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WO 2015/151078 A4 8 October 2015 (08.10.2015) P O P C T

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WO 2015/151078 A4 8 October 2015 (08.10.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/151078 A4 8 October 2015 (08.10.2015) P O P C T (51) International Patent Classification: (84) Designated States (unless otherwise indicated, for every C07F 9/6558 (2006.01) C07K 16/32 (2006.01) kind of regional protection available): ARIPO (BW, GH, A61K 38/05 (2006.01) C07F 9/572 (2006.01) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, A61K 47/48 (2006.01) A61K 31/537 (2006.01) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (21) Number: International Application DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, PCT/IB20 15/054521 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (22) International Filing Date: SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 15 June 2015 (15.06.2015) GW, KM, ML, MR, NE, SN, TD, TG). (25) Filing Language: English Declarations under Rule 4.17 : (26) Publication Language: English — as to the identity of the inventor (Rule 4.1 7(Ϊ)) — as to applicant's entitlement to apply for and be granted a (71) Applicant: HANGZHOU DAC BIOTECH CO., LTD patent (Rule 4.1 7(H)) [CN/CN]; Room B2001-B2019, Building 2, No. 452 Six Street, Heda, Hangzhou City, Zhejiang Province, 310018 — of inventorship (Rule 4.17(iv)) (CN). Published: (72) Inventor: ZHAO, Robert Yongxin; 7 Loring Road, Lex — with international search report (Art. 21(3)) ington, Massachusetts 02421 (US). — with amended claims (Art. 19(1)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — upon request of the applicant, before the expiration of the AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, time limit referred to in Article 21(2)(a) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (88) Date of publication of the international search report: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 10 March 2016 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, Date of publication of the amended claims: 14 July 20 16 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (54) Title: HYDROPHILIC LINKERS FOR CONJUGATION (57) Abstract: Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided. AMENDED CLAIMS received by the International Bureau on 26 May 2016 What is claimed is: 1. A hydrophilic linker compound of the Formula (I): Y_R Q_R J_LT_ — R4_ Z K 5 6 (J) Wherein: Y represents a functional group that enables reaction with a cell-binding agent. Y is pref erably a thiol, a disulfide substituent, a maleimido, a haloacetyl, an alkynyl, an alkoxylamino group, carboxylic acid, or an N-hydroxysuccinimide ester. Χ Ρ ΟΜ Q and Tare either - - (=0 )( )-, or-X S(0 2)-, or - X !-S(O)-; or -Xi-P(=0)(OM)- X2-, or or-X S(0 2)-X 2-, or-X - S(O)- x 2 - . X 1 X2 and X 3 are independently selected from N(R7), O, or S; In addition, when X is e i ther N(Pv7), or O, or S, then either X 2 or X or another X that connects to -P(=0), -S(O), or - S(0 2) can be CH2. m and n are integer from 0 to 5, but not 0 at the same time. Z represents a functional group that enables linkage of a cytotoxic drug via an alkyl, alkenyl, alkynyl, aromatic, heteroalkyl, disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, amine (secondary, tertiary, or quartary), imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond. Z is preferably a thiol, disulfide substituent, malei mido, haloacetyl, alkoxyamine, alkynyl, hydrazine group, carboxylic acid, or an N- hydroxysuccinimide ester. Pvi, Pv2, P 3, R4, R P , and R7 are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 3 to 6 carbon atoms, or 1-6 carbon atoms of esters, ether, amide, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 0 to about 1000, or combination thereof. Ν Additionally R 1 R2, R 3 and R 4 are respectively a chain of atoms selected from C, , O, S, Si, and P that covalently connects the cell-surface binding ligand, the phosphinate or sulfonyl group, the conjugated drug and among themselves (R 1 R2 , R 3 and R4). The atoms used in form ing Ri, R2, R3 or R 4 group can have a C1-C6 group of ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkox- ylamines, urethanes, amino acids, peptides, acyloxylamine s, heterocyclics, hydroxamic acids, or combination thereof. + M is H, or Na, or K, or N RiR 2 R 3 or a pharmaceutical salt. Ri, R 2 and R 3 are described above. 2. A cell-binding agent-drug conjugate compound of Formula (II): wherein: Cb represents a cell-binding agent/molecule. Drug represents a drug linked to t e cell-binding agent via the hydrophilic linker by an al- kyl, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, urethanes, amino acid, peptide, acyloxylamine, hydroxamic acid, disulfide, thioether, thioester, carbamate, car bonate, heterocyclic ring, heteroalkyl, heteroaromatic, or alkoxime bond, or combination thereof. q is 1 30. Wherein Q, T, m, n, R R2, R3, R , R 5 and R 5 are defined the same as in Claim 1. 3. Wherein: Q, T, Z, m, n, R R2, R3, R t, R 5 and R 5 are defined the same as in Claim 1. Cb and q are defined the same as in Claim 2 . 4. A compound of Formula (IV): Y - R - - - R T - - Drug 5 6 (IV) Wherein: Y, Q, T, m, n, R R2, R3, R t, R 5 and R 5 are defined the same as in Claim 1. Drug is defined the same as in Claim 2 . 5. The compound of Formula (I) of claims 1, wherein Q, or/and T is-Xi-P(=0)[Xi-Ri-Y]- X3-, thus the compound of the Formula (I) containing two or more Y groups, can be used to link to two or more sites, preferably link to a pair of sites of cell binding molecules. wherein X2 and X 3 are independently selected from N(R 7), O, CH2 or S; and Y, Ri and R7 are defined in Claim 1. 6. The compound of Formula (I) of claims 1, wherein Q, or/and T is -Xi-P(=0)[X 2 -R4 -Z]- X3-, thus the compound of the Formula (I) containing two or more Z groups can be used for linking two or more drugs, preferably two different drugs. Wherein X X2 and X 3 are inde pendently selected from N(R 7), O, CH2 or S; and Z, R 4 and R7 are defined in Claim 1. 7. The conjugate compound of Formula (II) of claims 2, wherein Q, or/and T is -Xi- P(=0)[Xi-Ri-Cb]-X3-, thus t e compound of the Formula (II) containing two or more Cb groups is linked to two or more sites, preferably a pair of sites of a cell binding molecule. Wherein X X2 and X 3 are independently selected from N(R 7), O, CH2 or S; Ri and R7 are de fined in Claim 1; and Cb is defined the same in Claim 2 . 8. The compound of Formula (II) of claims 2, wherein Q, or/and T is Drug]-X3-, thus the compound of the Formula (II) containing two or more "Drugs" is linked to two or more drugs, preferably two different drugs. Wherein X X2 and X 3 are independently se lected from N(R 7), O, CH2 or S; R and R7 are defined in Claim 1; and Drug is defined the same in Claim 2 . 9. The compound of Formula (III) of claims 3, wherein Q, or/and T is-Xi-P(=0)[X 2-Rr Cb]-X3-, thus the compound of the Formula (III) containing two or more Cb groups is linked to two or more sites, preferably a pair of sites of a cell binding molecule. Wherein X X2 and X 3 are independently selected from N(R 7), O, CH2 or S; Ri and R7 are defined in Claim 1; and Cb is defined the same in Claim 2 . 10. The compound of Formula (III) of claims 3, wherein Q, or/and T is X3-, thus the compound of the Formula (III) containing two or more Z groups can be used for linking to two or more drugs, preferably two different drugs. Wherein X X2 and X 3 are inde pendently selected from N(R 7), O, CH2 or S; and Z, R 4 and R7 are defined in Claim 1. 11. The compound of Formula (IV) of claims 4, wherein Q, or/and T is X3-, thus the compound of the Formula (IV) containing two or more Y groups can be used for linking to two or more sites, preferably to a pair of sites of a cell binding molecule.
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