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Linker Payload Contribution in GR Activation of Steroid-ADC As Tested in HEK293/PRLR/GRE-Luc Cells

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Linker Payload Contribution in GR Activation of Steroid-ADC As Tested in HEK293/PRLR/GRE-Luc Cells ( (51) International Patent Classification: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, A61K 47/68 (2017.01) C07J 71/00 (2006.01) KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/US20 19/0 12786 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (22) International Filing Date: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 08 January 2019 (08.01.2019) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available) . ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 62/614,905 08 January 2018 (08.01.2018) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: REGENERON PHARMACEUTICALS, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, INC. [US/US]; 777 Old Saw Mill River Road, Tarrytown, KM, ML, MR, NE, SN, TD, TG). New York 10591 (US). (72) Inventor: HAN, Amy; c/o Regeneron Pharmaceuticals, Declarations under Rule 4.17: Inc., 777 Old Saw Mill River Road, Tarrytown, New York — as to the identity of the inventor (Rule 4.17(i)) 10591-6707 (US). — as to applicant's entitlement to apply for and be granted a patent (Rule 4.17(H)) (74) Agent: RICE, Janice etal.; Squire PattonBoggs (US) LLP, — as to the applicant's entitlement to claim the priority of the 1801 page Mill Road, Suite 110, Palo Alto, California 94304 earlier application (Rule 4.17(iii)) (US). Published: (81) Designated States (unless otherwise indicated, for every — without international search report and to be republished kind of national protection available) : AE, AG, AL, AM, upon receipt of that report (Rule 48. 2(g)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, — with sequence listing part of description (Rule 5.2(a)) 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, HN, (54) Title: STEROIDS AND ANTIBODY-CONJUGATES THEREOF Linker Payload Contribution in GR activation of steroid-ADC as tested In HEK293/PRLR/GRE-Luc cells 24h (57) Abstract: Described herein protein steroid conjugates that are useful, for example, for the target-specific delivery of glucocorticoids (GCs) to cells. STEROIDS AND ANTIBODY-CONJUGATESTHEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to, and the benefit of, US Provisional Patent Application No. 62/614,905, entitled Steroids and Antibody Conjugates Thereof, which was filed January 8, 2018. The content of this provisional patent application is herein incorporated by reference in its entirety for all purposes. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on January 3, 2019, is named 114581_00228_ST25.txt and is 11,186 bytes in size. FIELD [0003] Provided herein are steroids, protein (e.g. antibody) conjugates thereof, and methods for treating diseases, disorders, and conditions comprising administering the steroids and conjugates. BACKGROUND [0004] Antibody-drug conjugates (ADCs) are antibodies that are covalently linked to biologically active small molecule drugs, thus combining the targeting specificity of antibodies with the mode-of-action and potency of small molecule drugs. The therapeutic utility of ADC(s) has been validated in cancer treatment and is a major ongoing focus of study. ADCETRIS ® (bentruximab vedotin) and KADCYLA ® (ado-trastuzumab emtansine) are ADCs approved for the treatment of certain cancer types, and several other ADCs are currently in clinical development. [0005] Glucocorticoids (GCs) are small molecule steroids that bind to glucocorticoid receptors (GRs) and are utilized in anti-inflammatory and immunosuppressive therapies. However, due to the ubiquitous expression of glucocorticoid receptors in many cell types, glucocorticoid treatments are compromised by toxicities to most organ systems. Thus, there is need for both novel glucocorticoids as well as novel therapies that minimize the side effects arising from glucocorticoid administration, particularly those arising from activating glucocorticoid receptors in non-target cells. The instant disclosure provides solutions to the aforementioned needs as well as other unmet needs in the field to which the instant disclosure pertains. Included in the instant disclosure are antibody-drug conjugates comprising glucocorticoid payloads. SUMMARY [0006] Provided herein are compounds and methods useful for the treatment of various diseases, disorders, or conditions. [0007] A first aspect is directed to a Compound of Formula (III): or a pharmaceutically acceptable salt, solvate, stereoisomer, or derivative thereof, wherein: R4 is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; x both R are hydrogen; and SP is -C(O)-C 1 -C1 0-alkylene-C(O)-, -C(O)-N(C 1-6 alkyl)-C 1 -C1 0 - alkylene- X1- where X1 is attached to L in Formula (III), -C(O)-N(H)-(C1-C10-alkylene)-S- where S is attached to L in Formula (III), -C(O)-N(C1-6alkyl)-(C1-C10-alkylene)-S- where S is attached to L in Formula the point of attachment on the right hand side (i.e. at N) is to L in Formula (III), -CH2-NH- where the N is attached to L in Formula (III), where the N is attached to L in Formula (III) and where Ar is optionally substituted arylene or optionally substituted heteroarylene, -(C1-C10- alkylene)-N R50C(O)-(C1-C10-alkylene)-NR50a - where NR50a is attached to L in Formula 50 50a 50a (III), -C(O)-(C 1-C1 0 -alkylene)-N R C(O)-(C 1 -C1 0-alkylene)-N R - where NR is attached to L in Formula (III) and where each C1 -C10 -alkylene is independently optionally substituted with one or more hydroxy, -C(O)-N( R5)-C1-C10-alkylene-C(O)NH-X2- where X2 is attached to L in Formula where X4 is attached to L in Formula (III); or both Rx are fluoro; and SP is -C(O)-C1-C10-alkylene-C(O)-, -C(O)-N(C1-6alkyl)-C1-C10- alkylene-X1b- where X1b is attached to L in Formula (III), -C(O)-N(H)-(C1-C10-alkylene)- X1b- where X1b is attached to L in Formula the point of attachment on the right hand side (i.e. at N) is to L in Formula (III), -CH2-NH- where the N is attached to L in Formula (III), where the N is attached to L in Formula (III) and where Ar is optionally substituted arylene or optionally substituted heteroarylene, -(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- where NR50a is attached to L in 50 50a 50a Formula (III), -C(O)-(C 1-C1 0 -alkylene)-N R C(O)-(C 1 -C1 0-alkylene)-N R - where NR is attached to L in Formula (III) and where each C1-C10-alkylene is independently optionally substituted with one or more hydroxy, -C(O)-N(R5)-(C1-C10-alkylene)-C(O)NH- X2- where X2 is attached to L in Formula (III), or where X4 is attached to L in Formula (III); and 1 X is -N(C1-6 alkyl)-; X1b is -S-, -NH-, or -N(C1-6alkyl)-; X2 is -NH-; 3 3 4 3 X is -CH2 -, X is -CH2 -O-(C1 -C10 -alkylene)-C(O)- where the C(O) is attached to X , or X is -C(O)-; X4 is -O-; 5 R is H, -OH, -OCH 3 , or C1-6 alkyl; 50 50a d e f R and R are independently hydrogen or C1 -C6-alkyl;R , R , and R are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CH2ORg, where each Rg is independently -CH2 C(O)OH or -CH2 C(O)O(alkyl); and m is 0 or 1; z is an integer selected from 1-30, inclusive; L is a linker; and BA is a binding agent. [0008] A second aspect is directed to a Compound according to Formula (I): or a pharmaceutically acceptable salt, solvate, stereoisomer, or derivative thereof, wherein: R4 is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; a) both Rx are hydrogen; and 3 Z 50 50a 50b R is -C(O)R ; -(C1-C1 0 -alkylene)-N R C(O)-(C 1 -C1 0-alkylene)-N R R ; -CH2 NH2 ; or RZ is -C4-10-alkylene-C(O)OH; -(C1-C10-alkylene)-NR50 C(O)-(C1-C10-alkylene)-NR50a R50b where each C1-C1 0 -alkylene is independently optionally substituted with one or more hydroxy; where where Ar is optionally substituted aryl or heteroaryl; or NR15R15a ; 15 15a R is H or C1 -C6 alkyl and R is -(C1 -C1 0 -alkylene)-SH or -(C1-6 -alkylene)-C(O)NHNH 2; b) both Rx are fluoro; and R3 is -C(O)RZ; -(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a R50b ; -CH2NH2; or RZ is -C4-10-alkylene-C(O)OH; -(C1-C10-alkylene)-NR50 C(O)-(C1-C10-alkylene)-NR50a R50b where each C1-C10-alkylene is independently optionally substituted with one or more hydroxy; where where Ar is optionally substituted aryl or heteroaryl; or NR16R16a ; 16 16a R is H or C1 -C6 alkyl and R is -(C1 -C1 0 -alkylene)-SH, -(C1 -C1 0 -alkylene)-NH 2, -(C1 - C10-alkylene)- -alkylene)-C(O)NHNH2; and each R50 , R50a , and R50b are independently hydrogen or C1-C6-alkyl; c d e f g one of R , R , R , and R is -CH2OR and the others are independently -H, -OH, hydroxyalkyl, g g -C(O)OH, or -CH2 OR , where each R is independently -(C1-6 -alkylene)-C(O)OH or -(C1-6 - alkylene)-C(O)O(alkyl); or one of Rc, Rd, Re, and Rf is hydroxyalkyl and the others are -H; and m is 0 or 1.
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