181013a(V2141-135)

[1254] Compounds UB-181011i (300 mg, 0.87 mmol), A3 (226 mg, 0.87 mmol), and HATU (661 mg, 1.74 mmol) were dissolved in DMF (5 mL) and DIPEA (1 mL) and reacted at room temperature for 2 hours. The reaction mixture was then extracted with water and ethyl acetate (20 mL x 3). The combined organic phases were dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give UB-181013a (270 mg, 53% yield). LC-MS: [M+H] + =587.3

[1255] Step 2: UB-181013b (V2141-139)

[1256] Compound UB-181013a (50 mg, 0.085 mmol), Pd / C (5 mg), was dissolved in DCM / MeOH = 10 / 1 (10 mL) and reacted at room temperature in H2 for 2 hours. 100 mL of DCM / MeOH = 10 / 1 was added to the reaction solution, and the product was stirred until fully dissolved before filtration. The filtrate was concentrated to obtain the target product UB-181013b (50 mg, 100% yield) as an oil. LC-MS: [M+H] + =560.3

[1257] Step 3: UB-181013 (V2141-146)

[1258] The method is similar to General Method 2.

[1259] 1 H NMR (400MHz, DMSO-d6) δ12.29–12.03(m,1H),11.05(s,1H),10.86(s,1H),9.29(s,2H),7.88(d,J=7.4 Hz,1H),7.73–7.47(m,5H),7.24–6.98(m,5H),6.75(d,J=7.4Hz,1H),5.17(dd,J=13.2,5.1Hz,1H),4.5 5–4.26(m,2H),4.03(s,2H),3.43–3.28(m,4H),2.99(d,J=18.9Hz,6H),2.62(d,J=17.2Hz,2H),2.36–2 .17(m,1H),2.12–1.99(m,1H),1.96–1.88(m,2H),1.82–1.53(m,10H),1.43–1.36(m,4H).LC-MS:[M+H] + =903,452

[1260] Synthetic method of compound UB-181019

[1261] Step 1: UB-181019 (V2141-147)

[1262] The method is similar to General Method 2.

[1263] 1H NMR(400MHz,DMSO-d6)δ12.16–11.78(m,1H),11.30(s,1H),10.99(s,1H),9.22(s,2H),7.96(s,1H),7 .76–7.61(m,4H),7.47(d,J=3.9Hz,1H),7.18–6.98(m,5H),6.74(d,J=7.4Hz,1H),5.09(dd,J=13.3,5 .1Hz,1H),4.56(s,1H),4.50–4.25(m,2H),4.03(s,2H),3.41–3.29(m,4H),2.93–2.87(m,7H),2.63–2 .57(m,1H),2.42–2.31(m,1H),2.05–1.87(m,3H),1.84–1.53(m,10H),1.48–1.39(m,4H).LC-MS:[M+H] + =903,452

[1264] Synthetic method of compound UB-181020

[1265]

[1266] Step 1: UB-181020c (V2141-108)

[1267] Compound UB-181020a (5 g, 28.5 mmol) was dissolved in UB-181020b (10 mL), and Bu4NHSO4 (19 g, 57 mmol) was added. The reaction mixture was reacted at 50 °C for 16 hours. The reaction solution was diluted with water and extracted with dichloromethane (20 mL * 3). The combined organic phases were dried and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to give the colorless oily target product UB-181020c (4.4 g, 60% yield). LC-MS: [M+H] + =282.3

[1268] Step 2: UB-181020d(V2141-116)

[1269] Compound UB-181020c (3 g, 10.6 mmol) was dissolved in acetone (300 mL), and NaI (16 g, 106 mmol) was added. The reaction mixture was reacted at 80 °C for 2 days. The reaction solution was concentrated, water was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product UB-181020d (3.4 g), which was used directly in the next step. LC-MS: [M+H] + =374.3

[1270] Step 3: UB-181020e (V2141-127)

[1271] Compound UB-181020d (3.4 g, 9.1 mmol) and NaN3 (1.82 g, 27 mmol) were dissolved in DMF (50 mL) and reacted at 80 °C for 16 hours. The reaction mixture was then extracted with water and ethyl acetate (20 mL * 3). The combined organic phases were dried and concentrated to give the crude product UB-181020e (3 g). LC-MS: [M + H] + =289.3

[1272] Step 4: UB-181020f(V2141-143)

[1273] Compound UB-181020e (6 g, 20.8 mmol) was dissolved in HCl / dioxane (50 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated to give the crude product UB-181020f (6 g, 100% yield). LC-MS: [M+H] + =188.3

[1274] Step 5: UB-181020g (V2141-144)

[1275] Compound UB-181020f (4.8 g, 25.5 mmol) was dissolved in CH3CN (200 mL), and K2CO3 (4.28 g, 25.5 mmol) and ethyl 2-bromoacetate (4.2 g, 25.5 mmol) were added. The reaction mixture was reacted at room temperature for 16 hours. The reaction solution was filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give UB-181020g (2.1 g, 30% yield). LC-MS: [M+H] + =274.3

[1276] Step 6: UB-181020h (V2141-145)

[1277] Compound UB-181020 g (2.1 g, 7.66 mmol) was dissolved in THF (100 mL), and (BOC)₂O (612 mg, 15.3 mmol) and NaHCO₃ (1.28 mg, 15.3 mmol) were added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was extracted with water and ethyl acetate (20 mL * 3). The organic phases were combined, dried, and concentrated to give UB-181020 h (3 g, 100% yield). LC-MS: [M + H] + =374.3

[1278] Step 7: UB-181020i (V2141-148)

[1279] Compound UB-181020h (3 g, 8 mmol), NaOH (1.28 g, 32 mmol), was dissolved in THF (20 mL), methanol (20 mL), and water (2 mL). The reaction mixture was reacted at 50 °C for 2 hours. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The pH of the aqueous phase was adjusted to 3 with 1 M HCl aqueous solution. Then, it was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried, and concentrated to give UB-181020i (2 g, 74% yield). LC-MS: [M+H] + =347.3

[1280] Step 8: UB-181020j(V2141-149)

[1281] Compounds UB-181020i (346 mg, 1 mmol), A3 (259 mg, 1 mmol), and HATU (760 mg, 2 mmol) were dissolved in DMF (3 mL) and DIPEA (0.3 mL) and reacted at room temperature for 2 hours. The reaction mixture was then extracted with water and ethyl acetate (20 mL x 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give UB-181011j (380 mg, 64.7% yield). LC-MS: [M+H] + =588.3

[1282] Step 9: UB-181020 (V2537-001)

[1283] The method is similar to General Method 3

[1284] 1H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.99(s,1H),10.02(s,1H),9.14(s,2H),8.69(s,1H),8.47(s,1H),8.31(d,J= 8.5Hz,1H),7.97–7.86(m,4H),7.80(d,J=8.5Hz,2H),7.70(s,2H),7.55(td,J=8.5,4.1Hz,1H),7.34(d,J=2.2Hz,1H), 7.17(t,J=9.0Hz,2H),5.09(dd,J=13.3,5.1Hz,1H),4.50–4.24(m,6H),4.04–3.86(m,4H),3.62–3.42(m,6H),3.10–2. 98(m,2H),2.91(ddd,J=18.0,13.5,5.4Hz,1H),2.67–2.55(m,2H),2.41–2.28(m,1H),2.05–1.84(m,3H).LC-MS:[M+H] + =904.9,473.2

[1285] Synthetic method of compound UB-181032

[1286] Step 1: UB-181032(V2537-005)

[1287] The method is similar to General Method 3

[1288] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.98(s,2H),7.93(s,1H),7.71(t,J=11.6Hz,3H),7.56(s,1H),7.38(d,J=4. 5Hz,1H),7.22–7.07(m,3H),6.99(d,J=3.6Hz,1H),6.94–6.81(m,1H),6.75–6.65(m,1H),5.09(dd,J=13.2,5.1Hz,1 H),4.54(s,1H),4.50–4.26(m,2H),4.03(s,2H),3.63–3.49(m,4H),3.37(t,J=6.3Hz,2H),3.23–3.16(m,2H),3.06( s,2H),2.99–2.83(m,2H),2.70–2.57(m,1H),2.42–2.25(m,1H),2.07–1.70(m,9H),1.69–1.59(m,2H).LC-MS:[M+H] + =906

[1289] Synthetic method of compound UB-181035

[1290]

[1291] Step 1: UB-181035a(V2537-002)

[1292] Compound UB-181020j (180 mg, 0.3 mmol), Pd / C (30 mg), was dissolved in DCM / MeOH = 10 / 1 (10 mL). The reaction was carried out at room temperature for 2 hours under H2 conditions. 100 mL of DCM / MeOH = 10 / 1 was added to the reaction solution, and after thorough stirring, the mixture was filtered. The filtrate was concentrated to obtain the white solid target product UB-181035a (160 mg, 100% yielded). LC-MS: [M+H] + =588.3

[1293] Step 2: UB-181035 (V2537-009)

[1294] The method is similar to General Method 3

[1295] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.99(s,1H),10.02(s,1H),9.14(s,2H),8.69(s,1H),8.47(s,1H),8.31(d,J= 8.5Hz,1H),7.97–7.86(m,4H),7.80(d,J=8.5Hz,2H),7.70(s,2H),7.55(td,J=8.5,4.1Hz,1H),7.34(d,J=2.2Hz,1H), 7.17(t,J=9.0Hz,2H),5.09(dd,J=13.3,5.1Hz,1H),4.50–4.24(m,6H),4.04–3.86(m,4H),3.62–3.42(m,6H),3.10–2. 98(m,2H),2.91(ddd,J=18.0,13.5,5.4Hz,1H),2.67–2.55(m,2H),2.41–2.28(m,1H),2.05–1.84(m,3H).LC-MS:[M+H] + =904.9,473.2

[1296] Synthetic method of compound UB-181040

[1297] Step 1: UB-181040 (V2537-012)

[1298] The method is similar to General Method 4

[1299] 1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),11.05(s,1H),10.87(s,1H),10.04(s,1H),9.26(s,2H),8.91 (s,1H),8.63(s,1H),8.32(s,1H),7.86(d,J=23.5Hz,2H),7.73–7.38(m,6H),7.21(s,1H),6.91(s, 1H),5.17(m,1H),4.65–4.33(m,3H),4.06(s,3H),3.46–3.36(m,7H),3.23(s,4H),3.06(s,4H),2.8 1(s,3H),2.68–2.61(m,1H),2.36–2.23(m,1H),2.11–1.87(m,3H),1.34–1.22(m,2H).LC-MS:[M+H] + =925.7

[1300] Synthetic method of compound UB-181047

[1301] Step 1: UB-181047 (V2537-018)

[1302] The method is similar to General Method 4

[1303] 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),11.43(s,1H),10.99(s,1H),10.24(s,1H),9.28(s,2H),8.96(d,J=4.9Hz,1H),8.59(d,J= 8.4Hz,1H),8.34(s,1H),7.99(s,1H),7.85(d,J=7.8Hz,1H),7.77–7.60(m,6H),7.55(t,J=7.9Hz,1H),7.22(t,J=7.6Hz,1H),5.0 9(dd,J=13.2,5.0Hz,1H),4.51–4.29(m,2H),4.06(d,J=6.0Hz,2H),3.63–3.40(m,12H),3.24(d,J=6.3Hz,2H),3.07(p,J=6.7Hz, 2H),3.00–2.78(m,4H),2.60(d,J=16.9Hz,1H),2.45–2.33(m,1H),1.98(dh,J=27.2,6.6Hz,3H),1.36–1.23(m,1H).LC-MS:[M+H]+ =925.7

[1304] Synthetic method of compound UB-181048

[1305] Step 1: UB-181048 (V2537-019)

[1306] The method is similar to General Method 4

[1307] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),11.05(s,1H),10.90(s,1H),10.11(d,J=16.7Hz,1H),9.38–9.20(m,2H),8.93(t, J=5.4Hz,1H),8.61(d,J=8.4Hz,1H),8.32(s,1H),7.96–7.75(m,2H),7.72–7.50(m,7H),7.30–7.15(m,1H),5.16(dd,J= 13.2,5.1Hz,1H),4.56–4.33(m,2H),4.04(s,2H),3.40(d,J=18.0Hz,8H),3.05–2.85(m,7H),2.81(d,J=4.3Hz,3H),2.6 3(d,J=16.9Hz,1H),2.28(m,1H),2.03(m,1H),1.78–1.71(m,2H),1.59–1.46(m,6H),1.27(d,J=6.8Hz,2H).LC-MS:[M+H] + =925.7

[1308] Synthetic method of compound UB-181049

[1309] Step 1: UB-181049 (V2537-020)

[1310] The method is similar to General Method 4

[1311] 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),11.30(s,1H),10.99(s,1H),10.01(s,1H),9.21(s,2H),8.89(d,J=4.7Hz,1H),8.63(d,J=8. 5Hz,1H),8.31(s,1H),7.97(s,1H),7.82(d,J=7.8Hz,1H),7.69(d,J=26.9Hz,4H),7.53(t,J=8.0Hz,3H),7.20(t,J=7.5Hz,1H),5. 09(dd,J=13.3,5.1Hz,1H),4.54–4.25(m,2H),4.03(t,J=5.6Hz,2H),3.42–3.35(m,8H),3.15–2.85(m,7H),2.81(d,J=4.5Hz,3H), 2.64–2.58(m,1H),2.46–2.31(m,1H),2.03–1.96(m,2H),1.78–1.70(m,2H),1.64–1.49(m,6H),1.24(d,J=3.6Hz,2H).LC-MS:[M+H] + =925.7

[1312] Synthetic method of compound UB-181059

[1313]

[1314] Step 1: UB-181059c(V907-066)

[1315] Compound UBI-1059a (10 g, 37 mmol) was dissolved in dichloroethyl ether (50 mL), and N(Bu)4HSO4 (12.5 g, 37 mmol) was added. The mixture was cooled to 0 °C, and 50% NaOH aqueous solution (100 mL) was slowly added. The reaction was allowed to proceed at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane (80 mL * 2). The dichloromethane solutions were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 5) to give the yellow oily target product UB-181059c (8.8 g, 63% yield). 1 H NMR (400MHz, Chloroform-d) δ7.43–7.14(m,10H),3.86(d,J=13.4Hz,2H),3.81–3.75(m,3H),3.72–3.52(m,11H),3.29–3.00(m,1H),2.89(s,1H).

[1316] Step 2: UB-181059d(V2312-139)

[1317] UB-181059c (5 g, 13.2 mmol) was dissolved in methanol, and Pd / C (2 g) was added under nitrogen protection. The reaction system was purged with hydrogen three times, and the reaction was carried out at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was filtered and evaporated to dryness under vacuum to obtain UB-181059d (2.8 g, 90% yield) as a yellow oil.

[1318] 1 H NMR(400MHz,Chloroform-d)δ3.80–3.73(m,2H),3.66(dddd,J=8.2,6.0,3.2,1. 5Hz,7H),3.60–3.46(m,4H),3.16(tt,J=6.3,4.5Hz,1H),3.01(s,4H).LCMS[M+H] + =198.

[1319] Step 3: UB-181059e (V2312-144)

[1320] UB-181059d (2.8 g, 14.2 mmol) and BOC2O (4.0 g, 17.04 mmol) were dissolved in THF, and then NaHCO3(aq) (2.4 g, 28.4 mmol) was added. The reaction mixture was reacted at room temperature for 18 h. The reaction mixture was extracted with water and ethyl acetate, and the combined organic layers were washed with saturated brine, dried on Na2SO4, and filtered. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel chromatography (EA / PE = 1 / 5) to give UB-181059e (3.0 g, 71% yield) as a pale yellow oil.

[1321] 1 H NMR(400MHz,Chloroform-d)δ5.25(s,1H),3.86–3.59(m,12H),2.53(s,1H),1.45(s,9H).LCMS[M+H] + =298.

[1322] Step 4: UB-181059f(V2312-148)

[1323] UB-181059e (3.0 g, 10.1 mmol) was dissolved in DMF (30 mL), and then NaN3 (1.32 g, 20.2 mmol) was added. The reaction mixture was heated to 80°C and reacted for 16 h. The reaction mixture was filtered and then extracted with water and ethyl acetate. The combined organic layers were washed with saturated brine, dried on Na2SO4, and filtered. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel chromatography (EA / PE = 1 / 10) to give UB-181059f (2.1 g, 68% yield) as a yellow oil.

[1324] 1 H NMR(400MHz,Chloroform-d)δ5.29(d,J=14.5Hz,1H),3.88–3.73(m,2H),3.72–3.55(m,9H),3.40(dd,J=5.6,4.3Hz,2H),2.67(s,1H),1.45(s,9H).LCMS[M+H] + =305.

[1325] Step 5: UB-181059h (V2595-003)

[1326] UB-181059f (500 mg, 1.64 mmol) and UB-181059g (283 mg, 3.3 mmol) were dissolved in anhydrous THF, and then NaH (4 mg, 0.08 mmol) was added. The reaction mixture was reacted at room temperature for 18 h. The reaction mixture was extracted with water and ethyl acetate, and the combined organic layers were washed with saturated brine, dried on Na2SO4, and filtered. The solvent was removed under vacuum to give the crude product, which was purified by silica gel chromatography (EA / PE = 1 / 5) to give UB-181059h (140 mg, 22% yield) as a pale yellow oil.

[1327] 1 H NMR(400MHz,Chloroform-d)δ3.73(td,J=6.3,1.7Hz,2H),3.70–3.65(m,5H),3.63(s,4H),3.57(dd,J=9.5,4.3Hz,2 H),3.48(ddd,J=9.4,6.1,3.4Hz,2H),3.42–3.36(m,2H),2.57(t,J=6.3Hz,2H),1.62(s,3H),1.44(s,9H).LCMS[M+H] + =390.

[1328] Step 6: UB-181059i (V2595-031)

[1329] UB-181059h (140 mg, 0.376 mmol) was dissolved in methanol, and then NaOH (60 mg, 1.5 mmol, aqueous solution) was added. The reaction mixture was reacted at room temperature for 2 h. Water was added to the reaction solution, and methanol was removed by vacuum rotary evaporation. The solution was extracted with ethyl acetate, and the pH of the resulting aqueous phase was adjusted to approximately 4 with 1 M dilute hydrochloric acid, followed by extraction with ethyl acetate. The resulting organic phase was then vacuum rotary evaporated to yield UB-181059i (110 mg, 80% yield) as a yellow oil. LCMS [M+H] + =377.

[1330] Step 7: UB-181059j(V2595-018)

[1331] UB-181059i (320 mg, 0.85 mmol), A3 (220 mg, 0.85 mmol), HATU (810 mg, 2.12 mmol), and DIPEA (330 mg, 2.55 mmol) were dissolved in DMF and reacted at room temperature for 18 h. The reaction mixture was filtered and then extracted with water and ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, and filtered. The solvent was removed under vacuum to give the crude product, which was purified by silica gel chromatography (MeOH / DCM = 1 / 15) to give UB-181059j (110 mg, 60% yield) as a yellow solid. LCMS [M+H] + =618.

[1332] Step 8: UB-181059 (V2537-026)

[1333] The method is similar to General Method 3

[1334] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.55(s,1H),10.01(s,1H),8.69(s,1H),8.45(s,1H),8.30(d, J=8.4Hz,1H),8.10-8.01(m,4H),7.93–7.78(m,4H),7.72–7.51(m,3H),7.33(s,1H),7.26–7.11(m,2H) ,5.09(d,J=5.1Hz,1H),4.56(t,J=5.2Hz,2H),4.45–4.22(m,2H),3.93–3.67(m,3H),3.39(s,6H),2.91 (t,J=16.4Hz,2H),2.72–2.54(m,1H),2.42–2.26(m,5H),2.09–1.90(m,1H),1.24(s,2H).LC-MS:[M+H] +=974.3

[1335] Synthetic method of compound UB-181064

[1336]

[1337] Step 1: UB-181064b (V2537-028)

[1338] Compound UB-181064a (V2537-028), Pd / C (10 mg), was dissolved in DCM / MeOH = 10 / 1 (10 mL) and reacted at room temperature in H2 for 2 hours. 100 mL of DCM / MeOH = 10 / 1 was added to the reaction solution, and after thorough stirring, the mixture was filtered. The filtrate was concentrated to give a white solid target product (180 mg, 94.7% yield). LC-MS: [M+H] + =561.3

[1339] Step 2: UB-181064 (V2537-031)

[1340] The method is similar to General Method 2.

[1341] 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.59(s,1H),8.14(s,3H),8.01(s,1H),7.80–7.64(m,4H),7. 49(t,J=3.1Hz,1H),7.20–7.04(m,5H),6.81(d,J=7.4Hz,1H),5.14–5.07(m,1H),4.55(s,1H),4.46–4 .23(m,2H),3.76(q,J=5.9Hz,2H),3.66–3.46(m,8H),3.38(m,3H),3.19(t,J=5.9Hz,2H),3.01–2.85 (m,3H),2.68(t,J=6.2Hz,2H),2.63–2.56(m,1H),2.43–2.30(m,1H),2.03–1.63(m,9H).LC-MS:[M+H] + =936

[1342] Synthetic method of compound UB-181065

[1343] Step 1: UB-181065 (V2537-032)

[1344] The method is similar to General Method 4

[1345] 1H NMR (400MHz, DMSO-d6) δ11.96(s,1H),10.98(s,1H),10.64(s,1H),10.01(s,1H),8.97–8.88(m,1H),8.63(d,J=8.5Hz,1 H),8.31(s,1H),8.18(d,J=5.3Hz,3H),8.03(s,1H),7.82(d,J=7.7Hz,1H),7.74–7.63(m,3H),7.57–7.43(m,3H),7.20(t ,J=7.5Hz,1H),6.90(s,1H),5.12–5.09(m,1H),4.46–4.29(m,2H),3.54(s,6H),3.45–3.36(m,10H),3.23(d,J=6.2Hz,2 H),2.98–2.77(m,4H),2.71(d,J=6.2Hz,2H),2.60(d,J=17.2Hz,1H),2.43–2.31(m,1H),2.05–1.95(m,2H).LC-MS:[M+H] + =956.

[1346] Synthetic method of compound UB-181073

[1347]

[1348] Step 1: UB-181073b (V2595-032)

[1349] UB-181073a (185 mg, 0.5 mmol), Al (127 mg, 0.5 mmol), HATU (467 mg, 1.25 mmol), and DIPEA (190 mg, 1.5 mmol) were dissolved in DMF and reacted at room temperature for 18 h. The reaction mixture was filtered and then extracted with water and ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, and filtered. The solvent was removed under vacuum to give the crude product, which was purified by silica gel chromatography (MeOH / DCM = 1 / 15) to give UB-181073b (85 mg, 28% yield) as a yellow solid. LCMS [M+H] + =618.

[1350] Step 2: UB-181073c(V2595-034)

[1351] UB-181073b (85 mg, 0.14 mmol) was dissolved in DCM / MeOH (v / v = 10 mL). Pd / C (50 mg) was added under nitrogen protection. The reaction system was purged three times with hydrogen, and the reaction was carried out at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was filtered and evaporated to dryness under vacuum to obtain UB-181073c (70 mg, 86% yield) as a yellow solid. LCMS [M+H] + =592.

[1352] Step 3: UB-181073 (v2537-039)

[1353] The method is similar to General Method 4

[1354] 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),11.02(s,1H),10.13(d,J=10.5Hz,1H),9.84(d,J=21.1Hz,1H),8. 86(s,1H),8.67(s,1H),8.37–8.13(m,4H),7.94–7.81(m,2H),7.63(s,2H),7.59–7.34(m,5H),7.18(t,J =7.7Hz,1H),6.86(s,1H),5.15(dd,J=13.3,5.0Hz,1H),4.41(q,J=17.6Hz,2H),3.56–3.17(m,19H),3.0 0–2.78(m,5H),2.75–2.60(m,4H),2.30(d,J=20.0Hz,2H),2.03(s,2H),1.33–1.26(m,2H).LC-MS:[M+H] + =956.

[1355] Synthetic method of compound UB-181085

[1356]

[1357] Step 1: UB-181085a(V2595-077)

[1358] UB-181076f (1.1 g, 2.5 mmol) was dissolved in DCM (50 mL), and then Dess-Martin (2.4 g) was added. The reaction mixture was reacted at room temperature for 40 min. The reaction mixture was diluted with distilled water / saline solution, and the product was extracted with ethyl acetate (80 mL * 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, and filtered. The solvent was removed under vacuum to give the crude product, which was purified by silica gel chromatography (MeOH / DCM = 1 / 10) to give UB-181085a (750 mg, 70% yield) as a yellow oil. LCMS [M+H] + =436.

[1359] Step 2: UB-181085b(V2537-053)

[1360] UB-181085a (80 mg, 0.18 mmol) was dissolved in TFA (1 mL) and DCM (3 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated to give UB-181085b (50 mg, 100% yield). LC-MS: [M+H] + =186.2

[1361] Step 3: UB-181085c(V2537-054)

[1362] Compounds UB-181085b (22 mg, 0.12 mmol) and UB-181085c (40 mg, 0.12 mmol) were dissolved in pyridine and reacted at room temperature for 2 hours. M1 (44 mg, 0.1 mmol) and DIPEA (0.3 mL) were added, and the reaction was continued for 1 hour. The reaction mixture was concentrated and purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain the white target product UB-181085c (20 mg, 26% yield). LC-MS: [M+H] + =649

[1363] Step 4: UB-181085 (V2537-057)

[1364] Under N2 protection, UB-181085c (30 mg, 0.045 mmol), UB-181085e (36 mg, 0.045 mmol), Pd(PPh3)2Cl2 (3 mg, 0.0045 mmol), and CuI (6 mg, 0.045 mmol) were dissolved in TEA (13 μL, 0.09 mmol) and DMF (6 mL). The mixture was reacted at 40 °C for 16 hours. The reaction solution was concentrated and purified by preparative TLC to obtain UB-181085 (1 mg, 2.56% yield). LC-MS: [M+H] + =892

[1365] Synthetic method of compound UB-181181

[1366]

[1367] Step 1: UB-181181c(V2954-006)

[1368] Compound UB-181181a (5 g, 43 mmol) was dissolved in methanol (100 mL), and AcOH (10 mL) was added. The reaction was carried out at 40 °C for 16 hours. NaBH3CN (5.4 g, 86 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 2 hours. The reaction solution was used directly for the next step. LC-MS: [M+H] + =228

[1369] Step 2: UB-181181d(V2954-010)

[1370] The reaction solution UB-181181c (5 g, 22 mmol) was added to methanol (100 mL), NaHCO3 (3.7 g, 44 mmol), and (Boc)2O (4.8 g, 22 mmol), and reacted at 40 °C for 30 minutes. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / WA = 1 / 1) to obtain UB-181181d (7 g, 97% yield). LC-MS: [M+H] + =328

[1371] Step 3: UB-181181e(V2954-012)

[1372] Compound UB-181181d (10 g, 31 mmol) was dissolved in DCM (50 mL), and MsCl (11 g, 92 mmol) and TEA (13 mL, 92 mmol) were added. The mixture was reacted at 40 °C for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL * 3). The organic phases were combined, dried, and concentrated to obtain the crude product, which was used directly in the next step.

[1373] Step 4: UB-181181f(V2954-013)

[1374] Compound UB-181181e (7 g, 17 mmol) was dissolved in DMF (20 mL), and NaN3 (1.68 g, 26 mmol) was added. The mixture was reacted at 80 °C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to give the colorless oily target product UB-181181f (4 g, 66.6% yield) as.1 HNMR(400MHz,Chloroform-d)δ4.16–3.98(m,1H),3.86(t,J=3.0Hz,1H),3.68(s,3H),3.61–3. 44(m,1H),2.81–2.54(m,3H),2.48–2.24(m,2H),2.12–1.88(m,4H),1.50(s,14H).LC-MS:[M+H] + =354

[1375] Step 5: UB-181181g (V2954-015)

[1376] Compound UB-181181f (2 g, 5.7 mmol) was dissolved in THF (30 mL) and cooled to 0 °C. LiAlH4 (6.8 mL, 6.8 mmol) was slowly added. The reaction mixture was reacted at 0 °C for 2 hours. Then, 10 H2O and Na2SO4 were added to the reaction solution and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the colorless oily target product UB-181181g (700 mg, 37.8% yield). 1 HNMR(400MHz,Chloroform-d)δ4.01–3.89(m,1H),3.86(p,J=3.0Hz,1H),3.62(d,J=5.0Hz,3H),2.32–2.11(m,4H),1.94(m,4H),1.50(m,13H).LC-MS:[M+H] + =325

[1377] Step 6: UB-181181h (V2954-017)

[1378] Compound UB-181181 g (700 mg, 2.16 mmol) was dissolved in DCM (50 mL), and Dess-Martin (1.1 g, 2.59 mmol) was added at 0 °C, followed by reaction at room temperature for 4 hours. NaHCO3 aqueous solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give UB-181181 h (470 mg, 67% yield). LC-MS: [M+H] + =323

[1379] Step 7: UB-181181i(V2954-020)

[1380] Compound UB-181181h (100 mg, 0.31 mmol) in MeOH (10 mL) was added with Bestmann-Ohirareagent (71 mg, 0.37 mmol) and K₂CO₃ (86 mg, 0.37 mmol). The mixture was stirred at 40 °C for 2 h. Then the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain UB-181181i (50 mg, 50.5% yield). 1 H NMR(400MHz,Chloroform-d)δ3.91–3.84(m,2H),3.67(s,1H),2.98–2.80(m,1H),2.71–2.54(m,2 H),2.49–2.39(m,2H),2.12(t,J=0.8Hz,1H),1.98–1.89(m,4H),1.76–1.46(m,13H).LC-MS:[M+H] + =319

[1381] Step 8: UB-181181j(V2954-021)

[1382] Under N2 protection, UB-181181i (44 mg, 0.12 mmol), A3 (50 mg, 0.12 mmol), Pd(PPh3)2Cl2 (8 mg, 0.012 mmol), and CuI (5 mg, 0.024 mmol) were dissolved in TEA (35 μL, 0.24 mmol) and DMF (8 mL). The mixture was reacted at 80 °C for 2 hours. The reaction solution was filtered and concentrated to obtain the crude product. The crude product was purified by preparative Prep-HPLC to obtain UB-181181j (8 mg, 12% yield) and UB-181181jk (2 mg, 3% yield).

[1383] UB-181181j: 1 H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.80(d,J=7.9Hz,1H),7.54–7.39(m,2H),5.22(dd,J=13.2,5.2Hz,1H),4.55–4.24(m,2H),3.9 4–3.78(m,2H),3.74(s,1H),3.02–2.70(m,5H),2.58–2.47(m,2H),2.42–2.16(m,2H),2.01–1.89(m,4H),1.71–1.45(m,13H).LC-MS:[M+H]+ =561

[1384] UB-181181k: 1 H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.82(d,J=7.8Hz,1H),7.58–7.43(m,2H),5.22(dd,J=13.3,5.2Hz,1H),4.56–4.25(m,3H),3.8 7(s,1H),3.70(m,1H),3.20(t,J=10.3Hz,1H),3.05–2.72(m,4H),2.42–2.17(m,4H),2.04–1.84(m,4H),1.75–1.43(m,13H).LC-MS:[M+H] + =561

[1385] Step 9: UB-181181l(V2954-022)

[1386] UB-181181j (50 mg, 0.07 mmol) was dissolved in THF (5 mL), and PMe3 (1 mL) was added. The mixture was reacted at 50 °C for 6 hours. The reaction solution was concentrated and purified by preparative TLC (MeOH / DCM = 1 / 10) to obtain the white solid target product UB-181181l (15 mg, 40.5% yield). LC-MS: [M+H] + =535

[1387] Step 10: UB-181181(V2954-025)

[1388] The method is similar to General Method 4

[1389] 1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),11.00(s,1H),9.27(s,2H),8.99–8.81(m,2H),8.38(s,1H),8.05–7.91(m,2H),7 .84(d,J=7.9Hz,1H),7.81–7.48(m,5H),7.24(t,J=7.6Hz,1H),6.12(d,J=4.5Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.5 0–4.29(m,2H),3.71(d,J=37.9Hz,2H),3.46–3.34(m,4H),3.21–3.00(m,6H),2.82(d,J=4.5Hz,3H),2.73–2.58(m,3H), 2.44–2.31(m,1H),2.01(dd,J=10.3,4.8Hz,2H),1.90–1.68(m,6H),1.57–1.46(m,2H),1.25–1.16(m,2H).LC-MS:[M+H] + =900

[1390] Synthesis method of compound UB-181050

[1391]

[1392] Step 1: UB-181050b (V2235-144)

[1393] Compound UB-181050a (30 mg, 0.05 mmol) was dissolved in methanol / dichloromethane (3 / 6 mL), and a catalytic amount of palladium on carbon was added. The reaction was carried out at room temperature for 1 hour under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give a yellow oily crude product UB-181050b (30 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =562.2

[1394] Step 2: UB-181050 (V2235-148)

[1395] The method is similar to General Method 3

[1396] 1H NMR(400MHz,DMSO-d6)δ11.94(s,1H),10.97(s,1H),10.59(s,1H),9.94(s,1 H),9.02–8.77(m,3H),8.65(d,J=8.3Hz,1H),8.29(s,1H),8.01(d,J=1.7Hz, 1H),7.80(dd,J=8.0,1.6Hz,1H),7.67(td,J=9.2,8.3,4.4Hz,4H),7.56–7.4 0(m,3H),7.20(td,J=7.6,1.2Hz,1H),6.96(s,1H),5.08(dd,J=13.3,5.1Hz,1 H),4.54–4.23(m,4H),3.76(dt,J=10.7,5.7Hz,6H),3.66(t,J=5.1Hz,2H),3 .46(t,J=5.7Hz,2H),3.36(s,4H),3.26(d,J=5.8Hz,2H),3.14(q,J=5.7Hz,4 H), 2.91 (ddd, J=17.1, 13.5, 5.4Hz, 1H), 2.81 (d, J=4.4Hz, 3H), 2.70 (t, J=6. 1Hz,2H),2.64–2.56(m,1H),2.42–2.30(m,1H),2.05–1.91(m,1H).LCMS[M+H] + =926.0

[1397] Synthesis method of compound UB-181051

[1398]

[1399] Step 1: UB-181151b(V2591-001)

[1400] Compound UB-181151a (400 mg, 1.16 mmol) and HATU (879 mg, 2.13 mmol) were dissolved in DMF (20 mL), and DIPEA (447 mg, 3.47 mmol) was added. The mixture was reacted at room temperature for 1 hour. Then, Al (269 mg, 1.04 mmol) was added, and the reaction was continued at room temperature for 12 hours. After the solvent was evaporated, the reaction mixture was separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the white solid target product UB-181151b (315 mg, yield 46%).

[1401] 1H NMR (400MHz, DMSO) δ10.97(s,1H),10.28(s,1H),7.99(s,1H),7.65(d,J=8.3Hz,1H),7.5 9(d,J=9.4Hz,1H),5.08(dd,J=13.3,5.1Hz,1H),4.35(dd,J=55.4,17.3Hz,2H),4.09(q,J =5.3Hz,2H),3.71(s,2H),3.54–3.45(m,6H),3.40–3.35(m,2H),3.18(s,2H),2.95–2.85( m,1H),2.63–2.56(m,3H),2.41–2.32(m,1H),2.03–1.95(m,1H),1.37(s,9H).LCMS:[M+H] + =588.6

[1402] Step 2: UB-181051c (V2235-146)

[1403] Compound UB-181051b (30 mg, 0.05 mmol) was dissolved in methanol / dichloromethane (3 / 6 mL), and a catalytic amount of palladium on carbon was added. The reaction was carried out at room temperature for 1 hour under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give a yellow oily crude product UB-181051c (30 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =562.2

[1404] Step 3: UB-181051 (V2596-003)

[1405] The method is similar to General Method 3

[1406] 1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),11.02(s,1H),10.12(s,1H),9.89( s,1H),9.12–8.77(m,3H),8.66(s,1H),8.29(s,1H),7.83(ddd,J=18.0,7. 6,1.7Hz,2H),7.76–7.58(m,3H),7.50(tt,J=13.8,7.0Hz,4H),7.19(t,J= 7.6Hz,1H),6.98(s,1H),5.15(dd,J=13.3,5.1Hz,1H),4.56–4.30(m,2H), 4.22(t,J=6.5Hz,1H),3.76(m,8H),3.52–3.43(m,2H),3.34(s,3H),3.25( d,J=5.8Hz,2H),3.15(dt,J=11.4,4.2Hz,4H),2.98–2.87(m,1H),2.81(d, J=4.5Hz,3H),2.70(q,J=7.3,6.7Hz,1H),2.66–2.57(m,2H),2.40–2.26(m ,1H),2.18–1.93(m,1H),1.75–1.55(m,1H),1.50–1.33(m,1H).LCMS[M+H] + =925.9

[1407] Synthesis method of compound UB-181053

[1408] Step 1: UB-181053 (V2596-004)

[1409] Method analogous to General Method 3

[1410] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),11.03(s,1H),10.30(s,1H),10.11(s,1H),9.18(s,2H),8.89(q,J=4. 5Hz,1H),8.61(d,J=8.4Hz,1H),8.33(s,1H),7.84(ddd,J=15.5,7.6,1.7Hz,2H),7.69–7.37(m,7H),7.33–6. 96(m,2H),5.15(dd,J=13.3,5.1Hz,1H),3.66–3.33(m,10H),3.24(q,J=6.6Hz,2H),3.07(p,J=6.0Hz,2H),3 .02–2.87(m,3H),2.81(d,J=4.4Hz,3H),2.70–2.57(m,1H),2.42–2.25(m,1H),2.13–1.91(m,1H).LCMS[M+H] + =837.7

[1411] Synthesis of compound UB-181054

[1412] Step 1: UB-181054 (V2596-005)

[1413] The method is similar to General Method 3

[1414] 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),10.98(s,1H),10.76(d,J=5.2Hz,1H),9.99(s,1H),9.10(s,2H),8.87(t,J=4.6Hz,1H ),8.64(d,J=8.3Hz,1H),8.30(s,1H),7.97(s,1H),7.81(dd,J=8.0,1.7Hz,1H),7.81–7.44(m,6H),7.20(t,J=7.5Hz,2H),5 .08(dd,J=13.2,5.1Hz,1H),4.58–4.14(m,2H),3.48–3.32(m,8H),3.25(p,J=6.8Hz,2H),3.10(ddt,J=16.9,9.8,4.6Hz,3H ),3.01–2.86(m,3H),2.81(d,J=4.5Hz,3H),2.67–2.55(m,2H),2.37(td,J=13.3,4.7Hz,1H),2.06–1.89(m,1H).LCMS[M+H] + =837.8

[1415] Synthesis of compound UB-181084

[1416]

[1417] Step 1: UB-181084b (V2596-043)

[1418] Compound UB-181084a (30 mg, 0.05 mmol) was dissolved in THF (3 mL), and then a 1 M / L solution of trimethylphosphine in tetrahydrofuran (0.1 mL) was added, and the mixture was reacted at 50 °C for 1 hour. Water (0.5 mL) was then added, and the mixture was reacted at 50 °C for 1 hour. The reaction solution was concentrated to give a yellow, oily crude product UB-181084b (30 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =567.2

[1419] Step 2: UB-181084 (V2596-045)

[1420] The method is similar to General Method 3

[1421] 1 H NMR (400MHz, DMSO-d6) δ11.84(s,1H),11.00(s,1H),9.75(s,1H),8.88–8.77(m,2H),8.67(s,1H),8.26(s,1H),7.79(dd,J=8.0,1.6Hz,1H),7.70(d ,J=7.8Hz,1H),7.63(d,J=11.0Hz,2H),7.51(dt,J=8.2,4.0Hz,2H),7.34 (s,2H),7.18(t,J=7.6Hz,1H),6.16(s,1H),5.11(dd,J=13.3,5.1Hz,1H), 4.54–4.27(m,2H),3.73–3.65(m,3H),3.61(t,J=6.5Hz,3H),3.56(t,J=5 .9Hz,3H),3.29(s,4H),2.96(d,J=15.7Hz,3H),2.89(dd,J=13.1,5.0Hz,1 H),2.81(d,J=4.5Hz,2H),2.73(t,J=6.5Hz,2H),2.66–2.55(m,1H),2.39 (qd,J=13.3,4.4Hz,1H),2.08–1.71(m,9H),1.57–1.40(m,2H).LCMS[M+H] + =930.8

[1422] Synthesis method of compound UB-181087

[1423]

[1424] Step 1: UB-181087a(V2596-050)

[1425] Compounds UBI-1338 (42 mg, 0.12 mmol), Al-I (32 mg, 0.12 mmol), Pd(PPh3)2Cl2 (17 mg, 0.02 mmol), CuI (5 mg, 0.02 mmol), and TEA (12 mg, 0.12 mmol) were dissolved in DMF (10 mL) and reacted at 80 °C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the brown oily target product UB-181087a (30 mg, yield 42%). LCMS [M+H] + =593.7

[1426] Step 2: UB-181087b(V2596-052)

[1427] Compound UB-181084a (30 mg, 0.05 mmol) was dissolved in THF (3 mL), followed by the addition of a 1 M / L solution of trimethylphosphine in tetrahydrofuran (0.1 mL) and reacted at 50 °C for 1 hour. Water (0.5 mL) was then added, and the reaction was continued at 50 °C for 1 hour. The reaction solution was concentrated to give a yellow, oily crude product UB-181087b (30 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =567.2

[1428] Step 3: UB-181087 (V2596-054)

[1429] The method is similar to General Method 3

[1430] 1H NMR (400MHz, DMSO-d6) δ11.89(s,1H),11.01(s,1H),9.90(s,1H),8.97(s,2H),8.87(q,J=4.6Hz,1H),8.66(d,J=8.4Hz,1H),8.29(s,1H),7.81(dd,J =7.9,1.6Hz,1H),7.72(d,J=7.5Hz,1H),7.68–7.63(m,2H),7.53(t,J=7.6 Hz,3H),7.19(t,J=7.5Hz,1H),6.33–6.07(m,1H),5.16(dd,J=13.3,5.1Hz, 1H),4.56–4.05(m,2H),3.71–3.67(m,3H),3.63(d,J=6.8Hz,3H),3.42–3. 30(m,4H),3.10–2.87(m,5H),2.81(d,J=4.5Hz,2H),2.75(t,J=6.6Hz,2H), 2.67–2.56(m,1H),2.45(d,J=4.6Hz,1H),2.08–1.90(m,4H),1.81(dd,J=2 2.5,12.8Hz,5H),1.47(d,J=10.2Hz,2H),1.20(t,J=7.3Hz,3H).LCMS[M+H] + =931.0

[1431] Synthesis method of compound UB-181095

[1432]

[1433] Step 1: UB-181095b (V2596-059)

[1434] Compound UB-181095a (200 mg, 0.90 mmol) was dissolved in MeCN (30 mL), followed by the addition of K₂CO₃ (273 mg, 1.98 mmol) and butynyl p-toluenesulfonate (201 mg, 0.90 mmol), and reacted at 70 °C for 16 hours. Then, (Boc)₂O (294 mg, 1.35 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was washed once with water (10 mL), extracted once with ethyl acetate (20 mL), and the organic phase was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 1 / 3) to give the yellow oily target product UB-181095b (150 mg, yield 28%). LCMS [M+H] + =339.3

[1435] Step 2: UB-181095c(V2596-060)

[1436] Compounds UB-181095b (80 mg, 0.24 mmol), A3-I (88 mg, 0.24 mmol), Pd(PPh3)2Cl2 (33 mg, 0.05 mmol), CuI (9 mg, 0.05 mmol), and TEA (24 mg, 0.24 mmol) were dissolved in DMF (10 mL) and heated to 80 °C for 2 hours using a microwave reactor. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the target product UB-181095c (28 mg, yield 20%) as a brown solid. LCMS [M+H] + =581.5

[1437] Step 3: UB-181095d(V2596-062)

[1438] Compound UB-181095c (28 mg, 0.05 mmol) was dissolved in THF (3 mL), followed by the addition of a 1 M / L solution of trimethylphosphine in tetrahydrofuran (0.14 mL) and reacted at 50 °C for 1 hour. Water (0.5 mL) was then added, and the reaction was continued at 50 °C for 1 hour. The reaction mixture was concentrated to give a yellow, oily crude product UB-181095d (25 mg, yield 82%). This crude product was used directly in the next reaction. LCMS [M+H] + =555.3

[1439] Step 4: UB-181095 (V2596-066)

[1440] The method is similar to General Method 3

[1441] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),11.00(s,1H),9.85(s,1H),9.26(s,2H),8. 90(dd,J=18.2,5.4Hz,2H),8.66(d,J=8.5Hz,1H),8.57(s,1H),8.28(s,1H),8.05 (t,J=6.9Hz,1H),7.81(d,J=7.9Hz,1H),7.75–7.67(m,2H),7.64(d,J=8.4Hz,1H) ,7.58(d,J=7.9Hz,1H),7.52(t,J=7.9Hz,1H),7.43(s,1H),7.19(t,J=7.5Hz,1H), 5.11(dd,J=13.2,5.0Hz,1H),4.58–4.11(m,2H),3.41–3.29(m,9H),3.15(q,J=6. 6Hz,3H),3.07(d,J=8.7Hz,2H),2.96(t,J=7.3Hz,4H),2.89(dd,J=12.9,4.8Hz,1 H),2.81(d,J=4.5Hz,3H),2.60(d,J=16.9Hz,2H),2.45–2.29(m,1H),2.08–1.88( m,2H),1.71(q,J=7.8Hz,2H),1.57(q,J=6.9Hz,2H),1.52–1.38(m,4H).LCMS[M+H] + =919.0

[1442] Synthesis method of compound UB-181098

[1443]

[1444] Step 1: UB-181098b (V2596-061)

[1445] Compound UB-181098a (80 mg, 0.24 mmol), Al-I (88 mg, 0.24 mmol), Pd(PPh3)2Cl2 (33 mg, 0.05 mmol), CuI (9 mg, 0.05 mmol), and TEA (24 mg, 0.24 mmol) were dissolved in DMF (10 mL) and reacted at 80 °C for 2 hours using a microwave synthesizer. The reaction solution was filtered, the filtrate was concentrated, and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the target product UB-181098b (35 mg, yield 25%) as a brown solid. LCMS [M+H] + =581.7

[1446] Step 2: UB-181098c(V2596-064)

[1447] Compound UB-181098b (35 mg, 0.06 mmol) was dissolved in THF (3 mL), followed by the addition of a 1 M / L solution of trimethylphosphine in tetrahydrofuran (0.18 mL) and reacted at 50 °C for 1 hour. Water (0.5 mL) was then added, and the reaction was continued at 50 °C for 1 hour. The reaction mixture was concentrated to give a yellow, oily crude product UB-181098c (32 mg, 94% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =555.3

[1448] Step 3: UB-181098 (V2596-067)

[1449] The method is similar to General Method 3

[1450] LCMS[M+H] + =918.8

[1451] Compound UB-181102

[1452]

[1453] Step 1: UB-181102c(V2596-056)

[1454] Compound UB-181102a (1.8 g, 20 mmol) was dissolved in dichloromethane (50 mL), and then UB-181102b (1.15 g, 10 mmol) and BF3·Et2O (0.127 mL) were added at 0 °C. The mixture was then reacted overnight at room temperature. The reaction solution was concentrated and separated by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the colorless oily target product UB-181102c (1.4 g, 80% yield). LCMS [M+H] + =177.2

[1455] Step 2: UB-181102d(V2596-057)

[1456] Compound UB-181102c (400 mg, 2.27 mmol) was dissolved in dichloromethane (15 mL), followed by the addition of PCC (980 mg, 4.55 mmol), and the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated to give a brown solid crude product UB-181102d (380 mg, 95% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =175.2

[1457] Step 3: UB-181102f(V2596-058)

[1458] Compound UB-181102d (203 mg, 1.15 mmol) was dissolved in ethanol (10 mL), followed by the addition of one drop of acetic acid and UB-181102e (400 mg, 2.30 mmol). The mixture was reacted at room temperature for 16 hours, then NaCNBH3 (217 mg, 3.45 mmol) was added, and the reaction was continued at room temperature for 2 hours. Then, (Boc)₂O (376 mg, 1.73 mmol) and NaHCO₃ (145 mg, 1.73 mmol) were added, and the reaction was continued at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the yellow oily target product UB-181102f (230 mg, yield 50%). LCMS [M+H] + =399.4

[1459] Step 4: UB-181102g (V2596-069)

[1460] Compound UB-181102f (230 mg, 0.58 mmol) was dissolved in methanol / tetrahydrofuran / water (1 / 6 / 2 mL), and then LiOH·H₂O (36 mg, 0.87 mmol) was added and reacted at room temperature for 3 hours. The reaction solution was concentrated, washed once with water (10 mL) and ethyl acetate (10 mL), and the aqueous phase was acidified to pH 6 with 1 M HCl. The solution was extracted once with ethyl acetate (15 mL), and the organic phase was concentrated to give a colorless, oily crude product UB-181102 g (220 mg, 95% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =371.4

[1461] Step 5: UB-181102h (V2596-073)

[1462] Compound UB-181102 g (100 mg, 0.27 mmol) was dissolved in DMF (8 mL), followed by the addition of HATU (205 mg, 0.54 mmol) and DIEA (105 mg, 0.81 mmol). The mixture was reacted at room temperature for 20 minutes, then Al (63 mg, 0.24 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was washed once with water (10 mL), extracted with ethyl acetate (15 mL), and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the yellow oily target product UB-181102 h (80 mg, yield 48%). LCMS [M+H] + =612.7

[1463] Step 6: UB-181102i(V2596-074)

[1464] Compound UB-181102h (40 mg, 0.07 mmol) was dissolved in methanol / dichloromethane (1 / 10 mL), and a catalytic amount of palladium on carbon was added. The reaction was carried out at room temperature for 1 hour under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give a yellow oily crude product UB-181102i (40 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =586.7

[1465] Step 7: UB-181102(V2596-077)

[1466] The method is similar to General Method 3

[1467] 1 H NMR (400MHz, DMSO-d6) δ11.87(s,1H),11.01(s,1H),9.90(s,1H),9.85(s,1H),9.21–8.79(m,3H),8.67(d,J=8.3Hz,1H),8.28(s,1H),7.79( ddd,J=12.0,7.8,1.4Hz,2H),7.65(s,2H),7.59–7.43(m,3H),7.30–7.00(m,1H),6.19(s,1H),5.15(dd,J=13.3,5.1Hz,1H),4.40(q,J=17.5 Hz,2H),4.14(s,2H),3.71(s,3H),3.55(d,J=5.7Hz,5H),3.34(s,4H),3.04(s,1H),2.98–2.88(m,3H),2.81(d,J=4.4Hz,2H),2.68–2.56(m, 1H),2.43–2.26(m,1H),2.01(ddd,J=16.0,8.0,4.3Hz,2H),1.91–1.72(m,7H),1.67(q,J=7.2,6.7Hz,2H),1.47(d,J=13.7Hz,2H).LCMS[M+H] + =950.0

[1468] Synthesis method of compound UB-181109

[1469]

[1470] Step 1: UB-181109b (V2596-070)

[1471] Compound UB-181109a (100 mg, 0.27 mmol) was dissolved in DMF (8 mL), followed by the addition of HATU (205 mg, 0.54 mmol) and DIEA (105 mg, 0.81 mmol). The mixture was reacted at room temperature for 20 minutes, then Al (63 mg, 0.24 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was washed once with water (10 mL), extracted once with ethyl acetate (15 mL), and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the yellow oily target product UB-181109b (80 mg, yield 48%). LCMS [M+H] + =612.7

[1472] Step 2: UB-181109c(V2596-071)

[1473] Compound UB-181109b (40 mg, 0.07 mmol) was dissolved in methanol / dichloromethane (1 / 10 mL), and a catalytic amount of palladium on carbon was added. The reaction was carried out at room temperature under hydrogen atmosphere for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to give the yellow oily target product UB-181109c (40 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =586.7

[1474] Step 3: UB-181109 (V2596-080)

[1475] The method is similar to General Method 3

[1476] LCMS[M+H] + =950.0

[1477] Synthesis method of compound UB-181112

[1478]

[1479] Step 1: UB-181112b(V2596-082)

[1480] Compound UB-181112a (60 mg, 0.10 mmol) was dissolved in THF (10 mL), followed by the addition of a 1 M / L tetrahydrofuran solution of trimethylphosphine (0.31 mL) and reacted at 50 °C for 1 hour. Water (0.5 mL) was then added, and the reaction was continued at 50 °C for 1 hour. The reaction mixture was concentrated and purified by column chromatography (methanol / dichloromethane = 1 / 10) to obtain the brown oily target product UB-181112b (30 mg, yield 48%). LCMS [M+H] + =553.6

[1481] Step 2: UB-181112(V2596-088)

[1482] The method is similar to General Method 3

[1483] 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),11.01(s,1H),10.21(s,1H),9.16–8.91(m,2H),8.86(d,J=5.0Hz,1H),8.61(s,1H),8.51(s,1H),7.81(dd ,J=8.0,1.6Hz,1H),7.76–7.63(m,3H),7.54(q,J=7.2Hz,3H),7.22(d,J=7.0Hz,1H),6.21(s,1H),5.16(dd,J=13.3,5.1Hz,1H),4.55–4.22(m,3 H),3.80(t,J=5.3Hz,7H),3.70(t,J=6.6Hz,4H),3.40(d,J=7.6Hz,3H),3.12(t,J=7.2Hz,3H),2.92(ddd,J=17.2,13.6,5.4Hz,1H),2.81(d,J=4 .9Hz,4H),2.66–2.55(m,1H),2.43(dd,J=13.3,4.5Hz,1H),2.01(ddt,J=12.6,9.9,4.9Hz,1H),1.82(d,J=11.8Hz,5H),1.45(s,2H).LCMS[M+H] + =907.9

[1484] Synthesis of compound UB-181114

[1485] Step 1: UB-181114(V2596-094)

[1486] The method is similar to General Method 3

[1487] 1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),11.00(s,1H),10.21(s,1H),9.03–8 .90(m,2H),8.86(d,J=4.8Hz,1H),8.60(s,1H),8.17–8.01(m,1H),7.81(dd ,J=8.0,1.6Hz,1H),7.70(d,J=7.8Hz,2H),7.65(s,1H),7.61–7.47(m,2H) ,7.21(t,J=7.6Hz,1H),6.23(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.52–4. 25(m,3H),3.80(t,J=5.1Hz,5H),3.72–3.63(m,5H),3.59(d,J=15.2Hz,1H ),3.41(q,J=6.2,5.3Hz,3H),3.14(s,3H),3.00–2.85(m,1H),2.87–2.74(m ,3H),2.64–2.57(m,1H),2.39(dd,J=13.2,4.5Hz,1H),2.11–1.91(m,1H),1 .85(q,J=11.3,8.4Hz,5H),1.70(d,J=11.0Hz,1H),1.47(s,2H).LCMS[M+H] + =907.8

[1488] Synthesis method of compound UB-181115

[1489] Step 1: UB-181115(V2596-097)

[1490] The method is similar to General Method 3

[1491] 1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),11.00(s,1H),10.04(s,1H),9.00(s,2H ),8.94–8.81(m,1H),8.63(d,J=8.2Hz,1H),8.31(s,1H),7.82(dd,J=7.9,1.6 Hz,1H),7.74–7.63(m,3H),7.60–7.47(m,3H),7.21(d,J=7.6Hz,1H),6.59(s, 1H),5.11(dd,J=13.3,5.1Hz,1H),4.55–4.23(m,3H),3.80(t,J=5.2Hz,3H),3 .69(t,J=6.7Hz,5H),3.49–3.34(m,4H),3.14(qd,J=7.0,4.7,3.9Hz,2H),3.0 6–2.95(m,1H),2.92–2.85(m,1H),2.80(dd,J=12.8,5.6Hz,4H),2.66–2.54(m ,1H),2.39(dd,J=13.2,4.6Hz,1H),2.12(d,J=11.8Hz,2H),2.06–1.94(m,1H) ,1.87(d,J=11.7Hz,2H),1.47(q,J=12.2Hz,2H),1.37–1.24(m,3H).LCMS[M+H] + =916.8

[1492] Synthesis of compound UB-181119

[1493] Step 1: UB-181119 (V2596-106)

[1494] The method is similar to General Method 3

[1495] 1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),11.02(s,1H),10.09(s,1H),9.05–8.8 8(m,3H),8.83(d,J=4.9Hz,1H),8.58(s,1H),8.07(dd,J=7.9,6.4Hz,1H),7.7 9(dd,J=7.9,1.6Hz,1H),7.73(d,J=7.5Hz,1H),7.65(t,J=8.5Hz,2H),7.53(q ,J=7.8Hz,2H),7.35(s,2H),7.19(t,J=7.5Hz,1H),6.49(s,1H),5.17(dd,J=1 3.3,5.1Hz,1H),4.59–4.17(m,3H),3.79(t,J=5.2Hz,4H),3.70(t,J=6.7Hz,4 H),3.47–3.38(m,2H),3.36–3.24(m,4H),3.13(dd,J=7.7,3.8Hz,2H),3.01–2 .86(m,2H),2.81(d,J=4.9Hz,4H),2.67–2.56(m,1H),2.48–2.37(m,1H),2.19 –1.94(m,4H),1.85(d,J=12.0Hz,2H),1.45(p,J=10.8,9.2Hz,2H).LCMS[M+H] + =907.7

[1496] Synthesis method of compound UB-181120

[1497] Step 1: UB-181120 (V2596-107)

[1498] The method is similar to General Method 3

[1499] 1H NMR (400MHz, DMSO-d6) δ11.93(s,1H),11.02(s,1H),9.98(s,1H),9.04(s,2H),8.88(d,J=4.7Hz,1H),8.65(d,J=8.5Hz,1H),8.30(s,1H),7.82(dd ,J=8.0,1.6Hz,1H),7.73(d,J=7.5Hz,1H),7.66(d,J=7.2Hz,2H),7.53(t d, J=7.8, 3.6Hz, 3H), 7.20 (t, J=7.6Hz, 1H), 6.56 (s, 1H), 5.17 (dd, J=13. 3,5.1Hz,1H),4.63–4.25(m,3H),3.80(t,J=5.3Hz,5H),3.70(t,J=6.7Hz ,5H),3.38(s,5H),3.13(dd,J=7.4,3.9Hz,2H),3.04–2.85(m,2H),2.93– 2.76(m,4H),2.69–2.55(m,1H),2.45(d,J=4.4Hz,1H),2.11(d,J=9.5Hz, 2H),2.06–1.94(m,1H),1.93–1.74(m,2H),1.62–1.39(m,2H).LCMS[M+H] + =916.7

[1500] Synthesis method of compound UB-181121

[1501] Step 1: UB-181121 (V2596-111)

[1502] The method is similar to General Method 3

[1503] 1H NMR (400MHz, DMSO-d6) δ11.62(s,1H),11.02(s,1H),9.39(s,1H),8.77(dd,J=10.0,6.3Hz,2H),8.20(s,1H),7.75(ddd,J=13.4,7.8,1 .3Hz,2H),7.65(dd,J=7.7,1.1Hz,1H),7.62–7.41(m,4H),7.14(t,J=7.5Hz,3H),6.21(d,J=7.6Hz,1H),5.17(dd,J=13.3,5.2Hz,1H), 4.55–4.20(m,2H),4.09(d,J=12.8Hz,2H),3.71(dt,J=19.2,6.0Hz,4H),3.09(s,2H),3.00–2.86(m,2H),2.85–2.77(m,5H),2.74–2.5 6(m,5H),2.44(d,J=4.6Hz,1H),2.01(dt,J=15.6,4.7Hz,4H),1.83(d,J=12.0Hz,2H),1.79–1.65(m,2H),1.55–1.30(m,5H).LCMS[M+H] + =916.9

[1504] Synthesis method of compound UB-181122

[1505] Step 1: UB-181122 (V2596-112)

[1506] The method is similar to General Method 3

[1507] 1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),11.00(s,1H),9.70(s,1H),9.03–8.77(m,3H ),8.68(d,J=8.4Hz,1H),8.26(s,1H),7.79(dd,J=7.9,1.6Hz,1H),7.70(d,J=7.9Hz ,1H),7.65(s,1H),7.53(dd,J=8.1,4.9Hz,3H),7.47(s,1H),7.18(t,J=7.7Hz,2H), 6.25(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.56–4.24(m,2H),4.10(d,J=12.7Hz,2H ),3.78(t,J=5.2Hz,2H),3.69(t,J=6.7Hz,3H),3.40(p,J=7.8Hz,2H),3.14(tt,J=6 .9,3.9Hz,2H),2.97(d,J=9.3Hz,1H),2.95–2.85(m,1H),2.85–2.76(m,4H),2.74–2 .54(m,5H),2.39(qd,J=13.1,4.4Hz,1H),2.10(d,J=11.7Hz,2H),2.03(dd,J=7.3,4 .4Hz,1H),1.92–1.80(m,2H),1.73(d,J=12.5Hz,2H),1.61–1.34(m,4H).LCMS[M+H] + =916.1

[1508] Synthesis of compound UB-181123

[1509] Step 1: UB-181123 (V2596-113)

[1510] The method is similar to General Method 3

[1511] 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),11.00(s,1H),9.90(s,1H),8.78(d,J=4.8Hz,1H),8.52(s,1H),8.44(s,1H),7.77(d,J=7.8Hz,1H),7.71 (d,J=7.9Hz,1H),7.64(s,1H),7.56–7.35(m,3H),7.26–7.09(m,1H),6.98–6.79(m,2H),6.35(d,J=7.6Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4. 58–4.18(m,2H),3.69(dd,J=15.4,8.7Hz,4H),3.42(d,J=5.2Hz,4H),3.38(s,1H),3.10(s,2H),3.04(s,3H),2.91(ddd,J=17.6,13.6,5.5Hz,2H ),2.85–2.77(m,4H),2.68–2.53(m,2H),2.39(dd,J=13.1,4.5Hz,1H),2.17–1.93(m,4H),1.84(d,J=12.0Hz,2H),1.40–1.28(m,4H).LCMS[M+H] + =908.0

[1512] Synthesis method of compound UB-181132

[1513] Step 1: UB-181132 (V2596-128)

[1514] The method is similar to General Method 3

[1515] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.74(d,J=40.0Hz,2H),9.00(s,2H),8.28(s,1H),7.93(dd,J=7.8,1.5Hz,1H),7.80(td,J=7.8,1.6Hz,1H),7. 73(dd,J=7.6,1.0Hz,1H),7.69–7.60(m,2H),7.58–7.47(m,2H),7.44(d,J =8.3Hz,2H),7.33(s,2H),6.54(s,1H),5.17(dd,J=13.3,5.1Hz,1H),4.58 –4.27(m,2H),3.82–3.75(m,3H),3.70(t,J=6.7Hz,6H),3.36(d,J=31.2Hz ,5H),3.13(s,2H),3.04–2.82(m,2H),2.80(t,J=6.7Hz,2H),2.68–2.55(m ,1H),2.45(d,J=4.6Hz,1H),2.10(d,J=11.7Hz,2H),2.06–1.93(m,2H),1. 85(d,J=11.9Hz,2H),1.45(q,J=12.5Hz,2H),1.33–1.25(m,2H).LCMS[M+H] + =884.8

[1516] Synthesis method of compound UB-181133

[1517] Step 1: UB-181133 (V2596-129)

[1518] The method is similar to General Method 3

[1519] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.80(d,J=46.1Hz,2H),8.99(s,2H),8 .29(s,1H),7.94(dd,J=7.8,1.5Hz,1H),7.81(td,J=7.8,1.6Hz,1H),7.70(d, J=7.9Hz,1H),7.67–7.62(m,2H),7.53(dd,J=7.7,1.2Hz,2H),7.44(d,J=8.1H z,2H),7.38(s,1H),6.58(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.52–4.24(m, 3H),3.79(t,J=5.2Hz,3H),3.69(t,J=6.7Hz,3H),3.38(d,J=25.4Hz,5H),3. 13(d,J=7.2Hz,2H),3.06–2.84(m,2H),2.79(t,J=6.6Hz,2H),2.67–2.53(m,1 H),2.39(qd,J=13.2,4.5Hz,1H),2.12(d,J=11.7Hz,2H),2.06–1.95(m,2H),1 .91–1.79(m,2H),1.47(q,J=12.8,12.3Hz,2H),1.33–1.25(m,2H).LCMS[M+H] + =884.8

[1520] Synthesis of compound UB-181134

[1521] Step 1: UB-181134 (V2596-133)

[1522] The method is similar to General Method 3

[1523] 1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.61(s,2H),8.94(s,2H),8.25(s,1H) ,7.93(dd,J=7.8,1.5Hz,1H),7.79(td,J=7.9,1.6Hz,1H),7.73(d,J=7.5Hz,1 H),7.65(t,J=7.9Hz,2H),7.52(dt,J=11.8,7.6Hz,2H),7.30(d,J=8.1Hz,2H ),6.93(d,J=8.3Hz,2H),6.22(s,1H),5.17(dd,J=13.3,5.1Hz,1H),4.52–4.2 2(m,2H),4.07(d,J=13.2Hz,2H),3.79(t,J=5.3Hz,2H),3.70(t,J=6.7Hz,2H ),3.46–3.30(m,2H),3.13(t,J=5.8Hz,2H),2.94(ddd,J=13.6,10.9,6.9Hz,2 H),2.80(t,J=6.7Hz,2H),2.72–2.60(m,3H),2.43(d,J=9.0Hz,1H),2.18–1.9 3(m,4H),1.91–1.76(m,2H),1.71–1.59(m,2H),1.52–1.32(m,5H).LCMS[M+H] + =884.0

[1524] Synthesis of compound UB-181135

[1525] Step 1: UB-181135 (V2596-134)

[1526] The method is similar to General Method 3

[1527] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.58(s,2H),8.92(dt,J=6.2,3.2Hz,2H ),8.24(s,1H),8.05(dd,J=7.8,6.4Hz,1H),7.93(dd,J=7.7,1.5Hz,1H),7.79 (td,J=7.8,1.6Hz,1H),7.75–7.60(m,3H),7.60–7.42(m,2H),7.30(d,J=8.1H z,2H),6.93(d,J=8.3Hz,2H),6.24(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.61 –4.22(m,2H),4.07(d,J=12.7Hz,2H),3.78(t,J=5.2Hz,2H),3.69(t,J=6.7Hz ,2H),3.47–3.34(m,2H),3.15(q,J=5.6Hz,2H),2.92(s,1H),2.79(t,J=6.7Hz ,2H),2.58(m,4H),2.39(dd,J=13.1,4.6Hz,1H),2.17–2.05(m,2H),2.06–1.9 6(m,2H),1.92–1.77(m,2H),1.73–1.50(m,2H),1.48–1.33(m,5H).LCMS[M+H] + =883.9

[1528] Synthetic method of compound UB-181139

[1529] Step 1: UB-181139 (V2596-139)

[1530] The method is similar to General Method 3

[1531] 1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.59(s,1H),9.43(s,1H),8.93(s,2H) ,8.48(d,J=8.1Hz,1H),8.29(s,1H),7.94(dd,J=8.0,1.6Hz,1H),7.74(dd,J =8.1,5.3Hz,2H),7.66(d,J=7.5Hz,1H),7.59–7.34(m,4H),7.09(d,J=8.3Hz ,2H),6.23(s,1H),5.17(dd,J=13.3,5.2Hz,1H),4.63–4.24(m,2H),4.09(d, J=12.7Hz,2H),3.79(t,J=5.2Hz,2H),3.70(t,J=6.7Hz,2H),3.39(s,2H),3. 27(s,3H),3.13(p,J=5.4Hz,2H),3.06–2.86(m,2H),2.80(t,J=6.7Hz,2H),2 .69(t,J=11.9Hz,2H),2.63–2.56(m,2H),2.49–2.33(m,1H),2.17–1.96(m,4 H),1.84(d,J=11.3Hz,2H),1.78–1.60(m,2H),1.56–1.35(m,4H).LCMS[M+H] + =936.9

[1532] Synthesis method of compound UB-181140

[1533] Step 1: UB-181140 (V2596-140)

[1534] The method is similar to General Method 3

[1535] 1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),9.58(s,1H),9.43(s,1H),8.85(s,2 H),8.48(d,J=8.2Hz,1H),8.29(s,1H),7.94(dd,J=8.0,1.6Hz,1H),7.82–7 .58(m,3H),7.60–7.26(m,4H),7.09(d,J=8.4Hz,2H),6.24(s,1H),5.11(d d,J=13.3,5.1Hz,1H),4.59–4.25(m,2H),4.09(d,J=12.8Hz,2H),3.78(t,J =5.1Hz,2H),3.69(t,J=6.7Hz,2H),3.27(s,3H),3.15(q,J=6.2,5.5Hz,2H ),3.02–2.85(m,3H),2.79(t,J=6.7Hz,2H),2.73–2.54(m,5H),2.45–2.30( m,1H),2.10(d,J=11.5Hz,2H),2.00(dp,J=12.1,4.4,3.5Hz,2H),1.85(d, J=12.2Hz,2H),1.74–1.64(m,2H),1.43(dd,J=12.5,4.1Hz,4H).LCMS[M+H] + =936.9

[1536] Synthetic method of compound UB-181141

[1537] Step 1: UB-181141 (V2596-145)

[1538] The method is similar to General Method 3

[1539] 1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),11.02(s,1H),9.94(s,1H),9.12(s,2H),8.91(d ,J=4.8Hz,1H),8.71(s,1H),8.44(s,1H),8.31(s,1H),8.25(dd,J=9.7,2.6Hz,1H),7. 82(dd,J=7.9,1.6Hz,1H),7.73(d,J=7.5Hz,1H),7.66(d,J=7.5Hz,1H),7.54(td,J=7. 5,4.7Hz,2H),7.45(d,J=9.8Hz,1H),7.18(t,J=7.5Hz,1H),6.50(s,1H),5.17(dd,J=1 3.3,5.1Hz,1H),4.62–4.20(m,3H),3.81(t,J=5.3Hz,2H),3.70(t,J=6.6Hz,6H),3.59 –3.41(m,3H),3.42(d,J=11.5Hz,1H),3.11(d,J=6.3Hz,2H),2.99–2.88(m,2H),2.87– 2.71(m,4H),2.66–2.57(m,1H),2.44(dd,J=13.2,4.4Hz,1H),2.23–2.06(m,2H),2.06 –1.92(m,1H),1.84(d,J=11.9Hz,2H),1.54–1.38(m,2H),1.36–1.24(m,3H).LCMS[M+H] + =917.8

[1540] Synthesis method of compound UB-181142

[1541] Step 1: UB-181142 (V2596-146)

[1542] The method is similar to General Method 3

[1543] 1H NMR (400MHz, DMSO-d6) δ11.84(s,1H),11.00(s,1H),9.66(s,1H),8.79(d,J= 45.6Hz,4H),8.42(s,1H),8.26(s,1H),8.14(s,1H),7.79(d,J=7.9Hz,1H),7. 70(d,J=7.9Hz,1H),7.65(s,1H),7.53(d,J=7.8Hz,2H),7.24(d,J=52.1Hz,1H ),7.15(d,J=7.5Hz,1H),6.44(d,J=7.1Hz,1H),5.11(dd,J=13.3,5.1Hz,1H), 4.62–4.19(m,2H),3.77(d,J=5.4Hz,2H),3.69(t,J=6.7Hz,2H),3.60(s,4H) ,3.15(d,J=8.2Hz,2H),3.02–2.85(m,3H),2.84–2.71(m,4H),2.68–2.56(m,2 H),2.39(qd,J=14.3,13.7,5.1Hz,1H),2.10(d,J=12.3Hz,2H),2.05–1.92(m, 2H),1.85(d,J=12.0Hz,2H),1.58–1.37(m,2H),1.34–1.22(m,4H).LCMS[M+H] + =918.8

[1544] Synthesis of compound UB-181184

[1545] Step 1: UB-181184 (V2891-057)

[1546] The method is similar to General Method 3

[1547] 1H NMR (400MHz, DMSO-d6) δ11.75(s,1H),11.00(s,1H),9.83(s,1H),9.23(s,2H),8.84(d,J=4.8Hz,1H),8.71(d,J=8.4Hz,1H),8.28(s ,1H),7.90(s,1H),7.84–7.78(m,2H),7.74–7.68(m,3H),7.56(dd,J=16.5,8.0Hz,2H),7.18(t,J=7.5Hz,1H),5.11(dd,J=13.3,5.1H z,1H),4.54–4.27(m,2H),3.82–3.73(m,3H),3.39(s,2H),3.19(d,J=16.2Hz,3H),2.99(t,J=7.5Hz,2H),2.81(d,J=4.5Hz,2H),2.6 7(s,2H),2.45–2.27(m,1H),2.18(s,2H),2.10–1.93(m,3H),1.89–1.70(m,6H),1.63–1.37(m,3H),1.20(t,J=7.3Hz,1H).LCMS[M+H] + =871.7

[1548] Synthesis of compound UB-181186

[1549] Step 1: UB-181186(V2891-061)

[1550] The method is similar to General Method 3

[1551] LCMS[M+H] + =871.8

[1552] Synthetic method of compound UB-181187

[1553] Step 1: UB-181187(V2891-064)

[1554] The method is similar to General Method 3

[1555] 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),11.57(s,1H),11.02(s,1H),9.30(s,2H),9.00–8.91(m,1H),8.86(t,J=7.8Hz,2H),8.52–8.23(m,2 H),8.07(d,J=9.6Hz,1H),8.02–7.87(m,2H),7.86(d,J=7.9Hz,1H),7.73(dd,J=15.2,7.6Hz,2H),7.59(ddd,J=26.4,12.5,6.5Hz,2H),7.2 6(d,J=6.4Hz,1H),6.13(s,1H),5.17(dd,J=13.3,5.2Hz,1H),4.62–4.25(m,3H),3.71(s,2H),3.14(dt,J=15.3,5.0Hz,5H),3.05–2.91(m ,5H),2.82(d,J=4.4Hz,3H),2.70–2.56(m,3H),2.31(d,J=20.3Hz,1H),2.07–1.95(m,2H),1.88(d,J=15.3Hz,5H),1.50(s,3H).LCMS[M+H] + =873.8

[1556] Synthesis method of compound UB-181188

[1557] Step 1: UB-181188(V2891-065)

[1558] The method is similar to General Method 3

[1559] 1H NMR (400MHz, DMSO-d6) δ12.35(s,1H),11.79(s,1H),11.00(s,1H),9.29(s,2H),8.97(t,J=4.6Hz,1H),8.84(d,J=8.4Hz,1H),8.41(s,1H),8.13( dd,J=9.6,2.9Hz,1H),7.98–7.82(m,2H),7.80–7.68(m,2H),7.61(dd,J=10.0,7.6Hz,3H),7.26(t,J=7.6Hz,1H),6.15(s,1H),5.11(dd,J=13.3, 5.1Hz,1H),4.55–4.17(m,2H),3.51(d,J=14.4Hz,4H),3.18(q,J=6.3,5 .0Hz,8H),3.00(t,J=7.4Hz,2H),2.95–2.86(m,1H),2.82(d,J=4.5Hz,3H ),2.65–2.55(m,1H),2.39(dd,J=13.3,4.7Hz,1H),2.01(tt,J=10.5,4.9Hz,2H),1.87(d,J=15.6Hz,5H),1.51(dt,J=14.7,7.5Hz,2H).LCMS[M+H] + =873.8

[1560] Synthetic methods of compounds UB-181170 & 181179

[1561]

[1562] Step 1: UB-181170b (V2891-013)

[1563] Compound UB-181179a (1 g, 3.57 mmol) was dissolved in THF (30 mL), and CDI (694 mg, 4.29 mmol) was added. The mixture was refluxed for 18 hours. After filtration, the solid was slurried through diethyl ether and filtered again to obtain the white solid target product UB-181170b (1 g, 100% yield). LCMS [M+H] + =263.2

[1564] Step 2: UB-181170c(V2891-020)

[1565] Compound UB-181170b (500 mg, 1.91 mmol) was dissolved in ethanol (20 mL), and a catalytic amount of palladium on carbon was added. The reaction was carried out at room temperature for 6 hours under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to give a yellow oily crude product UB-181170c (260 mg, 100% yield). This crude product was used directly in the next reaction. LCMS [M+H] + =129.0

[1566] Step 3: UB-181170e(V2891-022)

[1567] Compound UB-181170c (260 mg, 2.03 mmol) was dissolved in MeCN (20 mL), followed by the addition of TEA (339 mg, 3.35 mmol) and UB-181170d (1.1 g, 3.05 mmol). The reaction mixture was refluxed for 18 hours. The reaction mixture was washed once with water, extracted with dichloromethane, and the organic phase was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to give the white solid target product UB-181170e (180 mg, yield 24%). LCMS [M+H] + =371.1

[1568] Step 4: UB-181170g (V2891-025)

[1569] Compounds UB-181170f (70 mg, 0.23 mmol), UB-181170e (84 mg, 0.23 mmol), Pd(PPh3)2Cl2 (16 mg, 0.02 mmol), CuI (9 mg, 0.05 mmol), and TEA (23 mg, 0.23 mmol) were dissolved in DMF (5 mL) and reacted at 80 °C for 2 hours using a microwave synthesizer. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (methanol / dichloromethane = 1 / 10) to obtain the target product UB-181170g (30 mg, yield 24%) as a brown solid.

[1570] Step 5: UB-181170 (V2891-027)

[1571] Compound P1 (21 mg, 0.05 mmol) was dissolved in DMF (5 mL), followed by the addition of HATU (31 mg, 0.08 mmol) and DIEA (14 mg, 0.11 mmol). The reaction was carried out at room temperature for 20 minutes, and then UB-181170 g (30 mg, 0.05 mmol) was added, with the reaction continued at room temperature ...

Claims

1. A TED compound or a pharmaceutically acceptable salt thereof, characterized in that, The TED compounds mentioned are selected from the following table:

2. The TED compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The TED compound is either compound 937 or 961:

Images