NZ764814B2

NZ764814B2 - A conjugate of a tubulysin analog with branched linkers

Info

Publication number: NZ764814B2
Application number: NZ764814A
Authority: NZ
Inventors: Lu Bai; Xiang Cai; Mingjun Cao; Shun Gai; Huihui Guo; Yuanyuan Huang; Junxiang Jia; Jun Lei; Wenjun Li; Qianqian Tong
Original assignee: Hangzhou Dac Biotech Co Ltd
Filing date: 2017-12-31
Publication date: 2024-05-24

Abstract

The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.

Claims

1. A compound which is a side chain-linkaged conjugate compound of the Formula (I) : wherein “ ” represents a single bond; n is 1 to 30; T is a cell-binding agent/molecule, selected from the group consisting of an antibody, a single chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single chain monoclonal antibody, a monoclonal antibody fragment that binds to a target cell, a chimeric antibody, a chimeric antibody fragment that binds to a target cell, a domain antibody, a domain antibody fragment that binds to a target cell, an adnectin that mimics antibody, DARPin, a binding peptide, and an immunotherapeutic protein; L and L are independently adsent or independently selected from O, NH, N, S, P, NNH, 3 3 3’ NHNH, N(R ), N(R )N(R ), CH, CO, C(O)NH, C(O)O, NHC(O)NH, and NHC(O)O; R and R are independently H, C1~C8 alky, C2~C8 heteroalkyl, C2~C8 heterocyclic, C3~C8 aryl, C3~C8 Ar-alkyl, C3~C8 cycloalkyl, C3~C8 alkylcycloalkyl, C3~C8 heterocycloalkyl, C3~C8 het- eroalkylcycloalkyl, C3~C8 carbocyclic, or C3~C8 alkylcarbonyl; W, V , and V are independently composed of the following structures: *(CH CH O) * 2 2 r , , , , , ; , COOH COOH , , , , , , , COOH * N* N* N* * S* m m m , , , , , , , O R R ' * R ' * COOH *X Y 5 S* * S * m m , , , , , , H O O N COOH , , , , O O O , , , , (OCH CH ) OCH 2 2 r 3 , , , , N(CH CH O) CH (OCH CH ) OCH O 2 2 r 3 2 2 r 3 wherein the (*) atom is the site of attachment; X and Y are independently NH, O, or S; R , R ’ are are independently selected from H, C -C of alkyl; C ~C of alkenyl, alkynyl, heteroal- 5 5 1 8 2 8 kyl, or amino acid; C3-C8 of aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, het- eroaralkyl, alkylcarbonyl, or glycoside; or pharmaceutical cation salts r is 0-100; m is 0-20; w is 1 or 2 or 3; v and v are independently 0, 1 or 2, provided that v and v are not 0 at the same time; 1 2 1 2 wherein when v1 or v2 is 0, it means one of the side chain Q1 or Q2 fragment is absent; Q and Q are independently absent or independently selected from the following structures: Iq-07, Iq-08, Iq-12, Iq-14, Iq-17, , Iq-19, Iq-20, Iq-23, wherein R is selected from H, HC(O), CH C(O), CH C(NH), C -C alkyl; 25 3 3 1 8 X1 is selected from NH, N(R ’), O, CH2, S, C(O); p p are independently 0-10 but are not 0 at the same time; q1, is independently 0-10; R ’ is selected from H and C -C alkyl; D is selected from I-01 to I-69: I-01 , I-02 , I-03 , I-04 , I-05 , I-06 , I-07 , I-08 , I-09 , I-10 , I-11 , I-12 , I-13 , I-14 , I-15 , I-16 , I-17 , I-18 , I-19 , I-20 , I-21 , I-22 , I-23 , I-24 , I-25 , I-26 , I-27 , I-28 , I-29 , I-30 , I-31 , I-32 , I-33 , I-34 , I-35 , I-36 , I-37 , I-38 , I-39 , I-40 , I-41 , I-42 , I-43 , I-44 , I-45 , I-46 , I-47 , I-48 , I-49 , I-50 , I-51 , I-52 , I-53 , I-54 , I-55 , I-56 , I-57 , I-58 , I-59 , I-60 , I-61 , I-62 , I-63 , I-64 , I-65 , I-66 , I-67 , I-68 , I-69 , or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystal- line structures of these compounds; or their optical isomers, racemates, diastereomers or enantio- mers; wherein R is H; C -C of linear or branched alkyl or heteroalkyl; C -C of linear or 1 8 2 8 branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 linear or branched of aryl, Ar- 17 17 18 alkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR ), carbamate (-C(O)NR R ); or 1-8 carbon atoms of carboxylate, esters, ether, or amide; or R is absent and the oxygen forms a ketone, or combination above thereof; Z and Z are independently H, OH, NH 2, O, NH, COOH, COO, C(O),C(O), 18 18 18 18 C(O)NH, C(O)NH , R , OCH OP(O)(OR ) , OC(O)OP(O)(OR ) , OPO(OR ) , 2 2 2 2 18 18 18 18 18 18 NHPO(OR ) , OP(O)(OR )OP(O)(OR ) , OC(O)R , OC(O)NHR , OSO (OR ), O-(C -C 2 2 2 4 12- glycoside), of linear or branched alkyl or heteroalkyl; C -C of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 linear or branched of aryl, Ar-alkyl, heterocyclic, carbocy- clic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR ), carba- 17 18 mate (-C(O)NR R ), and link to W idenpendently; 17 18 R and R are independently H, C1-C8 linear or branched alkyl or heteroalkyl; C2-C8 of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C -C linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl.

2. A compound which is a side chain-linkaged conjugate compound of the Formula (III) : (III) wherein D, W, w, L1, L2, Q1, Q2, V1, V2, v1, v2, n, T are defined as in claim 1.

3. A compound which is a side chain-linkage compound of Formula (IV), which can readily react to a cell-binding agent/molecule T to form a conjugate of Formula (I) according to claim 1: wherein D, W, w, L , L , Q , Q , V , V , v , and v are defined as in claim 1; 1 2 1 2 1 2 1 2 Lv1 is selected from: acyl halide (acid halide), N-hydroxysuccinimide ester, ma- leimide, monosubstituted maleimide, disubstituted maleimide, monosubstituted succinimide, disubstituted succinimide, substituted maleic acid, -CHO aldehyde, methyl- sulfonephenyloxadiazole (ODA), alkyloxyamino, azido, or hydrazide ; wherein X1’ is F, Cl, Br, I or Lv3; Lv3 is a leaving group selected from F, Cl, Br, I, nitrophenol, N-hydroxysuccinimide (NHS), phenol, dinitrophenol, pentafluorophenol, tetrafluorophenol, difluorophenol, monofluoro- phenol, pentachlorophenol, triflate, imidazole, dichlorophenol, tetrachlorophenol, 1-hydroxyben- zotriazole, tosylate, mesylate, 2-ethylphenylisoxazolium-3 '-sulfonate, anhydrides, acetyl anhy- dride, formyl anhydride, or an intermediate molecule generated with a condensation reagent for peptide coupling reactions or for Mitsunobu reactions.

4. A compound which is a side chain-linkage compound of Formula (V), which can readily re- act to a cell-binding agent/molecule T to form a conjugate of Formula (III) according to claim 2: wherein D, W, w, L1, L2, Q1, Q2, V1, V2, v1, and v2 are defined as in Formula (I) in claim 1; wherein Lv1 and Lv2 have independently the same definition as Lv1 in Formula (IV) in claim 3.

5. A conjugate compound having one of the following structures: a-05, a-06, a-07, a-08, a-09, a-10, a-11, a-12, a-13, a-14, a-15, a-16, a-17, a-19, a-20, a-21, a-22, a-23, a-24, a-25, a-28, a-29, a-30, a-31, a-32, a-33, a-34, a-35, a-36, a-37, a-38, a-39, a-40, a-41, a-42, a-43, a-44, a-45, a-47, a-48, a-49, a-50, a-55, a-56, a-58, a-59, a-60, a-61, a-62, a-66, a-67, a-68, a-69, a-70, a-71, a-72, a-73, a-74, a-75, a-76, a-77, a-78, a-79, a-81, a-82, a-83, a-84, a-86, a-87, a-88, a-89, a-90, a-91, a-92, a-94, or a pharmaceutically acceptable salts, hydrates, hydrated salt, optical isomer, racemate, diastere- omer or enantiomer thereof; wherein mAb is an antibody or a cell-binding agent/molecule; wherein X , X1, Z2, Z3, q1, R , and n are defined as abovein claim 1; X is O, S, NH, NHNH, or CH ; p, p1 and p2 are independently 1-10; Y is CH or N.

6. A conjugate compound having one of the following structures of b-01 to b-29: b-01, b-02, b-03, b-04, b-05, b-06, b-07, b-08, b-09, b-10, b-11, b-12, b-13, b-14, b-15, b-16, b-17, b-18, b-19, b-20, b-21, b-22, b-23, a pharmaceutically acceptable salt, hydrate, hydrated salt, optical isomer, racemate, diastereomer or enantiomer thereof; wherein mAb, X1, X2, p1, p2, q1, q2, R , m, and n are as defined in claim 5; and wherein p and p’ are 1 to 10; wherein X3 is O, S, NH, NHNH, or CH2.

7. A side chain-linkage compound having one of the following structures: c-01, c-02, c-03, c-04, c-05, c-06, c-08, c-09, c-10, c-11, c-12, c-13, c-14, c-15, O HOOC c-16, O O R O HOOC c-17, c-18, c-19, c-20, c-21, c-22, c-23, c-24, c-25, c-26, c-27, c-28, c-29, c-30, c-31, c-32, c-33, c-34, c-35, c-36, c-37, c-38, c-39, c-40, c-41, c-42, c-43, c-44, c-45, c-46, c-47, c-48, c-49, c-50, c-51, c-52, c-53, c-54, c-55, c-56, c-57, c-58, c-59, c-61, c-62, c-63, c-64, c-65, c-66, c-67, c-68, c-69, c-70, c-71, c-72, c-73, c-74, c-75, c-76, c-77, c-78, c-79, c-80, c-81, c-83, c-84, c-85, c-86, c-88, c-89, c-90, c-91, c-92, c-93, c-94, c-96, or a pharmaceutically acceptable salt, hydrate, hydrated salts, optical isomer, racemate, diasteremer or enantiomer thereof; 1 2 3 wherein X , Z , Z , p, p1, p2, q1, q2, Lv3, R25, and m are defined in claim 1 or claim 3; and wherein X is as defined in claim 5.

8. A conjugate compound having one of the following structures: d-01, d-02, d-03, d-04, d-05, d-05a, d-06, d-07, d-08, d-09, d-10, d-11, d-12, d-13, d-14, d-15, d-16, d-17, d-18, d-19, d-20, d-21, S H O CO H O R d-22, wherein X , Z , Z , p, p , p , p , q , q Lv R and m are as defined in claim 1; 1 2 3 1 2 3 1 2, 3, 25, wherein X2 is as defined in claim 5; wherein X is as defined in claim 6; and wherein p’ is 1 to 10.

9. The compound of any one of claims 1, 2, 5, and 6, wherein the cell-binding agent/molecule T is selected from the group consisting of an antibody, an immunotherapeutic protein, a probody, a nanobody, and a binding peptide.

10. The compound of any one of claims 1, 2, or 9, wherein V or V are independently absent, provided that V1 and V2 are not absent at the same time, and the cell-binding agent/molecule T is linked directly to L or L of Formula (I) and (III), or wherein T links V or V , such that the com- 1 2 1 2 pound comprises one or more of the following linkage structures: R N T R N T , , , R N T NHNH N T HN OR N T , , , NH+ O R N T N N T N O NC T H H H H , , , O O O 21 20 20 S R N N N T R R NNH R N T H H H , , , NH+ O 20 20 N T N T S S R O Ar H H , , , , NHNH R N R N , , , , , , , , , , , , , , , 20 21 wherein R and R are independently C ~C alkyl; C ~C heteroalkyl, or heterocyclic; C ~C 1 8 2 8 3 8 aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; or C -C polyethylene glycol having formula of (CH CH O) . 2 100 2 2 p

11. The compound of any one of claims 1, 2, 5, 6, 9 and 10, wherein the cell-binding agent/mol- ecule is capable of targeting a tumor cell, a virus infected cell, a microorganism infected cell, a par- asite infected cell, an autoimmune disease cell, an activated tumor cells, a myeloid cell, an activated T-cell, an affecting B cell, or a melanocyte, or any cell expressing any one of the following antigens or receptors: CD1, CD1a, CD1b, CD1c, CD1d, CD1e ,CD2, CD3, CD3d, CD3e, CD3g, CD4, CD5, CD6, CD7, CD8, CD8a, CD8b, CD9, CD10, CD11a, CD11b, CD11c, CD11d, CD12w, CD14, CD15, CD16, CD16a, CD16b, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD32a, CD32b, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD49c, CD49d, CD49f, CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, CD65, CD65s, CD66, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD75, CD75s, CD76, CD77, CD78, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, CD85a, CD85b, CD85c, CD85d, CD85e, CD85f, CD85g, CD85g, CD85i, CD85j, CD85k, CD85m, CD86, CD87, CD88, CD89, CD90, CD91, CD92, CD93, CD94, CD95, CD96, CD97, CD98, CD99, CD100, CD101, CD102, CD103, CD104, CD105, CD106, CD107, CD107a, CD107b, CD108, CD109, CD110, CD111, CD112, CD113, CD114, CD115, CD116, CD117, CD118, CD119, CD120, CD120a, CD120b, CD121, CD121a, CD121b, CD122, CD123, CD123a, CD124, CD125, CD126, CD127, CD128, CD129, CD130, CD131, CD132, CD133, CD134, CD135, CD136, CD137, CD138, CD139, CD140, CD140a, CD140b, CD141, CD142, CD143, CD144, CD145, CDw145, CD146, CD147, CD148, CD149, CD150, CD151, CD152, CD153, CD154, CD155, CD156, CD156a, CD156b, CD156c, CD156d, CD157, CD158, CD158a, CD158b1, CD158b2, CD158c, CD158d, CD158e1, CD158e2, CD158f2, CD158g, CD158h, CD158i, CD158j, CD158k, CD159, CD159a, CD159b, CD159c, CD160, CD161, CD162, CD163, CD164, CD165, CD166, CD167, CD167a, CD167b, CD168, CD169, CD170, CD171, CD172, CD172a, CD172b, CD172g, CD173, CD174, CD175, CD175s, CD176, CD177, CD178, CD179, CD179a, CD179b, CD180, CD181, CD182, CD183, CD184, CD185, CD186, CDw186, CD187, CD188, CD189, CD190, CD191, CD192, CD193, CD194, CD195, CD196, CD197, CD198, CD199, CDw198, CDw199, CD200, CD201, CD202, CD202 (a, b), CD203, CD203c, CD204, CD205, CD206, CD207, CD208, CD209, CD210, CDw210a, CDw210b, CD211, CD212, CD213, CD213a1, CD213a2, CD214, CD215, CD216, CD217, CD218, CD218a, CD218, CD21b9, CD220, CD221, CD222, CD223, CD224, CD225, CD226, CD227, CD228, CD229, CD230, CD231, CD232, CD233, CD234, CD235, CD235a, CD235b, CD236, CD237, CD238, CD239, CD240, CD240ce, CD240d, CD241, CD242, CD243, CD244, CD245, CD246, CD247, CD248, CD249, CD250, CD251, CD252, CD253, CD254, CD255, CD256, CD257, CD258, CD259, CD260, CD261, CD262, CD263, CD264, CD265, CD266, CD267, CD268, CD269, CD270, CD271, CD272, CD273, CD274, CD275, CD276, CD277, CD278, CD279, CD281, CD282, CD283, CD284, CD285, CD286, CD287, CD288, CD289, CD290, CD291, CD292, CD293, CD294, CD295, CD296, CD297, CD298, CD299, CD300, CD300a, CD300b, CD300c, CD301, CD302, CD303, CD304, CD305, CD306, CD307, CD307a, CD307b, CD307c, CD307d, CD307e, CD307f, CD308, CD309, CD310, CD311, CD312, CD313, CD314, CD315, CD316, CD317, CD318, CD319, CD320, CD321, CD322, CD323, CD324, CD325, CD326, CD327, CD328, CD329, CD330, CD331, CD332, CD333, CD334, CD335, CD336, CD337, CD338, CD339, CD340, CD341, CD342, CD343, CD344, CD345, CD346, CD347, CD348, CD349, CD350, CD351, CD352, CD353, CD354, CD355, CD356, CD357, CD358, CD359, CD360, CD361, CD362, CD363, CD364, CD365, CD366, CD367, CD368, CD369, CD370, CD371, CD372, CD373, CD374, CD375, CD376, CD377, CD378, CD379, CD381, CD382, CD383, CD384, CD385, CD386, CD387, CD388, CD389, CRIPTO, CRIPTO, CR, CR1, CRGF, CRIPTO, CXCR5, LY64, TDGF1, 4-1BB, APO2, ASLG659, BMPR1B, 4-1BB, 5AC, 5T4 (trophoblastic glycoprotein, TPBG, 5T4, Wnt-activated inhibitory factor 1 or WAIF1), adenocarcinoma antigen, AGS-5, AGS-22M6, activin receptor-like kinase 1, AFP, AKAP-4, ALK, alpha integrin, alpha v beta6, amino-peptidase N, amyloid beta, androgen re- ceptor, angiopoietin 2, angiopoietin 3, annexin A1, anthrax toxin protective antigen, anti-transferrin receptor, AOC3 (VAP-1), B7-H3, bacillus anthracis anthrax, BAFF (B-cell activating factor), BCMA, B-lymphoma cell, bcr-abl, bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate an- tigen 125, MUC16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg, canis lupus famil- iaris IL31, carbonic anhydrase IX, cardiac myosin, CCL11(C-C motif chemokine 11), CCR4 (C-C chemokine receptor type 4), CCR5, CD3E (epsilon), CEA (carcinoembryonic antigen), CEACAM3, CEACAM5 (carcino-embryonic antigen), CFD (Factor D), Ch4D5, cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), clumping factor A, cMet, CRIPTO, FCSF1R (colony stimulating factor 1 receptor), CSF2 (colony stimulating factor 2, granulocyte-macrophage colony-stimulating factor (GM-CSF)), CSP4, CTLA4 (cytotoxic T-lymphocyte-associated protein 4), CTAA16.88 tumor anti- gen, CXCR4, C-X-C chemokine receptor type 4, cyclic ADP ribose hydrolase, cyclin B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, dabigatran, DLL3 (delta-like-ligand 3), DLL4 (delta-like-ligand 4), DPP4 (Dipeptidyl-peptidase 4), DR5 (Death receptor 5), E. coli shiga toxin type-1, E. coli shiga toxin type-2, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, endoglin, endothelin B receptor, endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, episialin, ERBB2 (epidermal Growth Factor Receptor 2), ERBB3, ERG (TMPRSS2 ETS fusion gene), escherichia coli, ETV6-AML, FAP (fibroblast activation protein al- pha), FCGR1, alpha-fetoprotein, fibrin II, beta chain, fibronectin extra domain-B, FOLR (folate re- ceptor), folate receptor alpha, folate hydrolase, fos-related antigen 1F protein of respiratory syncyt- ial virus, frizzled receptor, fucosyl GM1, GD2 ganglioside, G-28 (a cell surface antigen glyvolipid), GD3 idiotype, globoH, glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor a-chain, growth differentiation factor 8, GP100, GPNMB (trans-membrane glycoprotein NMB), GUCY2C (guanylate cyclase 2C, guanylyl cyclase C(GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor, heat-stable enterotoxin receptor (hSTAR)), heat shock proteins, hemagglutinin, hepatitis B surface antigen, hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2/neu, HER3 (ERBB-3), IgG4, HGF/SF (hepatocyte growth factor/scatter factor), HHGFR, HIV-1, histone complex, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB , HMW- MAA, human chorionic gonadotropin, HNGF, human scatter factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idiotype, IGF1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN- ?, influenza hemagglutinin, IgE, IgE Fc region, IGHE, inter- leukins (comprising IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-6R, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-17A, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-27, or IL-28), IL31RA, ILGF2 (Insulin-like growth factor 2), Integrins ( a4, aIIb ß3, av ß3, a4 ß7, a5 ß1, a6 ß4, a7 ß7, all ß3, a5 ß5, av ß5), interferon gamma-induced protein, ITGA2, ITGB2, KIR2D, Kappa Ig, LCK, Le, legu- main, Lewis-Y antigen, LFA-1 (Lymphocyte function-associated antigen 1, CD11a), LHRH, LINGO-1, ipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP-1, MIF (macrophage migration inhibi- tory factor, or glycosylation-inhibiting factor (GIF)), MS4A1 (membrane-spanning 4-domains sub- family A member 1), MSLN (mesothelin), MUC1(Mucin 1, cell surface associated (MUC1) or pol- ymorphic epithelial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1(monocyte chemotactic protein 1), MelanA/MART1, ML-IAP, MPG, MS4A1 (membrane-spanning 4-domains subfamily A), MYCN, myelin-associated glycoprotein, myostatin, NA17, NARP-1, NCA-90 (granulocyte an- tigen), nectin-4 (ASG-22ME), NGF, neural apoptosis-regulated proteinase 1, NOGO-A, notch re- ceptor, nucleolin, neu oncogene product, NY-BR-1, NY-ESO-1, OX-40, OxLDL (oxidized low- density lipoprotein), OY-TES1, P21, p53 nonmutant, P97, Page4, PAP, paratope of anti-(N-glycol- ylneuraminic acid), PAX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein 1), PDGF-R a (Alpha-type platelet-derived growth factor receptor), PDGFR- ß, PDL-1, PLAC1, PLAP- like testicular alkaline phosphatase, platelet-derived growth factor receptor beta, phosphate-sodium co-transporter, PMEL 17, polysialic acid, proteinase3 (PR1), prostatic carcinoma, PS (Phosphati- dylserine), prostatic carcinoma cells, pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI)), rhesus factor, RANKL, RhoC, ras mutant, RGS5, ROBO4, respiratory syncytial virus, RON, ROR1, sarcoma translocation breakpoints, SART3, scle- rostin, SLAMF7 (SLAM family member 7), selectin P, SDC1 (syndecan 1), sLe(a), somatomedin C, SIP (sphingosinephosphate), somatostatin, sperm protein 17, SSX2, STEAP1 (six-transmem- brane epithelial antigen of the prostate 1), STEAP2, STn, TAG-72 (tumor associated glycoprotein 72), survivin, T-cell receptor, T cell transmembrane protein, TEM1 (Tumor endothelial marker 1), TENB2, tenascin C (TN-C), TGF- a, TGF-ß (transforming growth factor beta), TGF- ß1, TGF- ß2 (transforming growth factor-beta 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF- a, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF-13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (tumor necrosis apoptosis inducing ligand receptor 1), TRAILR2 (death receptor 5 (DR5)), tumor-associated calcium signal transducer 2, tumor specific glycosylation of MUC1, TWEAK receptor, TYRP1(glycoprotein 75), TRP-2, tyrosinase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR2, or vimentin, WT1, XAGE 1, or cells expressing any insulin growth factor receptors, or any epidermal growth factor receptor, wherein the tumor cell is selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells, prostate can- cer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, none small-cell lung cancer cells, testicular cancer cells, malignant cells, or any cells that grow and divide at an unregulated, quickened pace to cause cancers.

12. A pharmaceutical composition comprising the conjugate compound according to of any one of claim 1, 2, 5, 6, and 9 to 11, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

13. The pharmaceutical composition according to claim 12, which is either in in the liquid for- mula or is formulated as a lyophilized solid; wherein the composition comprises 0.01%-99% by weight of one or more conjugate of any one of claims 1, 2, 5, 6, and 9 to 11; 0.0%-20.0% by weight of one or more polyol; 0.0%-2.0% by weight of one or more surfactant; 0.0% -5.0% by weight of one or more preservative; 0.0% -30% by weight of one or more amino acid; 0.0% -5.0% by weight of one or more antioxidant; 0.0% -0.3% by weight of one or more metal chelating agent; 0.0% - 30.0% by weight of one or more buffer salt for adjusting pH of the formulation to pH 4.5 to 7.5; and 0.0% -30.0% by weight of one or more of isotonic agent for adjusting osmotic pressure between about 250 to 350 mOsm when reconstituted for administration to a patient.

14. The pharmaceutical composition according to claim 13, wherein: the one or more polyol is selected from fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, glucose, sucrose, trehalose, sorbose, melezitose, raffinose, mannitol, xylitol, erythritol, maltitol, lactitol, erythritol, threitol, sorbitol, glycerol, or L-gluconate and its me- tallic salts); the one or more surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81, or polysorbate 85, poloxamer, poly(ethylene oxide)-poly(propylene oxide), polyethylene-polypropylene, triton; sodium dodecyl sulfate (SDS), sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine, linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocami- dopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-beta- ine (lauroamidopropyl), myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethyla- mine, sodium methyl cocoyl-, or disodium methyl oleyl-taurate, dodecyl betaine, dodecyl dimethyl- amine oxide, cocamidopropyl betaine and coco ampho glycinate, or isostearyl ethylimidonium ethosulfate, polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol; the one or more preservative is selected from benzyl alcohol, octadecyldimethylbenzyl ammo- nium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cy- clohexanol, 3-pentanol, or m-cresol; the one or more amino acid is selected from arginine, cystine, glycine, lysine, histidine, orni- thine, isoleucine, leucine, alanine, glycine glutamic acid or aspartic acid; the one or more antioxidant is selected from ascorbic acid, glutathione, cystine or and methio- nine; the one or more chelating agent is selected from EDTA or EGTA; the one or more buffer salt is selected from sodium, potassium, ammonium, or trihydroxy- ethylamino salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid; tris or tromethamine hydrochloride, phosphate or sulfate; arginine, glycine, glycylglycine, or histidine with anionic acetate, chloride, phosphate, sulfate, or succinate salts; and the one or more tonicity agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate, or sodium chloride.

15. The pharmaceutical composition according to any one of claims 12 to 14, wherein the phar- maceutical composition is packed in a vial, bottle, pre-filled syringe, or pre-filled auto-injector sy- ringe, in a form of a liquid or lyophilized solid.

16. Use of the compound according to any one of claims 1, 2, 5, 6, and 9 to 11, or a pharmaceu- tically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 12 to 15, in the manufacture of a medicament for the treatment and/or prevention of a cancer, an auto- immune disease, or an infectious disease.

17. The use according to claim 16, wherein the the compound according to any one of claims 1, 2, 5, 6, and 9 to 11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composi- tion according to any one of claims 12 to 15, wherein the medicament is to be administered with a further therapeutic agent selected from the group comprising a chemotherapeutic agent, a radiation therapy, an immunotherapy agent, an autoimmune disorder agent, an anti-infectious agents or the other conjugates for synergistically treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.

18. The use according to Claim 17, wherein the further therapeutic agent is a chemotherapeutic agent is selected from: (1) a) an alkylating agent: selected from nitrogen mustards: chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine ox- ide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1065 and adozelesin, car- zelesin, bizelesin; duocarmycin, KW-2189, CBI-TMI, or CBI dimers, benzodiazepine dimers or pyrrolobenzodiazepine (PBD) dimers, tomaymycin dimers, indolinobenzodiazepine dimers, imidaz- obenzothiadiazepine dimers, or oxazolidinobenzodiazepine dimers; nitrosoureas: comprising car- mustine, lomustine, chlorozotocin, fotemustine, nimustine, ranimustine; alkylsulphonates: including busulfan, treosulfan, improsulfan and piposulfan; triazenes or dacarbazine, platinum containing compounds: comprising carboplatin, cisplatin, and oxaliplatin; aziridines, benzodopa, carboquone, meturedopa, or uredopa; ethylenimines and methylamelamines including altretamine, triethy- lenemelamine, trietylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine]; b) a plant alkaloid: selected from the group consisting of vinca alkaloids: including vincristine, vinblastine, vindesine, vinorelbine, and navelbin; taxoids: comprising paclitaxel, docetaxol, may- tansinoids, maytansine, ansamitocins, cryptophycins (including the group of cryptophycin 1 and cryptophycin 8; epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; a sarcodictyin; spongistatin; c) a DNA Topoisomerase Inhibitor: selected from the groups of epipodophyllins: comprising 9- aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, iri- notecan, mitoxantrone, novantrone, retinoic acids (or retinols), teniposide, topotecan, 9-nitrocamp- tothecin or RFS 2000; and mitomycins; d) an antimetabolite: selected from the group consisting of {[anti-folate: (DHFR inhibitors: comprising methotrexate, trimetrexate, denopterin, pteropterin, aminopterin (4-aminopteroic acid) or folic acid); IMP dehydrogenase inhibitors selected from mycophenolic acid, tiazofurin, ribavirin, ribonucleotide reductase inhibitors: hydroxyurea, deferoxamine; uracil analogs selected from an- citabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxi- fluridine, enocitabine, 5-fluorouracil, floxuridine, ratitrexed; cytosine analogs: selected from cytara- bine, cytosine arabinoside, fludarabine; purine analogs selected from azathioprine, fludarabine, mercaptopurine, thiamiprine, thioguanine]; folic acid replenisher, frolinic acid}; e) a hormonal therapy: selected from receptor antagonists: [anti-estrogen selected from meges- trol, raloxifene, tamoxifen; LHRH agonists: selected from goscrclin, leuprolide acetate; anti- androgens: selected from bicalutamide, flutamide, calusterone, dromostanolone propionate, epiti- ostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, trilostane and other androgens inhibitors]; retinoids/reltoids: vitamin D3 selected from CB 1093, EB 1089 KH 1060, cholecalcif- erol, ergocalciferol; photodynamic therapies: selected from verteporfin, phthalocyanine, photosensi- tizer Pc4, demethoxyhypocrellin A; cytokines: selected from interferon-alpha, interferon-gamma, tumor necrosis factor (TNFs), human proteins containing a TNF domain]}; f) a kinase inhibitor, selected from the group consisting of BIBW 2992 (afatinib, anti- EGFR/Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (lenvatinib, anti-VEGFR2), mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinesib; g) a poly (ADP-ribose) polymerase (PARP) inhibitors selected from the group of olaparib, ni- raparib, iniparib, talazoparib, veliparib, CEP 9722 (Cephalon’s), E7016 (10-((4-Hydroxypiperidin- 1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one, Eisai's), pamiparib (BGB-290), or 3-amino- benzamide; h) an antibiotic, selected from the group consisting of an enediyne antibiotic (selected from the group of calicheamicin, calicheamicin ?1, d1, a1 or ß1; dynemicin, including dynemicin A and de- oxydynemicin, esperamicin, kedarcidin, C-1027, maduropeptin, or neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chro- momycins, dactinomycin, daunorubicin, detorubicin, 6-diazooxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxo- rubicin, epirubicin, eribulin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, strep- tonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; i) a polyketide (acetogenin), bullatacin and bullatacinone; gemcitabine, epoxomicins andcarfil- zomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, stimuvax, allovectin-7, xegeva, provenge, yervoy, isoprenylation inhibitors and lovas- tatin, dopaminergic neurotoxins and1-methylphenylpyridinium ion, cell cycle inhibitors (includ- ing staurosporine), actinomycins (including actinomycin D, dactinomycin), amanitins, bleomycins (including bleomycin A2, bleomycin B2, peplomycin), anthracyclines (including daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin, mtoxantrone, MDR inhibi- tors or verapamil, Ca ATPase inhibitors or thapsigargin, histone deacetylase inhibitors ((including vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat (MGCD0103), belinostat, PCI- 24781 (abexinostat), entinostat, SB939, resminostat, givinostat, AR-42, CUDC-101, sulforaphane, trichostatin A); thapsigargin, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinospo- ramide A; anti-adrenals, selected from the group of aminoglutethimide, mitotane, trilostane, acegla- tone, aldophosphamide glycoside, aminolevulinic acid, amsacrine, arabinoside, bestrabucil, bis- antrene, edatraxate, defofamine, demecolcine, diaziquone, eflornithine (DFMO), elfomithine, el- liptinium acetate, etoglucid, gallium nitrate, gacytosine, hydroxyurea; ibandronate, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofiran, spirogermanium, tenuazonic acid, triaziquone, 2, 2',2''-trichlorotriethylamine, trichothecenes (including the group of T-2 toxin, verrucarin A, roridin A and anguidine), urethane, siRNA, antisense drugs; (2) an anti-autoimmune disease agent: cyclosporine, cyclosporine A, aminocaproic acid, azathi- oprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids (including the group consisting of amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone danazol, dexamethasone, Triamcinolone acetonide, beclomet- asone dipropionate), DHEA (dehydroepiandrosterone), enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, sirolimus, tacrolimus; (3) an anti-infectious disease agents comprising: a) aminoglycosides: amikacin, astromicin, gentamicin (netilmicin, sisomicin, isepamicin), hy- gromycin B, kanamycin (amikacin, arbekacin, bekanamycin, dibekacin, tobramycin), neomycin (framycetin, paromomycin, ribostamycin), netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin; b) amphenicols: azidamfenicol, chloramphenicol, florfenicol, thiamphenicol; c) ansamycins: geldanamycin, herbimycin; d) carbapenems: biapenem, doripenem, ertapenem, imipenem, cilastatin, meropenem, panipenem; e) cephems: carbacephem (loracarbef), cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefaloridine, cefalotin or cefalothin, cefalexin, cefaloglycin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefroxadine, ceftezole, cefuroxime, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, ce- furoxime, cefuzonam, cephamycin (including cefoxitin, cefotetan, cefmetazole), oxacephem (flo- moxef, latamoxef); f) glycopeptides: bleomycin, vancomycin (including oritavancin, telavancin), teicoplanin (dal- bavancin), ramoplanin; g) glycylcyclines: tigecycline; h) ß-lactamase inhibitors: penam (sulbactam, tazobactam), clavam (clavulanic acid); i) lincosamides: clindamycin, lincomycin; j) lipopeptides: daptomycin, A54145, (lipopeptide antibiotics produced by Streptomyces fradiae), calcium-dependent antibiotics (CDA); k) macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide (telithromycin, cethromycin), midecamycin, miocamycin, ole- andomycin, rifamycins (rifampicin, rifampin, rifabutin, rifapentine), rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), troleandomycin, telithromycin; l) monobactams: aztreonam, tigemonam; m) oxazolidinones: linezolid; n) penicillins: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phe- noxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxa- cillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o) polypeptides: bacitracin, colistin, polymyxin B; p) quinolones: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxa- cin, enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, te- mafloxacin, tosufloxacin, trovafloxacin; q) streptogramins: pristinamycin, quinupristin/dalfopristin; r) sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasala- zine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole); s) steroid antibacterials: selected from fusidic acid; t) tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, lymecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracy- cline, glycylcyclines (including tigecycline); u) other antibiotics: selected from the group consisting of annonacin, arsphenamine, bacto- prenol inhibitors (Bacitracin), DADAL/AR inhibitors (cycloserine), dictyostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitors (fosfomycin), nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin (rifam- pin), tazobactam tinidazole, uvaricin; (4) anti-viral drugs comprising: a) entry/fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41 (enfuvirtide), PRO 140 (Ler- onlimab), CD4 (ibalizumab); b) integrase inhibitors: raltegravir, elvitegravir, globoidnan A; c) maturation inhibitors: bevirimat, vivecon; d) neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) nucleosides & nucleotides: abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine (ddI), elvucitabine, emtricitabine (FTC), entecavir, famciclovir, fluorouracil (5-FU), 3’-fluoro-substituted 2’, 3’-dideoxynucleoside ana- logues (including the group consisting of 3’-fluoro-2’,3’-dideoxythymidine (FLT) and 3’-fluoro- 2’,3’-dideoxyguanosine (FLG), fomivirsen, ganciclovir, idoxuridine, lamivudine (3TC), l-nucleo- sides selected from the group consisting of ß-l-thymidine and ß-l-2’-deoxycytidine, penciclovir, racivir, ribavirin, stampidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, tri- fluridine valaciclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT); f) non-nucleosides: amantadine, ateviridine, capravirine, diarylpyrimidines (etravirine, rilpi- virine), delavirdine, docosanol, emivirine, efavirenz, foscarnet (phosphonoformic acid), imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848), tromantadine; g) protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir (VX-950), tipranavir; h) other types of anti-virus drugs: abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate (EGCG), foscarnet, griffithsin, taribavirin (viramidine), hydroxyurea, KP-1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, seliciclib; (5) the pharmaceutically acceptable salts, acids, derivatives, hydrate or hydrated salt; or a crystalline structure; or an optical isomer, racemate, diastereomer or enantiomer of any of the above drugs.

19. The use according to claim 17 or claim 18, wherein the further therapeutic agent is selected from: abatacept, abemaciclib, abiraterone acetate, paclitaxel, acetaminophen/hydrocodone, acalabrutinib, aducanumab, adalimumab, ADXS31-142, afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, alitretinoin, ado-trastuzumab emtansine, amphetamine/ dextroamphetamine, anastro- zole, aripiprazole, anthracyclines, aripiprazole, atazanavir, atezolizumab, atorvastatin, avelumab, axicabtagene ciloleucel, axitinib, belinostat, BCG live (Bacillus Calmette-Guerin live), bevaci- zumab, bexarotene, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, brigatinib, budesonide, budesonide/ formoterol, buprenorphine, cabazitaxel, cabozantinib, capmatinib, capecit- abine, carfilzomib, chimeric antigen receptor-engineered T (CAR-T) cells, celecoxib, ceritinib, ce- tuximab, chidamide, ciclosporin, cinacalcet, crizotinib, cobimetinib, cosentyx, crizotinib, CTL019 (Tisagenlecleucel), dabigatran, dabrafenib, dacarbazine, daclizumab, dacomotinib, daptomycin, daratumumab, darbepoetin alfa, darunavir, dasatinib, denileukin diftitox, denosumab, depakote, dexlansoprazole, dexmethylphenidate, dexamethasone, dignicap cooling system, dinutuximab, doxycycline, duloxetine, duvelisib, durvalumab, elotuzumab, emtricibine/rilpivirine/tenofovir, disoproxil fumarate, emtricitbine/tenofovir/efavirenz, enoxaparin, ensartinib, enzalutamide, epoetin alfa, erlotinib, esomeprazole, eszopiclone, etanercept, everolimus, exemestane, everolimus, ex- enatide ER, ezetimibe, ezetimibe/simvastatin, fenofibrate, filgrastim, fingolimod, fluticasone propi- onate, fluticasone/salmeterol, fulvestrant, gazyva, gefitinib, glatiramer, goserelin acetate, icotinib, imatinib, ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, infliximab, imiquimod, immucyst, immuno BCG, iniparib, insulin aspart, insulin detemir, insulin glargine, insulin lispro, interferon alfa, interferon alfa-1b, interferon alfa-2a, interferon alfa-2b, interferon beta, interferon beta 1a, in- terferon beta 1b, interferon gamma-1a, lapatinib, ipilimumab, ipratropium bromide/ salbutamol, ix- azomib, kanuma, lanreotide acetate, lenalidomide, lenaliomide, lenvatinib mesylate, letrozole, levothyroxine, levothyroxine, lidocaine, linezolid, liraglutide, lisdexamfetamine, LN-144 (a scalp colling systerm), lorlatinib, memantine, methylphenidate, metoprolol, mekinist, mericitabine/ rilpi- virine/tenofovir, modafinil, mometasone, mycidac-C (mycobacterium-w), necitumumab, neratinib, nilotinib, niraparib, nivolumab, ofatumumab, obinutuzumab, olaparib, olmesartan, olmesartan/ hy- drochlorothiazide, omalizumab, omega-3 fatty acid ethyl esters, oncorine, oseltamivir, osimertinib, oxycodone, palbociclib, palivizumab, panitumumab, panobinostat, pazopanib, pembrolizumab, PD- 1 (programmed death-1) antibody, PD-L1 (programmed death-ligand 1) antibody, pemetrexed, per- tuzumab, pneumococcal conjugate vaccine, pomalidomide, pregabalin, proscavax, propranolol, quetiapine, rabeprazole, radium 223 chloride, raloxifene, raltegravir, ramucirumab, ranibizumab, regorafenib, ribociclib, rituximab, rivaroxaban, romidepsin, rosuvastatin, ruxolitinib phosphate, sal- butamol, savolitinib, semaglutide, sevelamer, sildenafil, siltuximab, sipuleucel-T, sitagliptin, sitagliptin/metformin, solifenacin, solanezumab , sonidegib, sorafenib, sunitinib, tacrolimus, tacri- mus, tadalafil, tamoxifen, tafinlar, talimogene laherparepvec, talazoparib, telaprevir, talazoparib, te- mozolomide, temsirolimus, tenofovir/ emtricitabine, tenofovir disoproxil fumarate, testosterone gel, thalidomide, TICE BCG bacillus calmette-guerin), tiotropium bromide, tisagenlecleucel, torem- ifene, trametinib, trastuzumab, trabectedin (ecteinascidin 743), trametinib, tremelimumab, tri- fluridine/tipiracil, tretinoin, uro-bcg, ustekinumab, valsartan, veliparib, vandetanib, vemurafenib, venetoclax, vorinostat, ziv-aflibercept, zostavax, and their pharmaceutically acceptable salts, carri- ers, diluents, or excipients thereof, or a combination above thereof. OEt OEt F (NH4)2s )”C=N MeQH, r.t.^ EtO'^Ss||'NH2 Br » EtO l^'C°2Et 3 AMS 2 EtOH, reflux 2NHC1 Tf20, NaN3 C02Et H2N n3 ¦qjj cat. CUSO4, K2C03 acetone, reflux OH 4 H20, MeOH Tf20, NaN3 qjj cat. CuS04, K2CO 'X, H20, MeOH “X EDA, ClTiCO'P^g C02Et S) Ti(OEt)4 then 4, THE, -78 °C •>>Ti» THE, reflux •T 0 11 NaBH4, Ti(OEt)4 4 N HCl/dioxane C02Et THE, -45 °C EtOH HC1H2N COOEt O OH 6,*Bu02CC1 6, (COCl)2 N3 N NMM, THE COOEt DIPEA TESC1 Imidazole, DCM O OTES o "Y" otes KHMDS, CH3I, THE -45 °C to r.t. COOEt COOEt or NaH, CH3I, THE, 0 °C O OTES HCIHjN, H2, Pd/C rj-c0lEt aq HCl/MeOH N3/Y'N' 8,'Bu02CC1 C02Et —-------- -------- ? nCin2N'^/YY COOEt H NMM, THE O OTES o OTES NaH, CH3I^ TESC1 >N3V'n r> 20 C02Et C02Et THE, 0 °C I Imidazole