A conjugate of a tubulysin analog with branched linkers

Abstract

Described is a 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. Also described are 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.

1 . A side chain-linkaged conjugate compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein
 “ ” represents a single bond; 
 n is 1 to 30; 
 
         T is a cell-binding agent 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 the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, an adnectin that mimics antibody, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule (a transferrin), and/or a cell-binding peptide, protein, or small molecule attached on albumin, a polymer, a dendrimer, a liposome, a nanoparticle, a vesicle, or on a (viral) capsid; 
         L 1  and L 2  are, the same or different, independently selected from O, NH, N, S, P, NNH, NHNH, N(R 3 ), N(R 3 )N(R 3′ ), CH, CO, C(O)NH, C(O)O, NHC(O)NH, NHC(O)O, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p OR 3 , or (OCH 2 CH—(CH 3 )) p OR 3 , or NH(CH 2 CH 2 O) p R 3 , or NH(CH 2 CH(CH 3 )O) p R 3 , or N[(CH 2 CH 2 O) p R 3 ]-[(CH 2 CH 2 O) p′ R 3′ ], or (OCH 2 CH 2 ) p COOR 3 , or CH 2 CH 2 (OCH 2 CH 2 ) p COOR 3 , wherein p and p′ are independently an integer selected from 0 to about 1000, or a combination of two or more thereof; C 1 -C 8  alkyl; C 2 -C 8  heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; or (Aa) r , r=1-12 (1 to 12 amino acid units), which is composed from natural or unnatural amino acids, or the same or different sequences of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; 
         W is a stretcher unit having C 1 -C 18 , normally a self-immolative spacer, a peptidic unit, a hydrazone, a disulfide, a thioether, an ester, or an amide bond; w is 1 or 2 or 3; 
         V 1  and V 2  are independently a spacer unit and selected from O, NH, S, C 1 -C 8  alkyl, C 2 -C 8  heteroalkyl, alkenyl, or alkynyl, C 3 -C 8  aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl, or (Aa) r , r=1-12 (1 to 12 amino acid units), which is composed from a natural or unnatural amino acid, or the same or different sequences of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; or (CH 2 CH 2 O) p , p is 0-1000; and v 1  and v 2  are independently 0, 1 or 2, but v 1  and v 2  are not 0 at the same time; when v 1  or v 2  is 0, one of the side chain Q 1  or Q 2  fragment is absent; 
         Q 1  and Q 2  are independently represented by Formula (I-q 1 ): 
       
       
         
           
           
               
               
           
         
         wherein   is a site linked to L 1  or L 2 ; G 1  and G 2  are independently OC(O), NHC(O), C(O), CH 2 , NH, OC(O)NH, NHC(O)NH, O, S, B, P(O)(OH), NHP(O)(OH), NHP(O)(OH)NH, CH 2 P(O)(OH)NH, OP(O)(OH)O, CH 2 P(O)(OH)O, NHS(O) 2 , NHS(O) 2 NH, CH 2 S(O) 2 NH, OS(O) 2 O, CH 2 S(O) 2 O, Ar, ArCH 2 , ArO, ArNH, ArS, ArNR 1 , or (Aa) q1 ; G 3  is OH, SH, OR 1 , SR 1 , OC(O)R 1 , NHC(O)R 1 , C(O)R 1 , CH 3 , NH 2 , NR 1 ,  + NH(R 1 )  + N(R 1 )(R 2 ), C(O)OH, C(O)NH 2 , NHC(O)NH 2 , BH 2 , BR 1 R 2 , P(O)(OH) 2 , NHP(O)(OH) 2 , NHP(O)(NH 2 ) 2 , S(O) 2 (OH), (CH 2 ) q1 C(O)OH, (CH 2 ) q1 P(O)(OH) 2 , C(O)(CH 2 ) q1 C(O)OH, OC(O)(CH 2 ) q1 C(O)OH, NHC(O)(CH 2 ) q1 C(O)OH, CO(CH 2 ) q1 P(O)(OH) 2 , NHC(O)O(CH 2 ) q1 C(O)OH, OC(O)NH(CH 2 ) q1 C(O)OH, NHCO(CH 2 ) q1 P(O)(OH) 2 , NHC(O)(NH)(CH 2 ) q1 C(O)OH, CONH(CH 2 ) q1 P(O)(OH) 2 , NHS(O) 2 (CH 2 ) q1 C(O)OH, CO(CH 2 ) q1 S(O) 2 (OH), NHS(O) 2 NH(CH 2 ) q1 C(O)OH, OS(O) 2 NH(CH 2 ) q1 C(O)OH, NHCO(CH 2 ) q1 S(O) 2 (OH), NHP(O)(OH)(NH)(CH 2 ) q1 C(O)OH, CONH(CH 2 ) q1 S(O)(OH), OP(O)(OH) 2 , (CH 2 ) q1 P(O)(NH) 2 , NHS(O) 2 (OH), NHS(O) 2 NH 2 , CH 2 S(O) 2 NH 2 , OS(O) 2 OH, OS(O) 2 OR 1 , CH 2 S(O) 2 OR 1 , Ar, ArR 1 , ArOH, ArNH 2 , ArSH, ArNHR 1 , or (Aa) q1 ; (Aa) q1  is a peptide containing the same or different sequence of natural or unnatural amino acids; X 1  and X 2  are independently O, CH 2 , S, S(O), NHNH, NH, N(R 1 )  + NH(R 1 )  + N(R 1 )(R 2 ), C(O), OC(O), OC(O)O, OC(O)NH, or NHC(O)NH; 
         Y 2  is O, NH, NR 1 , CH 2 , S, NHNH, or Ar; p 1 , p 2  and p 3  are independently 0-100 but are not 0 at the same time; q 1  and q 2  are independently 0-24; 
         R 1 , R 2 , R 3  and R 3′  are independently H, C 1 -C 8  alkyl; C 2 -C 8  heteroalkyl, or heterocyclic; C 3 -C 8  aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; 
         alternatively, any one or more of W, Q 1 , Q 2 , L 1 , L 2 , V 1 , or V 2  can be independently absent but Q 1  and Q 2  are not absent at the same time; 
         D is tubulysin analog having following formula (II): 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, or hydrated salt; or a polymorphic crystalline structure; or an optical isomer, racemate, diastereomer or enantiomer thereof, 
         wherein   is a linkage site that links to W independently; 
         wherein R 1 , R 2 , R 3 , and R 4  are independently H, C 1 -C 8  alkyl; C 2 -C 8  heteroalkyl, or heterocyclic; C 3 -C 8  aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; or R 1  and R 2 , R 1  and R 3 , R 2  and R 3 , R 3  and R 4 , R 5  and R 6 , R 11  and R 12 , or R 13  and R 14  form a 3-7 membered carbocyclic, cycloalkyl, heterocyclic, heterocycloalkyl, aromatic or heteroaromatic ring system; R 1  and R 2  can be independently absent when they link to W independently or simultaneously, Y 1  is N or CH; 
         wherein R 5 , R 6 , R 8 , R 10  and R 11  are independently H, or C 1 -C 4  alkyl or heteroalkyl; 
         wherein R 7  is independently H, R 14 , —R 14 C(═O)X 1 R 15 ; or —R 14 X 1 R 15 ; X 1  is O, S, S—S, NH, CH 2  or NR 14 ; 
         wherein R 9  is selected from H, OH, —O—, ═O, —OR″, —OC(═O)R 14 , —OC(═O)NHR 14 —, —OC(═O)R 14 SSR 15 —, OP(═O)(OR 14 )—, —OC(═O)NR 14 R 15 , OP(═O)(OR 14 ), or OR 14 OP(═O)(OR 15 ); 
         wherein R 11  is independently H, R 14 , —R 14 C(═O)R 16 , —R 14 X 2 R 16 , —R 14 C(═O)X 2 , wherein X 2  is —O—, —S—, —NH—, —N(R 14 )—, —O—R 14 —, —S—R 14 —, —S(═O)—R 14 —, or —NHR 14 ; 
         wherein R 12  is R 15 , —OH, —SH,—NH 2 , NH, NHNH 2 , —NH(R 15 ), —OR 15 , —R 15 COR 16 , —R 15 COOR 16 , —R 15 C(O)NH 2 , —R 15 C(O)NHR 17 , —SR 16 , R 15 S(═O)R 16 , —R 15 P(═O)(OR 17 ) 2 , —R 15 OP(═O)(OR 17 ) 2 , —CH 2 OP(═O)(OR 17 ) 2 , —R 15 SO 2 R 17 , —R 15 X 2 R 16 , —R 15 C(═O)X 2 , where X 2  is —O—, OH, SH, —S—, NH 2 , —NH—, —N(R 15 )—, —O—R 15 —, —S—R 15 —, —S(═O)—R 15 —, CH 2  or —NHR 15 —; 
         R 13  and R 14  are independently H, O, S, NH, N(R 15 ), NHNH, —OH, —SH, —NH 2 , NH, NHNH 2 , —NH(R 15 ), —OR 15 , CO, —COX 2 , —COX 2 R 16 , R 17 , F, Cl, Br, I, SR 16 , NR 16 R 17 , N═NR 16 , N═R 16 , NO 2 , SOR 16 R 17 , SO 2 R 16 , SO 3 R 16 , OSO 3 R 16 , PR 16 R 17  POR 16 R 17 , PO 2 R 16 R 17 , OP(O)(OR 17 ) 2 , OCH 2 OP(O)(OR 17 ) 2 , OC(O)R 17 , OC(O)OP(O)(OR 17 ) 2 , PO(OR 16 )(OR 17 ), OP(O)(OR 17 )OP(O)(OR 17 ) 2 , OC(O)NHR 17 , —O—(C 4 -C 12  glycoside), —N—(C 4 -C 12  glycoside); C 1 -C 8  alkyl or heteroalkyl; C 2 -C 8  alkenyl, alkynyl, heteroalkyl, or heterocycloalkyl; C 3 -C 8  aryl, Ar-alkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl, or C 2 -C 8  ester, ether, or amide; or peptide containing 1-8 amino acids (NH(Aa) -8 or CO(Aa) 1-8  (N-terminal or C-terminal 1-8 same or different amino acids), or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p  or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 0 to about 1000, or a combination of two or more thereof; X 2  is O, S, S—S, NH, CH 2 , OH, SH, NH 2 , CHR 14  or NR 14 ; 
         R 15 , R 16  and R 17  are independently H, C 1 -C 8  alkyl or heteroalkyl; C 2 -C 8  alkenyl, alkynyl, heteroalkyl, or heterocycloalkyl; C 3 -C 8  aryl, Ar-alkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, or alkylcarbonyl, or Na + , K + , Cs + , Li + , Ca 2+ , Mg + , Zn 2+ , N + (R 1 )(R 2 )(R 3 )(R 4 ), or HN + (C 2 H 5 OH) 3 salt ; 
         Y 1  and Y 2  are independently N or CH; q is 0 or 1; when q═O, Y 3  does not exist, Y 4 , Y 5 , Y 6  and Y 7  are independently CH, N, NH, O, S, or N(R 1 ), thus Y 2 , Y 4 , Y 5 , Y 6  and Y 7  form a heteroaromatic ring of furan, pyrrole thiophene, thiazole, oxazole, imidazole, pyrazole, triazole, tetrazole, or thiadiazole; when q=1, Y 3 , Y 4 , Y 5 , Y 6  and Y 7  are independently CH or N, thus Y 2 , Y 3 , Y 4 , Y 5 , Y 6  and Y 7  form an aromatic ring of benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine, or pentazine. 
       
     
     
         2 . The conjugate compound according to  claim 1 , wherein Q 1  and Q 2  are independently a C 2 -C 100  polycarboxylacid; a C 2 -C 100  polyalkylamine; a C 6 -C 100  oligosaccharide or polysaccharide; a C 6 -C 100  zwitterionic betaine or zwitterionic poly(sulfobetaine)) (PSB) that consists of a quaternary ammonium cation and a sulfonate anion; a C 6 -C 100  biodegradable polymer composed of poly(lactic/glycolic acid) (PLGA), poly(acrylates), chitosan, copolymer of N-(2-hydroxypropyl)methacrylamide, poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC), poly-L-glutamic acid, poly(lactide-co-glycolide) (PLG), poly(lactide-co-glycolide), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(lactide-co-glycolide), poly(ethylene glycol)-modified peptide, poly(ethylene glycol)-containing an amino acid or peptide, poly(ethylene glycol)-modified lipid, poly(ethylene glycol)-modified alkylcarboxic acid, poly(ethylene glycol)-modified alkylamine, poly(lactide-co-glycolide, hyaluronic acid (HA) (glycosaminoglycan), heparin/heparan sulfate (HSGAGs), chondroitin sulfate/dermatan sulfate (CSGAGs), poly(ethylene glycol)-modified alkylsulfate, poly(ethylene glycol)-modified alkylphosphate, or poly(ethylene glycol)-modified alkyl quaternary ammonium. 
     
     
         3 . The side chain-linkaged conjugate compound according to  claim 1 , wherein Q 1  and Q 2  are independently selected from Iq-01 to Iq-35: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 25  and R 25′  are independently selected from H; HC(O), CH 3 C(O), CH 3 C(NH), C 1 -C 18  alkyl, C 1 -C 18  alkyl, alkyl-Y 1 —SO 3 H, C 1 -C 18  alkyl-Y 1 PO 3 H 2 , C 1 -C 18  alkyl-Y 1 —CO 2 H, C 1 - C 18  alkyl-Y 1 —N + R 1 ′R 2 ′R 3 ′R 4 ′, C 1 -C 18  alkyl-Y 1 —CONH 2 , C 2 -C 18  alkylene, C 2 -C 18  ester, C 2 -C 18  ether, C 2 -C 18  amine, C 2 -C 18  alkyl carboxylamide, C 3 -C 18  Aryl, C 3 -C 18  cyclic alkyl, C 3 -C 18  heterocyclic, 1-24 amino acids; C 2 -C 18  lipid, a C 2 -C 18  fatty acid or a C 2 -C 18  fatty ammonium lipid; X 1  and X 2  are independently selected from NH, N(R1′), O, CH 2 , S, C(O), S(O), S(O 2 ), P(O)(OH), NHNH, CH═CH, Ar or (Aa)q 1 , q 1 =0-24 (0-24 amino acids, q 1 =0 means absent); X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2  and Y 3  are independently selected from NH, N(R 1 ′), O, C(O), CH 2 , S, S(O), NHNH, C(O), OC(O), OC(O)O, OC(O)NH, NHC(O)NH, Ar or (Aa)q 1 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2  and Y 3  can be independently absent; p 1 , p 2  and p 3  are independently 0-100 but are not 0 at the same time; q 1 , q 2  and q 3  are independently 0-24; R 1 ′, R 2 ′, R 3 ′ and R4 ′  are independently selected from H and C 1 -C 6  alkyl; Aa is natural or unnatural amino acid; Ar or (Aa)q 1 , is the same or different sequence of peptides; q 1 =0 means (Aa)q 1  absent. 
       
     
     
         4 . The side chain-linkaged conjugate compound according to  claim 1 , wherein D (tubulysin structure) is selected from I-01 to I-75: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or their phai eJiaceutically acceptable salts, hydrates, or hydrated salts; or polymorphic crystalline structures of these compounds; or their optical isomers, racemates, diastereomers or enantiomers; wherein R 20  is H; C 1 -C 8  linear or branched alkyl or heteroalkyl; C 2 -C 8  linear or branched alkenyl, alkynyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  linear or branched aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; carbonate (—C(O)OR 17 ), carbamate (—C(O)NR 17 R 18 ); or C 1 -C 8  carboxylate, ester, ether, or amide; or 1-8 amino acids; or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p  or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 0 to about 1000; or R 20  is absent and the oxygen atom forms a ketone, or a combination of two of more thereof; Z 3  and Z 3  are independently H, OH, NH 2 , O, NH, COOH, COO, C(O),C(O), C(O)NH, C(O)NH 2 , R 18 , OCH 2 OP(O)(OR 18 ) 2 , OC(O)OP(O)(OR 18 ) 2 , OPO(OR 18 ) 2 , NHPO(OR 18 ) 2 , OP(O)(OR 18 )OP(O)(OR 18 ) 2 , OC(O)R 18 , OC(O)NHR 18 , OSO 2 (OR 18 ), O—(C 4 -C 12 -glycoside), C 1 -C 8  linear or branched alkyl or heteroalkyl; C 2 -C 8  linear or branched alkenyl, alkynyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  linear or branched aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; carbonate (—C(O)OR 17 ), carbamate (—C(O)NR 17 R 18 ); R 17  and R 18  are independently H, C 1 -C 8 linear or branched alkyl or heteroalkyl; C 2 -C 8  linear or branched alkenyl, alkynyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  linear or branched aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; carbonate (—C(O)OR 17 ), carbamate (—C(O)NR 17 R 18 ); R 19  is H, OH, NH 2 , OSO 2 (OR 18 ), XCH 2 OP(O)(OR 18 ) 2 , XPO(OR 18 ) 2 , XC(O)OP(O)(OR 18 ) 2 , XC(O)R 18 , XC(O)NHR 18 , C 1 -C 8  alkyl or carboxylate; C 2 -C 8  alkenyl, alkynyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  aryl or alkylcarbonyl; or pharmaceutical salts; X is O, S, NH, NHNH, or CH 2 ; R 7  is defined the same as in  claim 1 . 
       
     
     
         5 . The side chain-linkaged conjugate compound according to  claim 1 , wherein W, L 1 , L 2 , V 1 , and V 2  independently is composed of one or more linker components of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or L- or D-, natural or unnatural peptides containing 1-20 the same or different amino acids; 
       
       
         
           
           
               
               
           
         
         wherein   is a site of linkage; X 2 , X 3 , X 4 , X 5 , and X 6  are independently selected from NH; NHNH; N(R 3 ); N(R 3 )N(R 3′ ); O, S; C 1 -C 6  alkyl; C 2 -C 6  heteroalkyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; or 1-8 amino acids; wherein R 3  and R 3′  are independently H; C 1 -C 8  alkyl; C 2 -C 8  hetero-alkyl, alkylcycloalkyl, or heterocycloalkyl; C 3 -C 8  aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, or heteroaryl; or C 1 -C 8  ester, ether, or amide; or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p  or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 0 to about 1000, or a combination of two or more thereof. 
       
     
     
         6 . The side chain-linkaged conjugate compound according to  claim 1 , wherein W, L 1 , L 2 , V 1 , and V 2  independently is composed of:
 (A): a self-immolative component, peptidic units, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond; the self-immolative unit includes aromatic compounds that are electronically similar to para-aminobenzyl-carbamoyl (PAB) groups, 2-aminoimidazol-5-methanol derivatives, heterocyclic PAB analogs, beta-glucuronide, and ortho or para-aminobenzylacetals; or one of the following structures:   
       
         
           
           
               
               
           
         
         wherein the (*) atom is a point of attachment of another component; X 1 , Y 1 , Z 2  and Z 3  are independently NH, O, or S; Z 1  is independently H, NHR 1 , OR 1 , SR 1 , or COX 1 R 1 , wherein X 1  and R 1  are defined the same as in  claim 1 ; v is 0 or 1; U 1  is independently H, OH, C 1 -C 6  alkyl, (OCH 2 CH 2 ) n , F, Cl, Br, I, OR 5 , SR 5 , NR 5 R 5 ′, N═NR 5 , N═R 5 , NR 5 R 5 ′, NO 2 , SOR 5 R 5 ′, SO 2 R 5 , SO 3 R 5 , OSO 3 R 5 , PR 5 R 5 ′, POR 5 R 5 ′, PO 2 R 5 R 5 ′, OPO(OR 5 )(OR 5 ′), or OCH 2 PO(OR 5 (OR 5 ′), wherein R 5  and R 5 ′ are independently selected from H, C 1 -C 8  alkyl; C 2 -C 8  alkenyl, alkynyl, heteroalkyl, or amino acid; C 3 -C 8  aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl, or glycoside; or pharmaceutical cation salts thereof;
 (B): a non-self-immolative linker component containing one of the following structures: 
 
       
       
         
           
           
               
               
           
         
         wherein the (*) atom is a site of attachment; X 1 , Y 1 , U 1 , R 5 , R 5 ′ are defined as above; r is 0-100; m and n are 0-20 independently;
 (C): a releasable component that at least one bond that can be broken under physiological conditions: a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile or enzyme-labile bond, which having one of the following structures: 
 
         —(CR 5 R 6 ) m (Aa) r (CR 7 R 8 ) n (OCH 2 CH 2 ) t —, —(CR 5 R 6 ) m (CR 7 R 8 ) n (Aa) r (OCH 2 CH 2 ) t —, -(Aa)r— (CR 5 R 6 ) m (CR 7 R 8 ) n (OCH 2 CH 2 ) t —, —(CR 5 R 6 ) m (CR 7 R 8 ) n (OCH 2 CH 2 ) r (Aa) t -, —(CR 5 R 6 ) m —(CR 7 ═CR 8 )(CR 9 R 10 ) n (Aa) t (OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (NR 11 CO)(Aa) t (CR 9 R 10 ) n- (OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (Aa) t (NR 11 CO)(CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (OCO)(Aa) t (CR 9 R 10 ) n —(OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (OCNR 7 )(Aa) t (CR 9 R 10 ) n (OCH 2 C 2 ) r —, —(CR 5 R 6 ) m (CO)(Aa) t —(CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (NR 11 CO)(Aa) t (CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m —(OCO)(Aa) t (CR 9 R 10 ) n -(OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (OCNR7)(Aa) t (CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m (CO)(Aa) t (CR 9 R 10 ) n —(OCH 2 CH 2 ) r —, —(CR 5 R 6 ) m -phenyl-CO(Aa) t (CR 7 R 8 ) n —, —(CR 5 R 6 ) m -furyl-CO(Aa) t (CR 7 R 8 ) n —, —(CR 5 R 6 ) m -oxazolyl-CO(Aa) t (CR 7 R 8 ) n —, —(CR 5 R 6 ) m -thiazolyl-CO(Aa) t (CCR 7 R 8 ) n —, —(CR 5 R 6 ) t -thienyl-CO(CR 7 R 8 ) n —, —(CR 5 R 6 ) t -imidazolyl-CO—(CR 7 R 8 ) n —, —(CR 5 R 6 ) t- -morpholino-CO(Aa) t -(CR 7 R 8 ) n —, —(CR 5 R 6 ) t piperazino-CO(Aa) t —(CR 7 R 8 ) n —, —(CR 5 R 6 ) t —N-methylpiperazin-CO(Aa) t - (CR 7 R 8 ) n —, —(CR 5 R) m -(Aa) t phenyl-, —(CR 5 R 6 ) m -(Aa) t furyl-, —(CR 5 R 6 ) m -oxazolyl(Aa) t -, —(CR 5 R 6 ) m -thiazolyl(Aa) t -, —(CR 5 R 6 ) m -thienyl-(Aa) t -, —(CR 5 R 6 ) m -imidazolyl(Aa) t -, —(C R 5 R 6 ) m -morpholino-(Aa) t -, —(CR 5 R 6 ) m -piperazino-(Aa) t -, —(CR 5 R 6 ) m —N-methylpiperazino-(Aa) t -, —K(CR 5 R 6 ) m (Aa) r (CR 7 R 8 ) n (OCH 2 CH 2 ) t —, —K(CR 5 R 6 ) m (CR 7 R 8 ) n -(Aa) r (OCH 2 CH 2 ) t —, —K(Aa) r -(CR 5 R 6 ) m (CR 7 R 8 ) n (OCH 2 CH 2 ) t —, —K(CR 5 R 6 ) m —(CR 7 R 8 ) n (OCH 2 -CH 2 ) r (Aa) t -, —K(CR 5 R 6 ) m -(CR 7 ═CR 8 )(CR 9 R 10 ) n (Aa) t (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m —(NR 11 CO—)(Aa) t (CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m (Aa) t (NR 11 CO)(CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m (OCO)(Aa) t (CR 9 R 10 ) n -(OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m (OCNR 7 )(Aa) t (CR 9 R 10 ) n —(OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m (CO)(Aa) t -(CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m (NR 11 CO)(Aa) t -(CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m -(OCO)(Aa) t (CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m —(OCNR 7 )(Aa) t (CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K—(CR 5 R 6 ) m CO)(Aa) t (CR 9 R 10 ) n (OCH 2 CH 2 ) r —, —K(CR 5 R 6 ) m -phenyl-CO(Aa) t (CR 7 R 8 ) n —, —K—(CR 5 R 6 ) m -furyl-CO(Aa) t —(CR 7 R 8 ) n —, —K(CR 5 R 6 ) m -oxazolyl-CO(Aa) t —(CR 7 R 8 ) n —, —K(CR 5 R 6 ) m -thiazolyl-CO(Aa) t —(CR 7 R 8 ) n —, —K(CR 5 R 6 ) t -thienyl-CO(CR 7 R 8 ) n —, —K(CR 5 R 6 ) t imidazolyl-CO—(CR 7 R 8 ) n —, —K(CR 5 R 6 ) t -morpholino-CO-(Aa) t (CR 7 R 8 ) n —, —K(CR 5 R 6 ) t -piperazino-CO(Aa) t —(CR 7 R 8 ) n —, —K(CR 5 R 6 ) t —N-methylpiperazin-CO(Aa) t (CR 7 R 8 ) n —, —K(CR 5 R) m -(Aa) t phenyl, —K—(CR 5 R 6 ) m -(Aa) t furyl-, —K(CR 5 R 6 ) m -oxazolyl(Aa) t -, —K(CR 5 R 6 ) m -thiazolyl(Aa) t -, —K(CR 5 R 6 ) m - thienyl-(Aa) t -, —K(CR 5 R 6 ) m -imidazolyl(Aa) t -, —K(CR 5 R 6 ) m -morpholino(Aa) t -, —K(CR 5 R 6 ) m -piperazino-(Aa) t -, —K(CR 5 R 6 ) m —N-methylpiperazino(Aa) t -; wherein Aa, m, and n are described above; t and r are 0-100 independently; R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are independently chosen from H; halide; C 1 -C 8  alkyl; C 2 -C 8  aryl, alkenyl, alkynyl, ether, ester, amine or amide, which is optionally substituted by one or more halide, CN, NR 1 R 2 , CF 3 , OR 1 , Aryl, heterocycle, S(O)R 1 , SO 2 R 1 , —CO 2 H, —SO 3 H, —OR 1 , —CO 2 R 1 , CONR 1 , —PO 2 R 1 R 2 , —PO 3 H or P(O)R 1 R 2 R 3 ; K is NR 1 , —SS—, —C(═O)—, —C(═O)NH—, —C(═O)O—, —C═NH—O—, —C═N—NH—, —C(═O)NH—NH—, O, S, Se, B, Het (heterocyclic or heteroaromatic ring having C 3 -C 8 ), or a peptide containing 1-20 amino acids. 
       
     
     
         7 . The side chain-linkaged conjugate compound according to  claim 1  having one of the following structures of b-01 to b-29: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or their pharmaceutically acceptable salts, hydrates, or hydrated salts; or polymorphic crystalline structures of these compounds; or their optical isomers. racemates, diastereomers or enantiomers; wherein mAb is an antibody or a cell-binding molecule; X 1 , X 2 , and X 3  are independently O, S, NH, NHNH, or CH 2 ; p 1 , p 2 , and p 3  are independently 1-100; q 1  and q 2  are independently selected from 0-24; Aa is natural or unnatural amino acid; r is 0-12; (Aa) r  is a peptide containing the same or different sequence of amino acids when r>2; r=0 means (Aa)r absent; m and n are 0-20 independently. 
       
     
     
         8 . The side chain-linkaged conjugate compound according to  claim 1 , wherein the cell binding agent is selected from:
 (A): the group consisting of an antibody, a protein, probody, nanobody, a vitamin (including folate), peptide, a polymeric micelle, a liposome, a lipoprotein-based drug carrier, a nano-particle drug carrier, a dendrimer, and a molecule or a particle thereof coating or linking with a cell-binding ligand, and a combination of two or more thereof;   (B): an antibody-like protein, a full-length antibody (polyclonal antibody, monoclonal antibody, antibody dimer, antibody multimer), multispecific antibody (selected from, bispecific antibody, trispecific antibody, or tetraspecific antibody); a single chain antibody, an antibody fragment that binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, a monoclonal antibody fragment that binds the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment that binds to the target cell, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment that binds to the target cell, anti-idiotypic (anti-Id) antibodies, CDR′s, diabody, triabody, tetrabody, miniantibody, a probody, a probody fragment, small immune proteins (SIP), a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule, large molecular weight proteins, fusion proteins, kinase inhibitors, gene-targeting agents, nanoparticles or polymers modified with antibodies or large molecular weight proteins;   (C): a cell-binding ligand or receptor agonist selected from: folate derivatives; glutamic acid urea derivatives; Somatostatin and its analogs (selected from the group consisting of octreotide (Sandostatin) and lanreotide (Somatuline)); aromatic sulfonamides; Pituitary adenylate cyclase activating peptides (PACAP) (PACT); Vasoactive intestinal peptides (VIP/PACAP) (VPAC 1,  VPAC2); Melanocyte-stimulating hormones (α-MSH); Cholecystokinins (CCK)/gastrin receptor agonists; Bombesins (selected from the group consisting of Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met—NH 2 )/gastrin-releasing peptide (GRP); Neurotensin receptor ligands (NTR1, NTR 2 , NTR 3 ); Substance P (NK1 receptor) ligands; Neuropeptide Y (Y1-Y6); Homing Peptides include RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimeric and multimeric cyclic RGD peptides (selected from cRGDfV), TAASGVRSMH and LTLRWVGLMS (Chondroitin sulfate proteoglycan NG2 receptor ligands) and F3 peptides; Cell Penetrating Peptides (CPPs); Peptide Hormones selected from the group consisting of luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, and gonadotropin-releasing hormone (GnRH) agonist, acts by targeting follicle stimulating hormone (FSH) and luteinizing hormone (LH), as well as testosterone production, selected from the group consisting of buserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), Gonadorelin (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly—NH 2 ), Goserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly—NH 2 ), Histrelin (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), leuprolide (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), Nafarelin (Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly—NH 2 ), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly—NH 2 ), Nafarelin, Deslorelin, Abarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla—NH 2 ), Cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala—NH 2 ), Degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala—NH 2 ), and Ganirelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N9,N10-diethyl)-homoArg-Leu-(N9, N10-diethyl)-homoArg-Pro-D-Ala—NH 2 ); Pattern Recognition Receptor (PRRs), selected from the group consisting of Toll-like receptors' (TLRs) ligands, C-type lectins and Nodlike Receptors' (NLRs) ligands; Calcitonin receptor agonists; integrin receptors' and their receptor subtypes' (selected from the group consisting of αvβ 1 , αvβ 3 , αvβ 5 , αvβ 6 , α 6 β 4 , α 7 β 1 , α L β 2 , α 11b β 3 ) agonists (selected from the group consisting of GRGDSPK, cyclo(RGDfV) (L1) and its derivatives [cyclo(—N(Me)R-GDfV), cyclo(R-Sar-DfV), cyclo(RG-N(Me)D-fV), cyclo(RGD-N(Me)f-V), cyclo(RGDf-N(Me)V-)(Cilengitide)]; Nanobody (a derivative of VHH (camelid Ig)); Domain antibodies (dAb, a derivative of VH or VL domain); Bispecific T cell Engager (BiTE, a bispecific diabody); Dual Affinity ReTargeting (DART, a bispecific diabody); Tetravalent tandem antibodies (TandAb, a dimerized bispecific diabody); Anticalin (a derivative of Lipocalins); Adnectins (10th FN3 (Fibronectin)); Designed Ankyrin Repeat Proteins (DARPins); Avimers; EGF receptors, or VEGF receptors' agonists;   (D): a small molecule of cell-binding molecule or a cell receptor agonist selected from the following: LB01 (Folate), LB02 (PMSA ligand), LB03 (PMSA ligand), LB04 (PMSA ligand), LB05 (Somatostatin), LB06 (Somatostatin), LB07 (Octreotide, a Somatostatin analog), LB08 (Lanreonde, a Somatostatin analog), LB09 (Vapreotide, a Somatostatin analog), LB10 (CAIX ligand), LB11 (CAIX ligand), LB12 (Gastrin releasing peptide receptor (GRPr), MBA), LB13 (luteinizing hormone-releasing hormone (LH-RH) ligand and GnRH), LB14 (luteinizing hormone-releasing hormone (LH-RH) and GnRH ligand), LB15 (GnRH antagonist, Abarelix), LB16 (cobalamin, vitamin B12 analog), LB17 (cobalamin, vitamin B12 analog), LB18 (for α v β 3  integrin receptor, cyclic RGD pentapeptide), LB19 (hetero-bivalent peptide ligand for VEGF receptor), LB20 (Neuromedin B), LB21 (bombesin for a G-protein coupled receptor), LB22 (TLR 2  for a Toll-like receptor,), LB23 (for an androgen receptor), LB24 (Cilengitide/cyclo(-RGDfV-) for an α v  integrin receptor, LB23 (Fludrocortisone), LB25 (Rifabutin analog), LB26 (Rifabutin analog), LB27 (Rifabutin analog), LB28 (Fludrocortisone), LB29 (Dexamethasone), LB30 (fluticasone propionate), LB31 (Beclometasone dipropionate), LB32 (Triamcinolone acetonide), LB33 (Prednisone), LB34 (Prednisolone), LB35 (Methylprednisolone), LB36 (Betamethasone), LB37 (Irinotecan analog), LB38 (Crizotinib analog), LB39 (Bortezomib analog), LB40 (Carfilzomib analog), LB41 (Carfilzomib analog), LB42 (Leuprolide analog), LB43 (Triptorelin analog), LB44 (Clindamycin), LB45 (Liraglutide analog), LB46 (Semaglutide analog), LB47 (Retapamulin analog), LB48 (Indibulin analog), LB49 (Vinblastine analog), LB50 (Lixisenatide analog), LB51 (Osimertinib analog), LB52 (a nucleoside analog), LB53 (Erlotinib analog) or LB54 (Lapatinib analog) which are shown in the following structures:   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein “ ” is a site to link the side chain linker; X 4  and Y 1  are independently O, NH, NHNH, NR 1 , S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R 1 ) N(R 1 )C(O)N(R 1 ) CH 2 , C(O)NHNHC(O) or C(O)NR 1 ; X 1  is H, CH 2 , OH, O, C(O), C(O)NH, C(O)N(R 1 ) R 1 , NHR 1 , NR 1 , C(O)R 1  or C(O)O; X 5  is H, CH 3 , F, or Cl; M 1  and M 2  are independently H, Na, K, Ca, Mg, NH 4 , N(R 1 R 2 R 3 R 4 ); R 1 , R 2 , R 3  and R 4  are defined the same as in  claim 1 . 
       
     
     
         9 . The side chain-linkaged conjugate compound according to  claim 1 , wherein the cell-binding molecule, T, when linking to V 1  and/or V 2 , or when T directly linking to L 1  and/or L 2 , wherein V 1  and/or V 2  are absent, has one or more of the following linkage structures: 
       
         
           
           
               
               
           
         
         wherein R 20  and R 21  are independently C 1 -C 8  alkyl; C 2 -C 8  heteroalkyl, or heterocyclic; C 3 -C 8  aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; or C 2 -C 100  polyethylene glycol having formula of (CH 2 CH 2 O) p . 
       
     
     
         10 . The side chain-linkaged conjugate compound according to  claim 1 , wherein the cell binding agent is capable of targeting against a tumor cell, a virus infected cell, a microorganism infected cell, a parasite infected cell, an autoimmune disease cell, an activated tumor cell, a myeloid cell, an activated T-cell, an affecting B cell, or a melanocyte, or a 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 receptor, 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 antigen 125, MUC16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg,  Canis lupus  familiaris IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11(C-C motif chemokine 11), CCR 4  (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 antigen, CXCR 4 , 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), DRS (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 alpha), FCGR1, alpha-Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR (folate receptor), Folate receptor alpha, Folate hydrolase, Fos-related antigen 1F protein of respiratory syncytial 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 α-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), HER 2 , HER 2/ neu, HER 3  (ERBB-3), IgG4, HGF/SF (Hepatocyte growth factor/scatter factor), HHGFR, HIV-1, Histone complex, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, 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-γ, Influenza hemagglutinin, IgE,  IgE  Fc region, IGHE, interleukins (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 (α4, α IIb β 3 , αvβ3, α 4 β 7 , α5β1, α6β4, α7β7, α11β3, α5β5, αvβ5), Interferon gamma-induced protein, ITGA2, ITGB2, KIR 2 D, Kappa Ig, LCK, Le, Legumain, Lewis-Y antigen, LFA-1 (Lymphocyte function-associated antigen 1, CD11a), LHRH, LINGO-1,  Lipoteichoic 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 inhibitory factor, or glycosylation-inhibiting factor (GIF)), MS4A1 (membrane-spanning 4-domains subfamily A member 1), MSLN (mesothelin), MUC1(Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM)), MUC 1 -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 antigen), Nectin-4 (ASG-22ME), NGF, Neural apoptosis-regulated proteinase 1, NOGO-A, Notch receptor, 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-glycolylneuraminic acid), PAX 3 , PAX5, PCSK9, PDCD1 (PD-1, Programmed cell death protein 1), PDGF-Rα (Alpha-type platelet-derived growth factor receptor), PDGFR-β, 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 (Phosphatidylserine), 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, Sclerostin, SLAMF7 (SLAM family member 7), Selectin P, SDC1 (Syndecan 1), sLe(a), Somatomedin C, SIP (Sphingosine-1-phosphate), Somatostatin, Sperm protein 17, SSX 2 , STEAP1 (six-transmembrane 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-α, TGF-β ( Transforming growth factor  beta), TGF-β1, TGF-β2 (Transforming growth factor-beta 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-α, 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), TRAILR 2  (Death receptor 5 (DRS)), 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, VEGFR 2 , or vimentin, WT1, XAGE 1, or cells expressing an insulin growth factor receptor, or any epidermal growth factor receptors. 
     
     
         11 . The side chain-linkaged conjugate compound according to  claim 10 , wherein the tumor cell is selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells, prostate cancer 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, and cells that grow and divide at an unregulated, quickened pace to cause cancers. 
     
     
         12 . A pharmaceutical composition comprising a therapeutically effective amount of at least one of the conjugate compound of  claim 1 , and a pharmaceutically acceptable salt, carrier, diluent, or excipient therefor. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , either in a liquid formula or in a formulated lyophilized solid, comprising by weight of: 0.01%-99% of one or more of the conjugate compound; 0.0%-20.0% of one or more polyols; 0.0%-2.0% of one or more surfactants; 0.0%-5.0% of one or more preservatives; 0.0%-30% of one or more amino acids; 0.0%-5.0% of one or more antioxidants; 0.0%-0.3% of one or more metal chelating agents; 0.0%-30.0% of one or more buffer salts for adjusting pH of the formulation to pH 4.5 to 7.5; and 0.0%-30.0% of one or more of isotonic agent for adjusting osmotic pressure bewteen about 250 to 350 mOsm when reconstituted for administration to a patient;
 wherein the 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 metallic salts;   wherein the 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-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodium methyl oleyl-taurate; dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine and coco ampho glycinate; or isostearyl ethylimidonium ethosulfate; polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol;   wherein the preservative is selected from benzyl alcohol, octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl and benzyl alcohol, alkyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol;   wherein the amino acid is selected from arginine, cystine, glycine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycine glutamic acid or aspartic acid;   wherein the antioxidant is selected from ascorbic acid, glutathione, cystine or methionine;   wherein the chelating agent is selected from EDTA or EGTA;   wherein the buffer salt is selected from sodium, potassium, ammonium, or trihydroxyethylamino 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;   wherein the tonicity agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate, or sodium chloride.   
     
     
         14 . The pharmaceutical composition according to  claim 12 , which is packed in a vial, bottle, pre-filled syringe, or pre-filled auto-injector syringe, in a form of a liquid or lyophilized solid. 
     
     
         15 . The conjugate compound of  claim 1 , having in vitro, in vivo or ex vivo cell killing activity. 
     
     
         16 . The pharmaceutical composition according to  claim 12 , further comprising a chemotherapeutic agent, a radiation therapy agent, an immunotherapy agent, an autoimmune disorder agent, an anti-infectious agent or another conjugate. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein the chemotherapeutic agent is selected from:
 (1) a) an alkylating agent selected from nitrogen mustards: chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1065 and adozelesin, carzelesin, bizelesin or their synthetic analogues; duocarmycin and its synthetic analogues, KW-2189, CBI-TMI, or CBI dimers; benzodiazepine dimers or pyrrolobenzodiazepine (PBD) dimers, tomaymycin dimers, indolinobenzodiazepine dimers, imidazobenzothiadiazepine dimers, or oxazolidinobenzodiazepine dimers; Nitrosoureas: comprising carmustine, 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, triethylenemelamine, 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 and their analogs, Maytansinoids including DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine, ansamitocins and their analogs, 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, irinotecan, mitoxantrone, novantrone, retinoic acids (or retinols), teniposide, topotecan, 9-nitrocamptothecin or RFS 2000; and mitomycins and their analogs;   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 analogues); IMP dehydrogenase Inhibitors: (including mycophenolic acid, tiazofurin, ribavirin, EICAR); Ribonucleotide reductase Inhibitors: (including hydroxyurea, deferoxamine)]; [Pyrimidine analogs: Uracil analogs: (including ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-Fluorouracil, floxuridine, ratitrexed); Cytosine analogs: (including cytarabine, cytosine arabinoside, fludarabine); Purine analogs: (including azathioprine, fludarabine, mercaptopurine, thiamiprine, thioguanine)]; folic acid replenisher, frolinic acid};   e) a hormonal therapy selected from Receptor antagonists: [Anti-estrogen: (including megestrol, raloxifene, tamoxifen); LHRH agonists: (including goscrclin, leuprolide acetate); Anti-androgens: (including bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, trilostane and other androgens inhibitors)]; Retinoids/Deltoids: [Vitamin D3 analogs: (including CB 1093, EB 1089 KH 1060, cholecalciferol, ergocalciferol); Photodynamic therapies: (including verteporfin, phthalocyanine, photosensitizer Pc4, demethoxyhypocrellin A); Cytokines: (comprising 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 (anti-EGFR/Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib. vandetanib, E7080 (anti-VEGFR 2 ), mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, Trastuzumab, Ranibizumab, Panitumumab, and ispinesib;   g) a poly (ADP-ribose) polymerase (PARP) inhibitor selected from the group consisting of olaparib, niraparib, iniparib, talazoparib, veliparib, CEP 9722, E7016, BGB-290, and 3-aminobenzamide;   h) an antibiotic selected from the group consisting of an enediyne antibiotic (selected from the group of calicheamicin, calicheamicin γ1, δ1, α1 or β1; dynemicin, including dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, or neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, eribulin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin;   i) a polyketide (acetogenin), bullatacin and bullatacinone; gemcitabine, epoxomicins andcarfilzomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, Isoprenylation inhibitors and Lovastatin, Dopaminergic neurotoxins and 1-methyl-4-phenylpyridinium ion, cell cycle inhibitors (including 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 inhibitors or verapamil, Ca 2+ ATPase inhibitors or thapsigargin, Histone deacetylase inhibitors ((including Vorinostat, Romidepsin, Panobinostat, Valproic acid, Mocetinostat (MGCD0103), Belinostat, PCI-24781, Entinostat, SB939, Resminostat, Givinostat, AR-42, CUDC-101, sulforaphane, Trichostatin A); Thapsigargin, Celecoxib, glitazones, epigallocatechin gallate, Disulfiram, Salinosporamide A; Anti-adrenals selected from the group consisting of aminoglutethimide, mitotane, trilostane; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine (DFMO), elfomithine; elliptinium acetate, etoglucid; gallium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK; 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, and antisense drugs;   (2) an anti-autoimmune disease agent: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids (including the group consisting of amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone danazol, dexamethasone, Triamcinolone acetonide, beclometasone dipropionate), DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, sirolimus, tacrolimus;   (3) an anti-infectious disease agent comprising:   a) Aminoglycosides: amikacin, astromicin, gentamicin (netilmicin, sisomicin, isepamicin), hygromycin 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, cefuroxime, cefuzonam, cephamycin (including cefoxitin, cefotetan, cefmetazole), oxacephem (flomoxef, latamoxef);   f) Glycopeptides: bleomycin, vancomycin (including oritavancin, telavancin), teicoplanin (dalbavancin), ramoplanin;   g) Glycylcyclines: tigecycline;   h) β-Lactamase inhibitors: penam (sulbactam, tazobactam), clavam (clavulanic acid);   i) Lincosamides: clindamycin, lincomycin;   j) Lipopeptides: daptomycin, A54145, calcium-dependent antibiotics (CDA);   k) Macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide (telithromycin, cethromycin), midecamycin, miocamycin, oleandomycin, 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 phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, 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, difloxacin, enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin;   q) Streptogramins: pristinamycin, quinupristin/dalfopristin;   r) Sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole);   s) Steroid antibacterials: fusidic acid;   t) Tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, lymecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, glycylcyclines (including tigecycline);   u) antibiotics selected from the group consisting of annonacin, arsphenamine, bactoprenol 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 (rifampin), tazobactam tinidazole, and uvaricin;   (4) anti-viral drugs comprising:   a) Entry/fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41 (enfuvirtide), PRO 140, 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 analogues (including the group consisting of 3′-fluoro-2′,3′-dideoxythymidine (FLT) and 3′-fluoro-2′,3′-dideoxyguanosine (FLG), fomivirsen, ganciclovir, idoxuridine, lamivudine (3TC), 1-nucleosides (including the group consisting of β-1-thymidine and β-1-2′-deoxycytidine), penciclovir, racivir, ribavirin, stampidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT);   f) Non-nucleosides: amantadine, ateviridine, capravirine, diarylpyrimidines (etravirine, rilpivirine), delavirdine, docosanol, emivirine, efavirenz, foscarnet (phosphonoformic acid), imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, NOV-205, 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) 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) 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.   
     
     
         18 . The pharmaceutical composition according to  claim 16 , comprising at least one synergistic agent selected from the following drugs: Abatacept, abemaciclib, Abiraterone acetate, Abraxane, Acetaminophen/hydrocodone, Acalabrutinib, aducanumab, Adalimumab, ADXS31-142, ADXS-HER 2 , afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, Alitretinoin, ado-trastuzumab emtansine, Amphetamine/dextroamphetamine, anastrozole, Aripiprazole, anthracyclines, Aripiprazole, Atazanavir, Atezolizumab, Atorvastatin, Avelumab, Axicabtagene ciloleucel, axitinib, belinostat, BCG Live, Bevacizumab, bexarotene, blinatumomab, Bortezomib, bosutinib, brentuximab vedotin, brigatinib, Budesonide, Budesonide/formoterol, Buprenorphine, Cabazitaxel, Cabozantinib, capmatinib, Capecitabine, carfilzomib, chimeric antigen receptor-engineered T (CAR-T) cells, Celecoxib, ceritinib, Cetuximab, Chidamide, Ciclosporin, Cinacalcet, crizotinib, Cobimetinib, Cosentyx, crizotinib, CTL019, 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, exenatide ER, Ezetimibe, Ezetimibe/simvastatin, Fenofibrate, Filgrastim, fingolimod, Fluticasone propionate, 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, Interferon beta 1b, Interferon gamma-la, lapatinib, Ipilimumab, Ipratropium bromide/salbutamol, Ixazomib, Kanuma, Lanreotide acetate, lenalidomide, lenaliomide, lenvatinib mesylate, letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, LN-144, lorlatinib, Memantine, Methylphenidate, Metoprolol, Mekinist, mericitabine/Rilpivirine/Tenofovir, Modafinil, Mometasone, Mycidac-C, Necitumumab, neratinib, Nilotinib, niraparib, Nivolumab, ofatumumab, obinutuzumab, olaparib, Olmesartan, Olmesartan/hydrochlorothiazide, Omalizumab, Omega-3 fatty acid ethyl esters, Oncorine, Oseltamivir, Osimertinib, Oxycodone, palbociclib, Palivizumab, panitumumab, panobinostat, pazopanib, pembrolizumab, PD-1 antibody, PD-L1 antibody, Pemetrexed, pertuzumab, Pneumococcal conjugate vaccine, pomalidomide, Pregabalin, ProscaVax, Propranolol, Quetiapine, Rabeprazole, radium 223 chloride, Raloxifene, Raltegravir, ramucirumab, Ranibizumab, regorafenib, ribociclib, Rituximab, Rivaroxaban, romidepsin, Rosuvastatin, ruxolitinib phosphate, Salbutamol, savolitinib, semaglutide, Sevelamer, Sildenafil, siltuximab, Sipuleucel-T, Sitagliptin, Sitagliptin/metformin, Solifenacin, solanezumab, Sonidegib, Sorafenib, Sunitinib, tacrolimus, tacrimus, Tadalafil, tamoxifen, Tafinlar, Talimogene laherparepvec, talazoparib, Telaprevir, talazoparib, Temozolomide, temsirolimus, Tenofovir/emtricitabine, tenofovir disoproxil fumarate, Testosterone gel, Thalidomide, TICE BCG, Tiotropium bromide, Tisagenlecleucel, toremifene, trametinib, Trastuzumab, Trabectedin (ecteinascidin 743), trametinib, tremelimumab, Trifluridine/tipiracil, Tretinoin, Uro-BCG, Ustekinumab, Valsartan, veliparib, vandetanib, vemurafenib, venetoclax, vorinostat, ziv-aflibercept, Zostavax, and their analogs, derivatives, pharmaceutically acceptable salts, carriers, diluents, or excipients thereof, or a combination of two or more thereof.