(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 2017/106957 Al 29 June 2017 (29.06.2017) W P O P C T (51) International Patent Classification: (74) Agents: MACINS, Andris, I., D. et al; C6 Patent Group C07J5/00 (2006.01) C07D 305/14 (2006.01) Incorporated, operating as Carbon Patent Group, Unit A61K 47/54 (2 ) C07D 487/04 (2006.01) 203A - 116 Geary Avenue, Toronto, Ontario M6H 4H1 A61P 35/00 (2006.01) C07J 41/00 (2006.01) (CA). A61P 37/06 (2006.01) C07J 43/00 (2006.01) (81) Designated States (unless otherwise indicated, for every C07D 295/185 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/CA20 16/000322 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, 22 December 2016 (22. 12.2016) KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (25) Filing Language: English MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (26) Publication Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (30) Priority Data: TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, 62/387,160 23 December 201 5 (23. 12.2015) US ZA, ZM, ZW. (71) Applicant: THE UNIVERSITY OF BRITISH (84) Designated States (unless otherwise indicated, for every COLUMBIA [CA/CA]; c/o University-Industry Liaison kind of regional protection available): ARIPO (BW, GH, Office, #103-6190 Agronomy Road, Vancouver, British GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Columbia V6T 1Z3 (CA). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: CIUFOLINI, Marco, A.; 313-212 1 W 6th Av DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, enue, Vancouver, British Colombia V6K 1V5 (CA). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, CULLIS, Pieter, R.; 3732 West 1st Avenue, Vancouver, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, British Colombia V6R 1H4 (CA). TAM, Yuen, Yi, C ; GW, KM, ML, MR, NE, SN, TD, TG). #1708 - 1420 W. Georgia Street, Vancouver, British Columbia V6G 3K4 (CA). ZAIFMAN, Joshua; 8-2057 Published: West 2nd Avenue, Vancouver, British Columbia V6J 1J5 — with international search report (Art. 21(3)) (CA). [Continued on next page] (54) Title: LIPID-LINKED PRODRUGS o (57) Abstract: This invention provides lipid-linked prodrugs having structures as set out herein. Uses of such lipid-linked prodrug © compounds for treatment of various indications, and methods for making and using lipid-linked prodrugs are also provided. w o 2017/106957 Al II 11 II I 1 I 1 II I Mi ll i l lllll II I II before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) LIPID-LINKED PRODRUGS TECHNICAL FIELD This invention relates to a conjugate of a therapeutic compound and a lipid moiety, compositions thereof, and methods for their use in the delivery of therapeutic compounds. In particular the invention relates to lipid-linked prodrugs, wherein the linker covalently bound to the prodrug is biodegradable. Methods for making and using the conjugates also are provided. CROSS REFERENCE TO RELATEDAPPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Serial Nos. 62/387,160 filed on 23 December 2015, entitled "LIPID-LINKED PRODRUGS". BACKGROUND Drug selectivity for a target tissue is an important consideration during drug design. Selective delivery of a drug to its target may allow for lower dosages and reduced side effects. Selectivity for a given target tissue may be particularly significant when the therapeutic agents being delivered are chemotherapeutics for the treatment of cancer. In particular, cytotoxic drug therapies are meant to target rapidly dividing cells, but may often be limited by the toxic side effects of the chemotherapeutic on healthy cells. Furthermore, other therapeutic moieties may benefit from selective targeting and improved pharmacokinetic characteristics (i.e. in υίυο stability, cellular uptake (for example, lipophilicity), etc.) Fatty acids have been used to improve selectivity of drugs for their target tissues (for example, US 7,235,583; US 8,552,054; US 6,090,800; US 2012/0264810; US 2013/0330401). Fatty acids previously have been conjugated with drugs to help the drugs as conjugates cross the blood brain barrier (for example, US 4,933,324). Lipid molecules, including fatty acids or fatty amines, also have been conjugated with drugs to render the conjugates more lipophilic than the unconjugated drugs. Fatty amines are lipid molecules that terminate in an amino group (unlike fatty acids which terminate in a carboxylic acid group). Fatty acids are naturally occurring whereas fatty amines are not a common tissue component in animals. SUMMARY This invention is based in part on the fortuitous discovery that conjugates of therapeutic compounds and lipid moieties described herein show improved selective delivery. Furthermore, some of the conjugates of therapeutic compounds and lipid moieties show improved loading, reduced toxicity, improved targeting, improved in vivo potency or improved vivo stability. In accordance with one embodiment, there is provided a compound, the compound having the structure of Formula I: Formula I wherein: 1 R may be H, a linear, branched or cyclic Ci-C20 al y , optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the Ci-Cio alkyl may optionally be substituted with F, CI, Br, I, OH, C1-C6 O-Alkyl, or -C O-Acyl, wherein the G -C6 O-Alkyl or the G -C6 O-Acyl may optionally be substituted with F, Cl, Br, I or OH; 2 R may be H, a G-Ce primary amine, G-Ce secondary amine or a C -C6 tertiary amine, a linear, branched or cyclic G-Go alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the Ci-Cio alkyl may optionally be substituted with F, Cl, Br, I, OH, G -C6 O-Alkyl, or C,-C O-Acyl, wherein the G -C6 O-Alkyl or the Ci-Ce O-Acyl may optionally be substituted with F, Cl, Br, I or OH; X1 may be O, S or NR 0 , wherein R10 may be H, a linear, branched or cyclic G-Go alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the C - C alkyl may optionally be substituted with F, Cl, Br, I, OH, C - C O-Alkyl, or Ci-Ce O-Acyl, wherein the G-Ce O-Alkyl or the G -C6 O-Acyl may optionally be substituted with F, Cl, Br, I or OH; o A — Z — Y - M A — Y - M -C^ G1I may be G G G 1 or ' G 1 ; wherein: A-ZG I may be a drug moiety, wherein Z I may be an electronegative atom selected from N and O, such that the drug moiety was derived from a drug having the formula A - ZGI- H when GI has lost an H to covalently bind to Y GI; 2 11 11 Y may be CH , O, S, C(=0), P0 3 , or NR wherein R may be H, a linear, branched or cyclic -C o alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the C -C10 alkyl may optionally be substituted with F, CI, Br, I, OH, G -C O-Alkyl, or G -C6 O-Acyl, and wherein the G -C O-Alkyl or the G -C6 O- Acyl may optionally be substituted with F, CI, Br, I or OH; M GI may be 0-12 atoms selected from C, N, O or S, wherein two or more C atoms optionally have one or more cis or trans C=C double bonds of E or Z geometry and wherein the C atoms may optionally be substituted with F, CI, Br, I, OH, =0, G -Ce O-Alkyl, C,-C O-Acyl or G-C6 S-Alkyl; 1 alternatively, G may be H, « or R 3-C(=0)-, wherein R may be C -C2 linear or branched carbon chain, optionally having one or more, cis or trans C=C double bonds and optionally substituted with OH; alternatively, G may be an ionizable moiety selected from: -COOH; -NH +; -OH; - + + 8 8 NH3 ; -NH ;-SH; -NMe2; -NHMe; and R wherein R' may be C,-C10 alkyl optionally + + + substituted with one or more of COOH, -NH , -OH, -NH3 , -NH ,-SH, -NMe2, -NHMe; ni may be O, l , 2 , 3, 4 or 5; R may be H, a linear, branched or cyclic G-Go alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the G-G 0 alkyl may optionally be substituted with F, CI, Br, I, OH, -C O-Alkyl, or G-Ce O-Acyl, wherein the G-C6 O-Alkyl or the G -C O-Acyl may optionally be substituted with F, CI, Br, I or OH; 4 R may be H, a linear, branched or cyclic G-G 0 alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the G-G 0 alkyl may optionally be substituted with F, CI, Br, I, OH, G-C6 O-Alkyl, or G -Ce O-Acyl, wherein the G-C O-Alkyl or the G-C6 O-Acyl may optionally be substituted with F, CI, Br, I or OH; n2 may be o, l, 2 , 3, 4 or 5 ; R may be H, -C6 primary amine, -C6 secondary amine or G -Ce tertiary amine, a linear, branched or cyclic G-G 0 alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the G-G 0 alkyl may optionally be substituted with F, CI, Br, I, OH, G -C6 O-Alkyl, or G -C6 O-Acyl, wherein the G -C6 O-Alkyl or the G - C 6 O-Acyl may optionally be substituted with F, CI, Br, I or OH; 2 1 14 X may be 0 , S or NR , wherein R may be H, a linear, branched or cyclic G-G 0 alkyl, optionally having one or more cis or trans C=C double bonds of E or Z geometry, wherein the G-G , alkyl may optionally be substituted with F, CI, Br, I, OH, -Ce O-Alkyl, or G-Ce O-Acyl, wherein the G-Ce O-Alkyl or the -C O-Acyl may optionally be substituted with F, CI, Br, I or OH; O I I A |— Z 2—YG2 - Q2 A - Z Q2 G2 Q2 G is G or wherein: A-ZG may be a drug moiety, wherein ZG2 may be an electronegative atom selected from N and O, such that the drug moiety was derived from a drug having the formula A- ZG2-H when ZG2 has lost an H to covalently bind to Y G ; 2 11 YG may be CH2 0 , S, C(=0), P0 3 , or NR.