ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS

Title:

ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS

Document Type and Number:

WIPO Patent Application WO/2024/097775

Kind Code:

Abstract:

The disclosure relates to anti-cancer compounds derived from nuclear receptor binders, such as nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.

Inventors:

HUNG DAVID (US)
MILLER CHRISTOPHER PAUL (US)
DARWISH IHAB S (US)

Application Number:

PCT/US2023/078379

Publication Date:

May 10, 2024

Filing Date:

November 01, 2023

Export Citation:

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Assignee:

NUVATION BIO INC (US)

International Classes:

C07D241/44; C07D487/04; A61P35/00

Attorney, Agent or Firm:

ZHONG, Qiwen et al. (US)

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Claims:

WHAT IS CLAIMED IS: 1. A compound of Formula I: or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein: A¹ is CH or N; A² is CH or N; A³ is N or CR³; A⁴ is C and is a double bond, or A⁴ is CH and is a single bond, or A⁴ is N and is a single bond; L is a covalent bond or a linking moiety; R¹ is a nuclear receptor-targeting epitope; R² is hydrogen, C_1-6 alkyl, C_3-6 cycloalkyl, C_1-6 haloalkyl, or C_1-6 alkoxy; R³ is hydrogen; or R² and R³ together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl; R⁴ is hydrogen, C_6-12 aryl, or 5- to 12-membered heteroaryl, wherein the C_6-12 aryl or 5- to 12- membered heteroaryl is optionally substituted with one or more R⁶; R⁵ is hydrogen, halo, or C_1-6 alkyl; each R⁶ is independently halo, cyano, nitro, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -OR¹⁰, -OC(O)R¹⁰, -C(O)OR¹⁰, -SR¹⁰, -NR¹⁰R¹¹, -NR¹⁰C(O)R¹¹, -C(O)NR¹⁰R¹¹, C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, or C_2-12 alkynyl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C_1-12 alkoxy, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; and each R¹⁰ and R¹¹ is independently hydrogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, or 5- to 12-membered heteroaryl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C_1-12 alkoxyl, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C_6-12 aryl, and 5- to 12-membered heteroaryl, wherein any hydrogen atom of the moiety in the brackets is replaced with attachment to L-R¹. 2. The compound of claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is not a compound selected from the compounds in Table 1A, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. 3. The compound of claim 1 or 2, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A¹ is CH. 4. The compound of claim 1 or 2, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A¹ is N. 5. The compound of any one of claims 1-4, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A² is CH. 6. The compound of any one of claims 1-4, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A² is N. 7. The compound of any one of claims 1-6, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A³ is CR³ and R³ is hydrogen. 8. The compound of any one of claims 1-6, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A³ is N. 9. The compound of any one of claims 1-8, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A⁴ is C. 10. The compound of any one of claims 1-8, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A⁴ is CH. 11. The compound of any one of claims 1-8, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein A⁴ is N. 12. The compound of any one of claims 1-11, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R² is C_1-6 alkyl. 13. The compound of any one of claims 1-11, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R² is methyl.

14. The compound of any one of claims 1-11, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R² is ethyl. 15. The compound of any one of claims 1-14, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen. 16. The compound of any one of claims 1-15, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen. 17. The compound of any one of claims 1-15, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R⁵ is halo. 18. The compound of any one of claims 1-15, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R⁵ is fluoro. 19. The compound of any one of claims 1-18, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound if of Formula IA: . 20. The compound of any one of claims 1-18, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound if of Formula IB: . 21. The compound of any one of claims 1-18, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound if of Formula IC:

22. The compound of any one of claims 1-18, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the compound is of Formula ID: . 23. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ binds to an estrogen receptor. 24. The compound of any one of claims 1-23, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ binds to a glucocorticoid receptor. 25. The compound of any one of claims 1-24, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ binds to a progesterone receptor 26. The compound of any one of claims 1-25, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ binds to an androgen receptor. 27. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is of Formula IIA: wherein: the wavy bond represents the point of connection to L; R³⁰ is hydrogen, C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, C_2-12 alkynyl, or C_3-12 cycloalkyl, wherein each C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, C_2-12 alkynyl, or C_3-12 cycloalkyl is optionally independently substituted with one or more R¹⁰⁰ as valency permits; R⁴⁰ is hydrogen, C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, C_2-12 alkynyl, or C_3-12 cycloalkyl, wherein each C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, C_2-12 alkynyl, or C_3-12 cycloalkyl is optionally independently substituted with one or more R¹⁰⁰ as valency permits; each of R⁵⁰ and R⁵¹ is independently halo, cyano, nitro, -OR¹⁷⁰, -SR¹⁷⁰, -NR¹⁷⁰R¹⁸⁰, C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, or C_2-12 alkynyl; wherein each C_1-12 alkyl, C_1-12 haloalkyl, C_2-12 alkenyl, or C_2-12 alkynyl is independently optionally substituted with one or more halo, hydroxyl or amino as valency permits; each R¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR¹⁷⁰, -SR¹⁷⁰, -SF5, -NR¹⁷⁰R¹⁸⁰, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R¹⁷⁰, -C(=O)OR¹⁷⁰, -OC(=O)OR¹⁷⁰, -OC(=O)R¹⁷⁰, -C(=O)NR¹⁷⁰R¹⁸⁰, -OC(=O)NR¹⁷⁰R¹⁸⁰, -NR¹⁷⁰C(=O)NR¹⁷⁰R¹⁸⁰, -S(=O)1-2R¹⁷⁰, -S(=O)1-2NR¹⁷⁰R¹⁸⁰, -NR¹⁷⁰S(=O)1-2R¹⁸⁰, -NR¹⁷⁰S(=O)1-2NR¹⁷⁰R¹⁸⁰, -NR¹⁷⁰C(=O)R¹⁸⁰, or -NR¹⁷⁰C(=O)OR¹⁸⁰, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C_1-12 alkoxy, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; and each of R¹⁷⁰ and R¹⁸⁰ is independently hydrogen or C_1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits, or R¹⁷⁰ and R¹⁸⁰ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C_1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. 28. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 29. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is of Formula IIB: , wherein: the wavy bond represents the point of connection to L; R⁶⁰ is hydrogen, -OR¹⁰¹, -NR¹⁰¹R¹⁰², C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R¹⁰¹, -C(=O)OR¹⁰¹, -OC(=O)R¹⁰¹, -OC(=O)NR¹⁰¹R¹⁰², -C(=O)NR¹⁰¹R¹⁰², -NR¹⁰¹C(=O)R¹⁰², -NR¹⁰¹C(=O)OR¹⁰², each optionally independently substituted with one or more R¹⁰⁰ as valency permits; R⁸⁰ is hydrogen, -OR¹⁰¹, -NR¹⁰¹R¹⁰², C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R¹⁰¹, -C(=O)OR¹⁰¹, -OC(=O)R¹⁰¹, -OC(=O)NR¹⁰¹R¹⁰², -C(=O)NR¹⁰¹R¹⁰², -NR¹⁰¹C(=O)R¹⁰², -NR¹⁰¹C(=O)OR¹⁰², each optionally independently substituted with one or more R¹⁰⁰ as valency permits; R⁸¹ is hydrogen, -OR¹⁰¹, -NR¹⁰¹R¹⁰², C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R¹⁰¹, -C(=O)OR¹⁰¹, -OC(=O)R¹⁰¹, -OC(=O)NR¹⁰¹R¹⁰², -C(=O)NR¹⁰¹R¹⁰², -NR¹⁰¹C(=O)R¹⁰², -NR¹⁰¹C(=O)OR¹⁰², each optionally independently substituted with one or more R¹⁰⁰ as valency permits; or R⁸⁰ and R⁸¹ are taken together with the atom to which they are attached to form heterocyclyl optionally substituted by halo or C_1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino; R⁸² is hydrogen, -OR¹⁰¹, -NR¹⁰¹R¹⁰², C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C_6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R¹⁰¹, -C(=O)OR¹⁰¹, -OC(=O)R¹⁰¹, -OC(=O)NR¹⁰¹R¹⁰², -C(=O)NR¹⁰¹R¹⁰², -NR¹⁰¹C(=O)R¹⁰², -NR¹⁰¹C(=O)OR¹⁰², each optionally independently substituted with one or more R¹⁰⁰ as valency permits; each of R¹⁰¹ and R¹⁰² is independently hydrogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C_6-12 aryl, or 5- to 12-membered heteroaryl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C_1-12 alkoxyl, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; each R¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR¹⁷⁰, -SR¹⁷⁰, -SF5, -NR¹⁷⁰R¹⁸⁰, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R¹⁷⁰, -C(=O)OR¹⁷⁰, -OC(=O)OR¹⁷⁰, -OC(=O)R¹⁷⁰, -C(=O)NR¹⁷⁰R¹⁸⁰, -OC(=O)NR¹⁷⁰R¹⁸⁰, -NR¹⁷⁰C(=O)NR¹⁷⁰R¹⁸⁰, -S(=O)1-2R¹⁷⁰, -S(=O)1-2NR¹⁷⁰R¹⁸⁰, -NR¹⁷⁰S(=O)1-2R¹⁸⁰, -NR¹⁷⁰S(=O)1-2NR¹⁷⁰R¹⁸⁰, -NR¹⁷⁰C(=O)R¹⁸⁰, or -NR¹⁷⁰C(=O)OR¹⁸⁰, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C_1-12 alkoxy, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C_6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; and each of R¹⁷⁰ and R¹⁸⁰ is independently hydrogen or C_1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits, or R¹⁷⁰ and R¹⁸⁰ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C_1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. 30. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 31. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 32. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is _.

33. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is of Formula IIC: wherein: W is O, S, or NH; each is independently a double bond or a single bond; each of R⁶¹ and R⁶² is independently hydrogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, or C_3-12 cycloalkyl, wherein each C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, or C_3-12 cycloalkyl is optionally independently substituted with one or more R¹⁰⁰ as valency permits; each R¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR¹⁷⁰, -SR¹⁷⁰, -SF5, -NR¹⁷⁰R¹⁸⁰, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, - -NR¹⁷⁰C(=O -NR¹⁷⁰C(=O)R¹⁸⁰, or -NR¹⁷⁰C(=O)OR¹⁸⁰, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C_1-12 alkoxy, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, C_3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; and each of R¹⁷⁰ and R¹⁸⁰ is independently hydrogen or C_1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits, or R¹⁷⁰ and R¹⁸⁰ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C_1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. 34. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is .

35. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is of Formula IID: wherein: the wavy bond refers to the point of connection to L; a is attached to ring a and bond b is attached to ring b; R^a and R^b are each independently -CH₃ or -CH₂CH₃; or R^a and R^b together with the atom to which they are attached form a C3-5 cycloalkyl, oxiranyl, oxetanyl, or tetrahydrofuranyl; A and A' are each independently O or S; E, E¹, E², and E³ are each independently CR^c or N, and each R^c is independently hydrogen, halo, CN, or methyl; E⁴ is CF, CH or N; Q¹ is a bond, CH₂, C=O, or (C=O)NH; Q² is NH, O, S, CH₂, NH(C=O), C(=O)NH, or C=O; R⁴⁴, R⁴⁵ and R⁴⁶ are each independently hydrogen, CN, or C1-2 alkyl; t is 0, 1, 2, 3 or 4; each of R^e and R^f is independently halo, cyano, C_1-4 alkyl, or C_1-4 haloalkyl; R⁴¹ is halo, CN, or NO₂; R⁴² is halo, CH₃, CH₂F, CHF₂, or CF₃; or R⁴¹ and R⁴² together form a wherein the broken lines indicate bonds to ring a; R⁴³ is hydrogen, halo, C_1-2 alkyl, C₂ alkenyl, NO₂, CF₃; or R⁴² and R⁴³ together form a or , wherein each is a single or double bond, and wherein the broken lines indicate bonds to ring a. 36. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 37. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 38. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is _. 39. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is

. 40. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 41. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is . 42. The compound of any one of claims 1-22, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein R¹ is derived from progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19- nortestosterone, progesterone, andarine, cortisol, prednisone, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB- 4124, Proellex, Progenta), or an analog thereof. 43. The compound of any one of claims 1-42, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein L is of formula: -(L^a)_q-, wherein: each L^a is independently -NR¹¹⁰-, -O-, -S(O)_0-2-, -NR¹¹⁰C(O)-, -C(O)NR¹¹⁰-, -NR¹¹⁰C(O)NR¹¹⁰-, -NR¹¹⁰S(O)₂-, -S(O)₂NR¹¹⁰-, -NR¹¹⁰S(O)₂NR¹¹⁰-, -CR¹²⁰=N-NR¹¹⁰-, -NR¹¹⁰-N=CR¹²⁰-, -C(O)-, -OC(O)-, -OC(O)O-, -C(O)O-, C_1-12 alkylene, C_2-12 alkenylene, C_2-12 alkynylene, C_6-12 arylene, C_3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- membered heteroarylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, C_1-4 alkyl, C_1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, and 5- to 12- membered heterocyclyl; each R¹¹⁰ is independently hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R¹²⁰ is independently hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and q is an integer from 0 to 20. 44. The compound of any one of claims 1-42, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein L is of the formula: -Y¹⁰-(CHR¹³⁰)n’-Y²⁰-(CHR¹⁴⁰)n''-Y³⁰-(CHR¹⁵⁰)m''-Y⁴⁰- wherein: each of Y¹⁰, Y²⁰, Y³⁰, and Y⁴⁰ are independently a bond, - -, -O-, -S(O)0-2-, -NR¹¹⁰C(O)-, -C(O)NR¹¹⁰-, -NR¹¹⁰C(O)NR¹¹⁰-, -NR¹¹⁰S(O)2-, -S(O)2NR¹¹⁰-, -NR¹¹⁰S(O)2NR¹¹⁰-, -CR¹²⁰=N-NR¹¹⁰-, -NR¹¹⁰-N=CR¹²⁰-, -C(O)-, -OC(O)-, -OC(O)O-, -(CH₂CH₂O)1-5-, -C(O)O-, C_1-12 alkylene, C_2-12 alkenylene, C_2-12 alkynylene, C6-12 arylene, C_3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- membered heteroarylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each R¹¹⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R¹²⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C_6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R¹³⁰ is independently hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R¹⁴⁰ is independently hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R¹⁵⁰ is independently hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxy, C_1-4 haloalkoxy, C_6-12 aryl, 5- to 12-membered heteroaryl, C_3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and n', n'', and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. 45. The compound of any one of claims 1-42, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein L is Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 ,n _^y- Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 46. The compound of any one of claims 1-42, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein L is n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 , n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 n _^y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 wherein the “*”and the wavy or dashed line represent a covalent bond. n _^ y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 47. The compound of any one of claims 1-46, or tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the linking moiety does not comprise a heteroarylene. 48. The compound of any one of claims 1-47, or tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein the linking moiety does not comprise a pyridylene (e.g., ^^^ 49. The compound of any one of claims 1-48, or tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein -L-R¹ does not comprise , wherein R^aa is hydrogen, halo, C1-4 alkyl, or C1-4 haloalkyl; and R^bb is hydrogen or C1-4 alkyl. 50. A compound as provided in Table 1, or tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. 51. A pharmaceutical composition comprising a compound of any one of claims 1-50, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 52. A method of treating cancer, comprising administering an effective amount of the compound of clams 1-50, or the pharmaceutical composition of claim 51 to an individual in need thereof. 53. The method of claim 52, wherein the cancer is liver cancer, melanoma, Hodgkin’s disease, non- Hodgkin’s lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi’s sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, n _^ y-2633819 Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, trophoblastic neoplasms, or prostatic carcinoma. n _^ y-2633819

Description:

ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Patent Application No. 63/382,095, filed November 2, 2022, the disclosure of which is hereby incorporated herein by reference in 5 its entirety. BACKGROUND The disclosure relates to anti-cancer compounds derived from nuclear receptor binders, such as nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation. 10 PARP inhibitors are pharmacologic agents that prevent DNA repair leading to the death of cells and hence tumor growth inhibition. Inhibitors of PARP enzymes (such as olaparib, rucaparib, niraparib, and talzoparib) have been approved for the treatment of breast cancer in patients with BRCA mutations, and ovarian cancer. There are several others (e.g., velaparib) that are in clinical testing for breast, prostate and ovarian cancers. The use of PARP inhibitors is not without side effects, and one of the major roadblocks to 15 the long-term use of PARP inhibitors is the rapid and dose dependent development of neutropenia. This requires dosing holidays and/or dose reductions in clinical practice, which compromise the ability to achieve maximal efficacy. Other anticancer agents, e.g., alkylating agents such as chlorambucil, can have serious side effects, such as bone marrow suppression, an increased long-term risk of further cancer, infertility, and allergic reactions. Accordingly, targeted delivery of anticancer agents would be beneficial. 20 It has now been suggested that only PARP1 inhibition and trapping is required for synthetic lethal efficacy in homologous recombination repair deficient (HRD) cells. Thus, combining a selective PARP1 inhibitor and a nuclear receptor-targeting epitope may improve the therapeutic index versus first-generation PARP inhibitors. SUMMARY 25 Provided herein are compounds comprising a nuclear payload and a nuclear receptor-targeting epitope. Compounds described herein are designed to bind nuclear receptors within the cell and allow the compound, with its nuclear payload, to accumulate in the nucleus. Not wishing to be bound by theory, one potential mode of enhanced utility is that this approach may provide for compounds having cell-type selectivity, not merely improved potency, working toward a higher therapeutic index. However, it may be 30 that the compounds may be active by other modes, such as, but not limited to, passive localization in the nucleus. Further, the compounds described herein offer targeted delivery of a nuclear payload. The compounds both target and localize within tumor tissue. The transport of the compound, which comprises at least one nuclear receptor-targeting epitope, such as a nuclear steroid receptor-targeting epitope, covalently attached to at least one nuclear payload, to the nucleus allows for accumulation of the nuclear payload in the nucleus, enhancing tumor cell death. By doing so, compounds described in this disclosure may exhibit superior efficacy. In addition, the compounds described in this disclosure could, by accumulating preferentially in the nucleus of nuclear receptor positive cells, such as steroid receptor positive cells, spare 5 cells that do not express the specific nuclear steroid receptor, and therefore reduce side effects. In certain embodiments, provided is a compound of Formula I: or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein: 10 A ¹ is CH or N; A ² is CH or N; A ³ is N or CR ³; A ⁴ is C and is a double bond, or A ⁴ is CH and is a single bond, or A ⁴ is N and is a single bond; 15 L is a covalent bond or a linking moiety; R ¹ is a nuclear receptor-targeting epitope; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, or C _1-6 alkoxy; R ³ is hydrogen; or R ² and R ³ together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl 20 or 5- or 6-membered heteroaryl; R ⁴ is hydrogen, C6-12 aryl, or 5- to 12-membered heteroaryl, wherein the C6-12 aryl or 5- to 12- membered heteroaryl is optionally substituted with one or more R ⁶; R ⁵ is hydrogen, halo, or C1-6 alkyl; each R ⁶ is independently halo, cyano, nitro, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, 25 C6-12 aryl, 5- to 12-membered heteroaryl, -OR ¹⁰, -OC(O)R ¹⁰, -C(O)OR ¹⁰, -SR ¹⁰, -NR ¹⁰R ¹¹, -NR ¹⁰C(O)R ¹¹, -C(O)NR ¹⁰R ¹¹, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, or C _2-12 alkynyl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxy, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; and ^{each R10 and R11 is independently hydrogen, C} _1-12 ^{alkyl, C} _2-12 ^{alkenyl, C} _2-12 ^{alkynyl, C} _3-12 ^cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, or 5- to 12-membered heteroaryl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxyl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd 5 heterocyclyl, C _6-12 aryl, and 5- to 12-membered heteroaryl, wherein any hydrogen atom of the moiety in the brackets is replaced with attachment to L-R ¹. In certain embodiments, the compound is not a compound selected from Table 1A, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. 10 Also provided is a compound of Table 1, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. Also provided is a composition comprising a compound as described herein or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 15 Also provided is a method of treating or preventing cancer, comprising administering an effective amount of a compound or composition as described herein to an individual in need thereof. The cancer can be a blood cancer, lung cancer, breast cancer, fallopian tube cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, or skin cancer, such as, but not limited to, liver cancer, melanoma, Hodgkin’s disease, non-Hodgkin’s lymphomas, acute 20 lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small- cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant 25 carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi’s sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, trophoblastic neoplasms, prostatic 30 carcinoma, glioma, breast cancer, or prostate cancer. Also provided is a method of treating or preventing cancer, comprising administering an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with an additional chemotherapeutic agent, to an individual in need thereof. DETAILED DESCRIPTION The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. 5 1. Definitions As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. The term “about” refers to a variation of ±1%, ±3%, ±5%, or ±10% of the value specified. For 10 example, “about 50” can in some embodiments includes a range of from 45 to 55. For integer ranges, the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. Also, the singular forms “a” and “the” include plural 15 references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more compounds and equivalents thereof known to those skilled in the art. “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 12 carbon atoms (a “C _1-12 alkyl”), 1 to 10 carbon atoms (i.e., C _1-10 alkyl), 1 to 8 carbon atoms (i.e., 20 C _1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C _1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. 25 -(CH ₂) ₃CH ₃), sec-butyl (i.e. -CH(CH ₃)CH ₂CH ₃), isobutyl (i.e. -CH ₂CH(CH ₃) ₂) and tert-butyl (i.e. -C(CH ₃) ₃); and “propyl” includes n-propyl (i.e. –(CH ₂) ₂CH ₃) and isopropyl (i.e. -CH(CH ₃) ₂). “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. 30 Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF ₂) and trifluoromethyl (-CF ₃). “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term 35 “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O) ₂-, and the like. As used herein, heteroalkyl includes 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. “Heteroalkyl” refers to an alkyl group in which one or more of the carbon 5 atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NH-, -O-, -S-, -S(O)-, -S(O) ₂-. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH ₂OCH ₃, -CH(CH ₃)OCH ₃, 10 -CH ₂CH ₂OCH ₃, -CH ₂CH ₂OCH ₂CH ₂OCH ₃, etc.), thioethers (e.g., -CH ₂SCH ₃, -CH(CH ₃)SCH ₃, -CH ₂CH ₂SCH ₃,-CH ₂CH ₂SCH ₂CH ₂SCH ₃, etc.), sulfones (e.g., -CH ₂S(O)2CH ₃, -CH(CH ₃)S(O)2CH ₃, -CH ₂CH ₂S(O)2CH ₃, -CH ₂CH ₂S(O)2CH ₂CH ₂OCH ₃, etc.), and amines (e.g., -CH ₂NHCH ₃, -CH(CH ₃)NHCH ₃, -CH ₂CH ₂NHCH ₃, -CH ₂CH ₂NHCH ₂CH ₂NHCH ₃, etc. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 15 heteroatom. “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C _2-20 alkenyl), 2 to 8 carbon atoms (i.e., C _2-8 alkenyl), 2 to 6 carbon atoms (i.e., C _2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C _2-4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl). 20 “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C _2-20 alkynyl), 2 to 8 carbon atoms (i.e., C _2-8 alkynyl), 2 to 6 carbon atoms ( ^{i.e., C}2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C _2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond. “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, 25 n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. “Alkoxyalkyl” refers to the group “alkyl-O-alkyl”. “Amino” refers to the group -NR ^yR ^z wherein R ^y and R ^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. 30 “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C _6-20 aryl), 6 to 12 carbon ring atoms (i.e., C _6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C _6-10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl 5 groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp ³ carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C _3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C _3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C _3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C _3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C _3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl,10 cyclohexyl, cycloheptyl, and cyclooctyl. Further, the term cycloalkyl is intended to encompass any non- aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom. “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, 15 with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C _1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C _3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C _3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 20 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, 25 dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and 30 triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused 35 rings). Heteroaryl does not encompass or overlap with aryl as defined above. “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged- heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a 5 single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O-) moieties Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to 10 a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8- tetrahydroquinazolinyl are heterocyclyl, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C _2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C _2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C _2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., 15 C _2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C _3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, 20 benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, 25 tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings 30 include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system. “Alkylene” refers to a divalent alkyl group as defined above. “Alkenylene” refers to a divalent alkenyl group as defined above. “Alkynylene” refers to a divalent alkynyl group as defined above. 35 “Arylene” refers to a divalent aryl group as defined above. “Cycloalkylene” refers to a divalent cycloalkyl group as defined above. “Heterocyclylene” refers to a divalent heterocyclyl group as defined above. “Heteroarylene” refers to a divalent heteroaryl group as defined above. “Oxo” refers to =O. “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. 5 The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur. The term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. “Substituted” as used herein means one or more hydrogen atoms of the group is replaced with a substituent atom or group commonly used in pharmaceutical chemistry. Each substituent can be the same or 10 different. Examples of suitable substituents include, but are not limited to, hydrazide, halo, -CN, -NO ₂, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -OR ⁵⁶, -C(O)OR ⁵⁶, -C(O)R ⁵⁶, -O-alkyl-OR ⁵⁶, -alkyl-OR ⁵⁶, haloalkyl, haloalkoxy, SR ⁵⁶, S(O)R ⁵⁶, SO2R ⁵⁶, NR ⁵⁶R ⁵⁷, -C(O)NR ⁵⁶R ⁵⁷, NR ⁵⁶C(O)R ⁵⁷, including seleno and thio derivatives thereof, wherein each R ⁵⁶ and R ⁵⁷ are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkyl-alkyl-, heterocyclyl, heterocyclyl-alkyl-, aryl, aryl-alkyl-, 15 heteroaryl, or heteroaryl-alkyl-, and wherein each of the substituents can be optionally further substituted. Provided are also are stereoisomers, mixture of stereoisomers, tautomers, hydrates, solvates, isotopically enriched analog, and pharmaceutically acceptable salts of the compounds described herein. The compounds disclosed herein, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that 20 may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers 25 include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. 30 A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another and “diastereomers,” which refers to stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of 35 each other. Thus, all stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including those of the salts, solvates, and hydrates of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated. 5 Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the 10 diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds may be atropisomers and are considered as part of this disclosure. Stereoisomers can also be separated by use of chiral HPLC. Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of 15 which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers. The term “hydrate” refers to the complex formed by the combining of a compound described herein 20 and water. A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid, and ethanolamine. Any compound or structure given herein, is also intended to represent unlabeled forms as well as 25 isotopically labeled forms of the compounds. These forms of compounds may also be referred to as an “isotopically enriched analog.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, 30 ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of 35 patients. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Certain compounds disclosed herein contain one or more ionizable groups (groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)). 5 All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein. With regard to salts of the compounds described herein, one of ordinary skill in the art can select from among a wide variety of available counterions those that are appropriate. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt. 10 As used herein, the term “non-biocleavable linking moiety” is intended to refer to a linking moiety which is not readily hydrolyzed under physiological conditions. As used herein, the term “biocleavable linking moiety” is intended to refer to a linking moiety which is readily hydrolyzed under physiological conditions. In certain embodiments, at least one linking moiety is hydrolyzed under intracellular conditions (e.g., low pH). In some embodiments, the biocleavable is self-cleaving and does not require physiological 15 hydrolysis, in other embodiments, the biocleavable linker’s cleavage is initiated by metabolic activation such as oxidation or pH dependent cleavage without hydrolysis such as by base or acid induced elimination, etc. More broadly speaking, a biocleavable linker may in some instances be analogous to a prodrug wherein after cleavage, one or more drugs is released. In this sense, there are many mechanisms to cleave prodrugs and release the active(s) or a precursor that yields the active and there are also many varieties of cleavage 20 moieties known in the prodrug art and are included in our definition herein. As used herein, the term “cancer” refers to a class of diseases of mammals characterized by uncontrolled cellular growth. The term “cancer” is used interchangeably with the terms “tumor,” “solid tumor,” “malignancy,” “hyperproliferation,” and “neoplasm.” Cancer includes all types of hyperproliferative growth, hyperplasic growth, neoplastic growth, cancerous growth, or oncogenic processes, metastatic tissues 25 or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Illustrative examples include, lung, prostate, head and neck, breast and colorectal cancer, melanomas and gliomas (such as a high grade glioma, including glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors in adult humans). The phrase “solid tumor” includes, for example, lung cancer, head and neck cancer, brain cancer, 30 oral cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, and liver cancer. Other types of solid tumors are named for the particular cells that form them, for example, sarcomas formed from connective tissue cells (for example, bone cartilage, fat), carcinomas formed from epithelial tissue cells (for example, breast, colon, pancreas), and lymphomas formed from lymphatic tissue cells (for example, lymph nodes, spleen, and thymus). Treatment of all types of solid tumors regardless of naming convention is 35 within the scope of this disclosure. “Chemotherapeutic agent” refers to any substance capable of reducing or preventing the growth, proliferation, or spread of a cancer cell, a population of cancer cells, tumor, or other malignant tissue. The term is intended also to encompass radiotherapy, or any antitumor or anticancer agent. As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, 5 such as a clinical result. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In one variation, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a cognitive disorder, a psychotic 10 disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. In one embodiment, treatment of a disease or condition with a compound of the disclosure or a pharmaceutically acceptable salt thereof is accompanied by no or fewer side effects than are associated with currently available therapies for the disease or condition and/or improves the quality of life of the individual. The terms “inhibit,” “inhibiting,” and “inhibition” refer to the slowing, halting, or reversing the 15 growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting. As used herein, by “combination therapy” is meant a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and anther 20 compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances. In various embodiments, treatment with a combination therapy may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of a single compound of the disclosure alone. In some embodiments, a lower amount of each compound is used as part of a combination 25 therapy compared to the amount generally used for individual therapy. In one embodiment, the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a compound in a combination therapy than the amount generally used for individual compound or therapy. Preferably, the use of a small amount of30 compound results in a reduction in the number, severity, frequency, and/or duration of one or more side- effects associated with the compound. As used herein, the term “effective amount” intends such amount of a compound of the disclosure which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective 35 amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds. 5 As used herein, the term “agonist” refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the protein, such as, for example, PARP. As used herein, the term “partial agonist” refers to a compound the presence of which results in a biological activity of a protein that is of the same type as that resulting from the presence of a naturally 10 occurring ligand for the protein, but of a lower magnitude. As used herein, the term “antagonist” or “inhibitor” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a protein. In certain embodiments, the presence of an antagonist or inhibitor results in complete inhibition of a biological activity of a protein, such as, for example, the enzyme poly(ADP-ribose) polymerase (PARP). In certain embodiments, the term 15 “inhibitor” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of an enzyme, such as, for example, the enzyme poly(ADP-ribose) polymerase (PARP). In certain embodiments, the term “antagonist” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of an enzyme, such as, for example, the enzyme poly(ADP-ribose) polymerase (PARP). 20 As used herein, the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of PARP, in an assay that measures such response. As used herein, EC ₅₀ refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, 25 provoked or potentiated by the particular test compound. The term “cancer,” as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid)), prostate, skin (melanoma) 30 or hematological tumors (such as the leukemias). The term “carrier,” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues. As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy. As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, 5 administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and 10 the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like). As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological 15 effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological 20 activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, 25 e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci.1977 Jan; 66(1):1-19. Pharmaceutically acceptable 30 salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the disclosure in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, 35 and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. 5 The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, 10 suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (directly compressible), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., 15 croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, 20 fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. Compounds Provided herein are targeted compounds for treating cancer. The compounds described herein are capable of targeting the nucleus of a cell by recognition and binding of a nuclear receptor-targeting epitope 25 to the respective binding site and delivering the nuclear payload to the nucleus of the cell. The nuclear payload then is capable of binding to one or more target sites within the nucleus and/or disrupting one or more cellular processes, causing the cell to die. In certain embodiments, the nuclear payload is bonded to the nuclear receptor-targeting epitope(s) via a linking moiety. In certain embodiments, the linking moiety provides a single or mono-linkage, meaning that the linker is only conjugated to one atom of each of the 30 payload and the epitope. In certain embodiments, the compound as described herein is binds to a poly(ADP-ribose) and/or inhibits the activity of polymerase-1 (e.g., PARP-1) and/or PARP-2 with an IC50 of less than about 500 nM, or less than about 400 nM, or less than about 350 nM, or less than about 300 nM, or less than about 200 nM, or less than about 100 nM, or less than about 50 nM. In some embodiments, a compound of this invention 35 has higher affinity and/or enzyme inhibitory potency for PARP-1 compared to PARP-2. In some embodiments, the potency and/or affinity ratio of PARP binding and or PARP inhibitory activity indicates that its activity against PARP-1 is greater than 5 times; greater than 10 times; greater than 20 times; greater than 30 times; greater than 50 times; or 100 times the potency and/or inhibitory activity against PARP-2. Provided herein is a compound of Formula I: 5 or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein: A ¹ is CH or N; A ² is CH or N; A ³ is N or CR ³; 10 A ⁴ is C and is a double bond, or A ⁴ is CH and is a single bond, or A ⁴ is N and is a single bond; L is a covalent bond or a linking moiety; R ¹ is a nuclear receptor-targeting epitope; R ² is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, or C _1-6 alkoxy; 15 R ³ is hydrogen; or R ² and R ³ together with the atoms to which they are attached form a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl; R ⁴ is hydrogen, C _6-12 aryl, or 5- to 12-membered heteroaryl, wherein the C _6-12 aryl or 5- to 12- membered heteroaryl is optionally substituted with one or more R ⁶; 20 R ⁵ is hydrogen, halo, or C1-6 alkyl; each R ⁶ is independently halo, cyano, nitro, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, 5- to 12-membered heteroaryl, -OR ¹⁰, -OC(O)R ¹⁰, -C(O)OR ¹⁰, -SR ¹⁰, -NR ¹⁰R ¹¹, -NR ¹⁰C(O)R ¹¹, -C(O)NR ¹⁰R ¹¹, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, or C _2-12 alkynyl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, 25 amino, C _1-12 alkoxy, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; and each R ¹⁰ and R ¹¹ is independently hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, or 5- to 12-membered heteroaryl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxyl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, and 5- to 12-membered heteroaryl, wherein any hydrogen atom of the moiety in the brackets is replaced with attachment to L-R ¹. 5 In certain embodiments, the compound is not a compound selected from Table 1A, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. In certain embodiments, A ¹ is CH. In certain embodiments, A ¹ is N. In certain embodiments, A ² is CH. In certain embodiments, A ² is N. 10 In certain embodiments, A ³ is CR ³ and R ³ is hydrogen. In certain embodiments, A ³ is N. In certain embodiments, A ¹ is CH, A ² is CH, and A ³ is N. In certain embodiments, A ¹ is N, A ² is CH, and A ³ is CH. In certain embodiments, A ⁴ is C. In certain embodiments, A ⁴ is CH. In certain embodiments, A ⁴ is N. 15 In certain embodiments, R ² is C1-6 alkyl. In certain embodiments, R ² is methyl. In certain embodiments, R ² is ethyl. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁵ is hydrogen. In certain embodiments, R ⁵ is halo. In certain embodiments, R ⁵ is fluoro. 20 In certain embodiments, the compound is of Formula IA: . In certain embodiments, the compound is of Formula IC: . In certain embodiments, the compound is of Formula ID: . In certain embodiments of a compound of Formula I, IA, IB, IC, or ID, the linking moiety does not 5 comprise a heteroarylene. In certain embodiments of a compound of Formula I, IA, IB, IC, or ID, the linking moiety does not comprise a pyridylene In certain embodiments of a compound of Formula I, IA, IB, IC, or ID, -L-R ¹ does not comprise a pyridylene 10 In certain embodiments of a compound of Formula I, IA, IB, IC, or ID, -L-R ¹ does not comprise , wherein R ^aa is hydrogen, halo, C1-4 alkyl, or C1-4 haloalkyl; and R ^bb is hydrogen or C1-4 alkyl. Nuclear Receptor-Targeting Epitopes 15 In certain embodiments, R ¹ is a nuclear hormone receptor-targeting epitope. In certain embodiments, R ¹ is a nuclear steroid receptor-targeting epitope. As used herein, “nuclear receptor-targeting epitope” refers to the portion of the compound described herein (e.g., R ¹) which portion is derived from a nuclear targeting agent as disclosed herein and interacts with a ligand-binding domain of the target nuclear receptor, i.e., the portion of the compound which drives a ligand-binding interaction. In some embodiments, 20 the nuclear target epitope binds to a non-ligand binding domain of the receptor. Not wishing to be bound by theory, the nuclear receptor-targeting epitope serves to associate the compound with a target nuclear receptor, e.g. a nuclear steroid receptor, facilitate the localization of compound to nuclear steroid receptor- expressing cells, and translocate the nuclear payload from the cytosol to nucleus, allowing the compound to accumulate in the nucleus. The level of accumulation can be controlled by selecting the appropriate nuclear 5 receptor-targeting epitope. For example, the compounds described herein can accumulate in the nucleus to varying degrees, high in the case of a full agonist (e.g., dihydrotestosterone (DHT)), moderate in the case of a partial agonist (e.g., bicalutamide), and low, in the case of antagonists (e.g., enzalutamide), through nuclear translocation of the nuclear steroid receptor which happens, following epitope binding to the receptor. The steroid receptor target can be any steroid receptor, including, but not limited to, those which are 10 over-expressed in cancer cells. In certain embodiments, at least one nuclear steroid receptor-targeting epitope is capable of binding to a ligand binding domain of a nuclear steroid receptor, such as a ligand binding domain on an estrogen receptor, glucocorticoid receptor, progesterone receptor, or androgen receptor. Exemplary nuclear steroid receptor-targeting epitopes include those derived from an androgen 15 receptor agonist, an androgen receptor antagonist, a selective androgen-receptor modulator (SARM), an estrogen receptor agonist, an estrogen receptor antagonist, a selective estrogen receptor modulator (SERM), a glucocorticoid receptor antagonist, a glucocorticoid receptor agonist, a selective glucocorticoid receptor modulator (SGRM), a progesterone receptor antagonist, a progesterone receptor agonist, a selective progesterone receptor modulator (SPRM), or a combination thereof. 20 The nuclear steroid receptor-targeting epitopes are typically capable of binding to a nuclear steroid r ^{eceptor with an IC}50 of less than about 500 nM, or less than about 400 nM, or less than about 300 nM, or less than about 200 nM, or less than about 100 nM, or with an EC ₅₀ of less than about 1 ^M, or less than about 900 nM, or less than about 800 nM, or less than about 700 nM, or less than about 600 nM, or less than about 500 nM, or less than about 400 nM, or less than about 3400 nM, or less than about 200 nM, or less 25 than about 100 nM. In certain embodiments, the nuclear hormone receptor binding affinity of a compound of this disclosure can be defined according to its affinity relative to a reference nuclear hormone receptor binding compound. In certain embodiments, compounds of this disclosure can bind to a mammalian (e.g., human) 30 androgen receptor. In some instances, a compound disclosed herein binds the human androgen receptor with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of that of dihydrotestosterone (DHT). In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is an agonist at the androgen receptor. In certain embodiments, the nuclear steroid receptor-targeting epitope is an antagonist at the androgen receptor and/or partial agonist/antagonist at the androgen receptor. In 35 certain embodiments, the AR-targeting epitope binds the androgen receptor with an affinity > 1% of testosterone; >2%; >5%; >10%; >25%; >50%; >100%. In certain embodiments, compounds of this disclosure can bind to the estrogen receptor. In some instances, a compound disclosed herein binds a mammalian (e.g., human) estrogen receptor with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of that of 17E- estradiol. In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is an agonist at 5 the estrogen receptor. In certain embodiments, the nuclear steroid receptor-targeting epitope is an antagonist and/or partial antagonist at the estrogen receptor. In certain embodiments, the ER-targeting epitope binds the estrogen receptor with an affinity > 1% of 17b-estradiol; >2%; >5%; >10%; >25%; >50%; >100%.In certain embodiments, compounds of this disclosure can bind to a mammalian (e.g., human) progestin receptor. In some instances, a compound disclosed herein binds the progestin receptor with an affinity of at 10 least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%of that of progesterone. In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is an agonist at the progestin receptor. In certain embodiments, the nuclear steroid receptor-targeting epitope is an antagonist and/or partial antagonist at the progestin receptor. In certain embodiments, the PR-targeting epitope binds the progestin receptor with an affinity > 1% of progesterone; >2%; >5%; >10%; >25%; >50%; >100%. 15 In certain embodiments, compounds of this disclosure can bind to a mammalian (e.g., human) glucocorticoid receptor. In some instances, a compound disclosed herein binds the glucocorticoid receptor with an affinity of at least 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of that of cortisone. In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is an agonist at the glucocorticoid receptor. In certain embodiments, the nuclear steroid receptor-targeting epitope20 is an antagonist and/or partial antagonist at the glucocorticoid receptor. In certain embodiments, the GR- targeting epitope binds the glucocorticoid receptor with an affinity > 1% of cortisol; >2%; >5%; >10%; >25%; >50%; >100%. In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is steroidal (e.g., dihydrotestosterone). In certain embodiments, the nuclear steroid receptor-targeting epitope is non-steroidal 25 (e.g., enzalutamide, apalutamide, AZD9496, and bicalutamide). The analogs are derived from the known nuclear steroid receptor-targeting epitope described herein (e.g., R ¹) and are modified to be conjugated to at least one nuclear steroid payload, optionally via a linking moiety. The analogs, even after modification to arrive at the compounds described herein, maintain biological activity, which is comparable to that observed in the original, unmodified nuclear steroid receptor- 30 targeting epitope. In certain embodiments, the compounds exhibit a binding activity or inhibition which is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50%, or about 5-50% of that observed in the original, unmodified nuclear steroid receptor-targeting epitope. In certain embodiments, the analogs are derived from a known nuclear receptor-targeting epitope 35 (e.g., R ¹), such as a known nuclear steroid receptor-targeting epitope. In certain embodiments, the term “derived from” as used in reference to a nuclear receptor-targeting epitope, means that at most, one non- hydrogen atom of an original, unmodified nuclear receptor-targeting compound (i.e., a known nuclear steroid receptor-targeting compound) is replaced by a covalent bond to the nuclear payload, optionally via a linking moiety. Exemplary non-hydrogen atoms include, but are not limited to, -CH ₃, -OH, =O, and -NH ₂. In certain embodiments, the term “derived from” as used in reference to a nuclear receptor-targeting epitope, 5 means that at most, one non-hydrogen atom of an original, unmodified nuclear receptor-targeting compound (i.e., a known nuclear steroid receptor-targeting compound) is replaced by a covalent bond to the nuclear payload, optionally via a linking moiety. In certain embodiments, one hydrogen atom bound to a heteroatom (e.g., N, O, or S) of the original, unmodified nuclear receptor-targeting compound (i.e., a known nuclear steroid receptor-targeting compound) is replaced by a covalent bond to the nuclear payload, optionally via a 10 linking moiety. In certain embodiments, a single atom on the nuclear receptor-targeting epitope (R ¹) as disclosed herein is replaced for attachment to the remainder of the compound (e.g., the moiety -L-R ¹). In certain embodiments, a halogen atom on a nuclear receptor-targeting epitope disclosed herein is replaced for attachment to the remainder of the compound. In certain embodiments, a hydrogen atom on a nuclear 15 receptor-targeting epitope disclosed herein is replaced for attachment to the remainder of the compound. In certain embodiments, the hydrogen atom is on a heteroatom. In certain embodiments, the hydrogen atom is on a nitrogen. In certain embodiments, the hydrogen atom is on an oxygen. In certain embodiments, the hydrogen atom is on a carbon. In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is an androgen 20 receptor-targeting epitope. As used herein, the term “androgen receptor-targeting epitope” is intended to refer to the portion of the compound which binds to an androgen receptor agonist or androgen receptor antagonist (including partial androgen receptor agonists or partial androgen receptor antagonists) and which is capable of shuttling a compound from the cytoplasm into the nucleus of a cell. The “androgen receptor” (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear 25 receptor that, when activated by binding an androgen receptor binder (e.g., an androgenic hormone such as testosterone, or dihydrotestosterone) in the cytoplasm, is capable of translocating the androgenic hormone into the nucleus. Exemplary androgen receptor-targeting epitopes which can be used in the compounds described herein include (e.g., R ¹) but are not limited to, an androgen receptor agonist, a selective androgen-receptor 30 modulator (SARM) (e.g., enobosarm), an androgen receptor antagonist (e.g., bicalutamide, flutamide, nilutamide, or enzalutamide), a selective estrogen receptor modulator (SERM) (e.g., tamoxifen, toremifene, or raloxifene), an estrogen receptor antagonist (e.g., fulvestrant), a progestin (e.g., megestrol acetate), an estrogen (e.g., estramustine), ketoconazole, abiraterone, darolutamide, or an analog thereof. In certain embodiments, the nuclear steroid receptor-targeting epitope (e.g., R ¹) is a selective 35 androgen receptor modulator (SARM). In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from testosterone, a testosterone ester (e.g., testosterone enanthate, propionate, cypionate, etc., or an analog thereof), enobosarm, BMS-564929, PS178990, LGD-4033 (ligandrol), LGD-2941, AC-262,356, JNJ-28330835, JNJ-37654032, JNJ-26146900, LGD-2226, LGD-3303, LGD-121071, LG-120907, S-40503, S-23, testolone (RAD-140), acetothiolutamide, andarine (S-4), LG-121071, TFM-4AS-1, YK-11, MK-0773 (PF-05314882), 5 GSK2849466, GSK2881078, GSK8698, GSK4336, ACP-105, TT701, LY2452473 (TT-701), 1-(2-hydroxy- 2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitrile-derivat ives (J Med Chem.2014, 57(6), 2462-71), or an analog thereof. In certain embodiments, R ¹ is of Formula IIA: 10 wherein: the wavy bond represents the point of connection to L; R ³⁰ is hydrogen, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl, wherein each C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl is optionally independently substituted with one or more R ¹⁰⁰ as valency permits; 15 R ⁴⁰ is hydrogen, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl, wherein each C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl is optionally independently substituted with one or more R ¹⁰⁰ as valency permits; each of R ⁵⁰ and R ⁵¹ is independently halo, cyano, nitro, -OR ¹⁷⁰, -SR ¹⁷⁰, -NR ¹⁷⁰R ¹⁸⁰, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, or C _2-12 alkynyl; wherein each C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, or 20 C _2-12 alkynyl is independently optionally substituted with one or more halo, hydroxyl or amino as valency permits; each R ¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR ¹⁷⁰, -SR ¹⁷⁰, -SF ₅, -NR ¹⁷⁰R ¹⁸⁰, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, 5- to 12-membered heteroaryl, 25 -NR ¹⁷⁰C(=O -NR ¹⁷⁰C(=O)R ¹⁸⁰, or -NR ¹⁷⁰C(=O)OR ¹⁸⁰, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxy, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; and each of R ¹⁷⁰ and R ¹⁸⁰ is independently hydrogen or C _1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits, or R ¹⁷⁰ and R ¹⁸⁰ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C _1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. 5 In certain embodiments, R ¹ is: . In certain embodiments, R ¹ is of Formula IIB: wherein: 10 the wavy bond represents the point of connection to L; R ⁶⁰ is hydrogen, -OR ¹⁰¹, -NR ¹⁰¹R ¹⁰², C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R ¹⁰¹, -C(=O)OR ¹⁰¹, -OC(=O)R ¹⁰¹, -OC(=O)NR ¹⁰¹R ¹⁰², -C(=O)NR ¹⁰¹R ¹⁰², -NR ¹⁰¹C(=O)R ¹⁰², -NR ¹⁰¹C(=O)OR ¹⁰², each optionally independently substituted with one or more R ¹⁰⁰ as valency permits; 15 R ⁸⁰ is hydrogen, -OR ¹⁰¹, -NR ¹⁰¹R ¹⁰², C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R ¹⁰¹, -C(=O)OR ¹⁰¹, each optionally independently substituted with one or more R ¹⁰⁰ as valency permits; R ⁸¹ is hydrogen, -OR ¹⁰¹, -NR ¹⁰¹R ¹⁰², C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 20 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R ¹⁰¹, -C(=O)OR ¹⁰¹, -OC(=O)R ¹⁰¹, -OC(=O)NR ¹⁰¹R ¹⁰², -C(=O)NR ¹⁰¹R ¹⁰², -NR ¹⁰¹C(=O)R ¹⁰², -NR ¹⁰¹C(=O)OR ¹⁰², each optionally independently substituted with one or more R ¹⁰⁰ as valency permits; or R ⁸⁰ and R ⁸¹ are taken together with the atom to which they are attached to form heterocyclyl optionally substituted by halo or C _1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino; R ⁸² is hydrogen, -OR ¹⁰¹, -NR ¹⁰¹R ¹⁰², C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, 5- to 12-membered heteroaryl, -C(=O)R ¹⁰¹, -C(=O)OR ¹⁰¹, each optionally independently substituted with one or more R ¹⁰⁰ as valency permits; 5 each of R ¹⁰¹ and R ¹⁰² is independently hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, or 5- to 12-membered heteroaryl, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxyl, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C _6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; 10 each R ¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR ¹⁷⁰, -SR ¹⁷⁰, -SF ₅, -NR ¹⁷⁰R ¹⁸⁰, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered -NR ¹⁷⁰C(=O)R ¹⁸⁰, or -NR ¹⁷⁰C(=O)OR ¹⁸⁰, each independently optionally substituted with one or more 15 substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxy, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; and each of R ¹⁷⁰ and R ¹⁸⁰ is independently hydrogen or C _1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits, 20 or R ¹⁷⁰ and R ¹⁸⁰ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C _1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. In certain embodiments, R ¹ is: . In certain embodiments, R ¹ is: 25 . In certain embodiments, R ¹ is: _. In certain embodiments, R ¹ is of Formula IIC: 5 wherein: W is O, S, or NH; each is independently a double bond or a single bond; each of R ⁶¹ and R ⁶² is independently hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, or 10 C _3-12 cycloalkyl, wherein each C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl is optionally independently substituted with one or more R ¹⁰⁰ as valency permits; each R ¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR ¹⁷⁰, -SR ¹⁷⁰, -SF5, -NR ¹⁷⁰R ¹⁸⁰, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, 15 -NR ¹⁷⁰C(=O -NR ¹⁷⁰C(=O)R ¹⁸⁰, or -NR ¹⁷⁰C(=O)OR ¹⁸⁰, each independently optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxyl, amino, C _1-12 alkoxy, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, 5- to 12-membererd heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, as valency permits; and 20 each of R ¹⁷⁰ and R ¹⁸⁰ is independently hydrogen or C _1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits, or R ¹⁷⁰ and R ¹⁸⁰ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C _1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. In certain embodiments, R ¹ is: . In certain embodiments, R ¹ is of Formula IID: wherein: 5 the wavy bond refers to the point of connection to L; a is attached to ring a and bond b is attached to ring b; R ^a and R ^b are each independently -CH ₃ or -CH ₂CH ₃; or R ^a and R ^b together with the atom to which 10 they are attached form a C _3-5 cycloalkyl, oxiranyl, oxetanyl, or tetrahydrofuranyl; A and A' are each independently O or S; E, E ¹, E ², and E ³ are each independently CR ^c or N, and each R ^c is independently hydrogen, halo, CN, or methyl; E ⁴ is CF, CH or N; 15 Q ¹ is a bond, CH ₂, C=O, or (C=O)NH; Q ² is NH, O, S, CH ₂, NH(C=O), C(=O)NH, or C=O; R ⁴⁴, R ⁴⁵ and R ⁴⁶ are each independently hydrogen, CN, or C1-2 alkyl; t is 0, 1, 2, 3 or 4; each of R ^e and R ^f is independently halo, cyano, C1-4 alkyl, or C1-4 haloalkyl; 20 R ⁴¹ is halo, CN, or NO ₂; R ⁴² is halo, CH ₃, CH ₂F, CHF2, or CF3; or R ⁴¹ and R ⁴² together form a , , , wherein the broken lines indicate bonds to ring a; R ⁴³ is hydrogen, halo, C _1-2 alkyl, C ₂ alkenyl, NO ₂, CF ₃; or 5 R ⁴² and R ⁴³ together form a , wherein each is a single or double bond, and wherein the broken lines indicate bonds to ring a. In certain embodiments, R ¹ is: 10

. 5 In certain embodiments, R ¹ is: . In certain embodiments, R ¹ is: . In certain embodiments, R ^a and R ^b are each independently CH ₃ or CH ₂CH ₃. In certain embodiments, R ^a and R ^b together with the atom to which they are attached form a C3-5 cycloalkyl, oxiranyl, 5 oxetanyl, or tetrahydrofuranyl. In certain embodiments, A is O. In certain embodiments, A is S. In certain embodiments, A is O. In certain embodiments, A is S. In certain embodiments, E, E ¹, E ², and E ³, are each independently CR ^c. In certain embodiments, E and E ¹ are each independently CR ^c, and E ² and E ³ are each N. 10 In certain embodiments, E is CR ^c, and each R ^c is independently hydrogen, halo, CN, or methyl. In certain embodiments, E is N. In certain embodiments, E is CH. In certain embodiments, E ¹ is CR ^c, and each R ^c is independently hydrogen, halo, CN, or methyl. In certain embodiments, E ¹ is N. In certain embodiments, E ¹ is CH. In certain embodiments, E ² is CR ^c, and each R ^c is independently hydrogen, halo, CN, or methyl. In 15 certain embodiments, E ² is N. In certain embodiments, E ² is CH. In certain embodiments, E ³ is CR ^c, and each R ^c is independently hydrogen, halo, CN, or methyl. In certain embodiments, E ³ is N. In certain embodiments, E ³ is CH. In certain embodiments, E ⁴ is CF. In certain embodiments, E ⁴ is CH. In certain embodiments, E ⁴ is N. 20 In certain embodiments, D is a bond. In certain embodiments, D is CH ₂. In certain embodiments, D is C=O. In certain embodiments, D is (C=O)NH. In certain embodiments, Dƍ is NH. In certain embodiments, Dƍ is O. In certain embodiments, Dƍ is S. In certain embodiments, D' is CH ₂. In certain embodiments, Dƍ is NH(C=O). In certain embodiments, Dƍ is C(=O)NH. In certain embodiments, D¶ƍ is C=O. In certain embodiments, R' is hydrogen. In certain embodiments, R' is CN. In certain embodiments, R' is C1-2 alkyl. In certain embodiments, R” is hydrogen. In certain embodiments, R” is CN. In certain embodiments, R” is C1-2 alkyl. 5 In certain embodiments, R” is hydrogen. In certain embodiments, R” is CN. In certain embodiments, R” is C1-2 alkyl. In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3, In certain embodiments, t is 4. In certain embodiments, at least one R ^e is independently halo. In certain embodiments, each R ^e is 10 independently halo. In certain embodiments, at least one R ^e is independently cyano. In certain embodiments, at least one R ^e is independently C _1-4 alkyl. In certain embodiments, at least one R ^e is independently C _1-4 haloalkyl. In certain embodiments, R ⁴¹ is halo. In certain embodiments, R ⁴¹ is CN. In certain embodiments, R ⁴¹ is NO ₂. 15 In certain embodiments, R ⁴² is halo. In certain embodiments, R ⁴² is CH ₃. In certain embodiments, R ⁴² is CH ₂F. In certain embodiments, R ⁴² is CHF ₂. In certain embodiments, R ⁴² is CF ₃. In certain embodiments, R ⁴¹ and R ⁴² together form a . In certain embodiments, R ⁴¹ and R ⁴² together form a . In certain embodiments, R ⁴¹ and R ⁴² together form a . In certain embodiments, R ⁴¹ and R ⁴² together form a H . 20 In certain embodiments, R ⁴³ is hydrogen. In certain embodiments, R ⁴³ is halo. In certain embodiments, R ⁴³ is C _1-2 alkyl. In certain embodiments, R ⁴³ is C ₂ alkenyl. In certain embodiments, R ⁴³ is NO ₂. In certain embodiments, R ⁴³ is CF ₃. In certain embodiments, R ⁴² and R ⁴³ together form a , wherein each is a single or double bond. In certain embodiments, R ⁴² and R ⁴³ together form a , wherein each is a single or double bond. In certain embodiments, R42 and R43 together form a , wherein each is a single or double bond. In certain embodiments, R ¹ is: . 5 In certain embodiments, R ¹ is: . In certain embodiments, R ¹ is: _. In certain embodiments, R ¹ is: 10 . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is . In certain embodiments, R ¹ is of Formula IIE: 5 wherein: the wavy bond refers to the point of connection to L; A'' and A''' are each independently O or S; R ^a and R ^b are each independently CH ₃ or CH ₂CH ₃; or R ^a and R ^b together with the atom to which they are attached form a C3-5 cycloalkyl, oxirane, oxetane, or tetrahydrofuran; 10 B, B ¹⁰, B ², B ³, Bƍ, B ^1ƍ, B ^2ƍ, and B ^3ƍ are each independently CR ^c or N; each R ^c is independently hydrogen, fluoro, CN, or methyl; D is NH, O, S, CH ₂, or C=O; X'' is CN, halo, or NO ₂; Y'' is CH ₃, CH ₂R ^d, CHF ₂, or CF ₃; 15 R ^d is halo; Z'' is hydrogen, C _1-2 alkyl, C ₂ alkenyl, or NO ₂; or X'' and Y'' together form a , , , wherein the broken lines indicate bonds to the ring; or Y'' and Z'' together form a , is a single or double bond, and 20 wherein the broken lines indicate In certain embodiments, R ¹ is: wherein: R ³⁰ is hydrogen, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl, wherein 5 each C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl is optionally independently substituted with one to five R ¹⁰⁰ as valency permits; R ⁴⁰ is hydrogen, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl, wherein each C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl is optionally independently substituted with one to five R ¹⁰⁰ as valency permits; 10 each R ⁵⁰ is independently halo, cyano, nitro, -OR ¹⁷⁰, -SR ¹⁷⁰, -NR ¹⁷⁰R ¹⁸⁰, C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, or C _2-12 alkynyl; wherein each C _1-12 alkyl, C _1-12 haloalkyl, C _2-12 alkenyl, or C _2-12 alkynyl is independently optionally substituted with one to five halo, hydroxyl or amino as valency permits; R ⁶⁰ is hydrogen, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl, wherein each C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, or C _3-12 cycloalkyl is optionally independently substituted with one to five R ¹⁰⁰ 15 as valency permits; each R ¹⁰⁰ is independently oxo, halo, cyano, nitro, -OR ¹⁷⁰, -SR ¹⁷⁰, -SF ₅, -NR ¹⁷⁰R ¹⁸⁰, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(=O)R ¹⁷⁰, -C(=O)OR ¹⁷⁰, 20 -C=NOR ¹⁷, wherein each C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R ¹⁰⁰ are independently optionally substituted with one or more halo or C _1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; each R ¹⁷⁰ and R ¹⁸⁰ is independently hydrogen or C _1-12 alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R ¹⁷⁰ and R ¹⁸⁰ are taken together with the atoms to which they are 25 attached to form heterocyclyl optionally substituted by halo or C _1-12 alkyl optionally substituted by oxo, halo, hydroxyl or amino. A'' and A''' are each independently O or S; R ^a and R ^b are each independently CH ₃ or CH ₂CH ₃; or R ^a and R ^b together with the atom to which they are attached form a C _3-5 cycloalkyl, oxirane, oxetane or tetrahydrofuran; B, B ¹⁰, B ², B ³, Bƍ, B ^1ƍ, B ^2ƍ and B ^3ƍ are each independently CR ^c or N; each R ^c is independently hydrogen, fluoro, CN, or methyl; D'' is NH, O, S, CH ₂ or C=O; X'' is CN, halo, or NO ₂; 5 Y'' is CH ₃, CH ₂R ^d, CHF ₂, or CF ₃; R ^d is halo; Z''' is H, C _1-2 alkyl, C ₂ alkenyl, or NO ₂; or X'' and Y'' together form a , , , where the broken lines indicate bonds to form a fused ring; 10 single or double bond and where the broken lines indicate bonds to form a fused ring; Z' is CH or N. In certain embodiments, R ¹ is: 15

5 bond refers to the point of connection to L. In certain embodiments, R ¹ is:

5 , , ,

In certain embodiments, R ¹ is: 5 , or a tautomer, stereoisomer or a mixture of stereoisomers thereof, or an analog thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety. In certain embodiments, R ¹ is derived from, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19-nortestosterone, progesterone, andarine, cortisol, 10 prednisone, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta), or an analog thereof. In certain embodiments, R ¹ is derived from, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, 15 bazedoxifene, ospemifene, megestrol acetate, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof. In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from:

or a tautomer, stereoisomer or a mixture of stereoisomers thereof, or an analog thereof, wherein one or more atoms are replaced by a direct covalent bond to L. 5 In certain embodiments, R ¹ comprises a nuclear receptor-targeting epitope derived from:

5 , , , , , , or a tautomer, stereoisomer or a mixture of stereoisomers thereof or an analog thereof, wherein at least one hydrogen atom is replaced by a direct covalent bond to L. These and other selective androgen receptor modulator (SARMs) which can be used as a nuclear 5 steroid receptor-targeting epitope in R ¹ described herein can be found in US 6,462,038, US 6,777,427, WO2001/027086, WO2004/013104, WO2004/000816, WO2004/0113309, US2006/0211756, US2006/0063819, US2005/245485, US2005/250741, US2005/277681, WO2006/060108, WO2004/041277, WO2003/034987, US2006/0148893, US2006/0142387, WO2005/000795, WO2005/085185, WO2006/133216, WO2006/044707, WO2006/124447, WO2007/002181, WO2005/108351, 10 WO2005/115361, and US2006/0160845. In certain embodiments, R ¹ is a selective estrogen receptor modulator (SERM). In certain embodiments, R ¹ comprises an epitope derived from anordrin, bazedoxifene, broparestrol (Acnestrol), clomifene (Clomid), cyclofenil (Sexovid), lasofoxifene (Fablyn), ormeloxifene (Centron, Novex, Novex-DS, Sevista), ospemifene (Osphena, deaminohydroxytoremifene), raloxifene (Evista), tamoxifen (Nolvadex), 15 toremifene (Fareston; 4-chlorotamoxifen), acolbifene, afimoxifene (4-hydroxytamoxifen; metabolite of tamoxifen), elacestrant, enclomifene ((E)-clomifene), endoxifen (4-hydroxy-N-desmethyltamoxifen; metabolite of tamoxifen), zuclomifene ((Z)-clomifene), bazedoxifene, arzoxifene, brilanestrant, clomifenoxide (clomiphene N-oxide; metabolite of clomifene), droloxifene (3-hydroxytamoxifen), etacstil, fispemifene, GW-7604 (4-hydroxyetacstil), idoxifene (pyrrolidino-4-iodotamoxifen), levormeloxifene ((L)- 20 ormeloxifene), miproxifene, nafoxidine, nitromifene (CI-628), panomifene, pipendoxifene (ERA-923), trioxifene, keoxifene, LY117018, onapristone, fareston (toremifine citrate), or zindoxifene (D-16726), or an analog thereof. In certain embodiments, the SERM is classified structurally as a triphenylethylene (tamoxifen, clomifene, toremifene, droloxifene, idoxifene, ospemifene, fispemifene, afimoxifene, etc., or an analog 25 thereof), a benzothiophene (raloxifene, arzoxifene, etc., or an analog thereof), an indole (bazedoxifene, zindoxifene, pipendoxifene, etc., or an analog thereof), a tetrahydronaphthalene (lasofoxifene, nafoxidine, etc., or an analog thereof), or a benzopyran (acolbifene, ormeloxifene, levormeloxifene, etc., or an analog thereof). In certain embodiments, R ¹ is a selective estrogen receptor downregulator (SERD). In certain 30 embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from fulvestrant, brilanestrant (ARN-810), etacstil (GW5638), AZD9496, giredestrant (GDC-9545), or GW7604. In certain embodiments, R ¹ is a selective progesterone receptor modulator (SPRM). In certain embodiments, B comprises an epitope derived from ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta), or an analog thereof. In certain embodiments, R ¹ comprises an epitope derived from, estrogen, estetrol, estriol, estrone, 5 progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof. In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an androgen receptor-targeting epitope, and comprises: 10

, or a tautomer, stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety. 5 In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an androgen receptor-targeting epitope, and comprises: 10

or a tautomer, stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety. 5 In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an estrogen receptor-targeting epitope, and comprises:

or a tautomer, stereoisomer or a mixture of stereoisomers thereof, or an analog thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety. 5 In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an estrogen receptor-targeting epitope, and comprises:

or a tautomer, stereoisomer, or a mixture of stereoisomers thereof, or an analog thereof, where the 5 wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety. In certain embodiments, at least one nuclear steroid receptor-targeting epitope comprises: 10

5 or a tautomer, stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the nuclear payload, optionally via a linking moiety. In certain embodiments, the nuclear steroid receptor-targeting epitope is not, or does not contain, a peptide, protein, nanoparticle or antibody. Linking moiety 10 The “linking moiety” of any compounds described herein can be biocleavable (e.g., acid labile) or non-biocleavable. Linking moieties can be linear, branched, saturated, unsaturated, all-carbon or heteroatomic. Linking moieties can also contain one or more rings that are fused, saturated, unsaturated, as well as be all-carbon or heteroatomic. In certain embodiments, the linking moiety is a non-biocleavable linking moiety. In certain embodiments, the linking moiety is a biocleavable linking moiety. In certain15 embodiments, a nuclear payload is bonded to one nuclear steroid receptor-targeting epitope via a non- biocleavable linking moiety and one or more nuclear steroid receptor-targeting epitope(s) via a biocleavable linking moiety. In certain embodiments, the biocleavable linking moiety is an acid-labile linking moiety. In some embodiments, the linking moiety comprises a hydrazone linkage. It is contemplated that any linking moiety can be used in the compounds described herein, provided 20 that it does not significantly interfere with or disrupt the desired binding of the nuclear payload or the nuclear receptor-targeting epitope. In some embodiments, the linking moiety (L) is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, may optionally comprise an arylene, heteroarylene, cycloalkylene or heterocycloalkylene; and further wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C _1-4 alkyl, C _1-4 alkoxy, and 5 C _1-4 haloalkyl. In the linkers shown, where not directionality is specified, none is intended. Where not specified, either end of the linker can be bonded to R ¹ or a PARP-binding portion of the compound. In certain embodiments, L is of formula: -(L ^a) _q-, 10 wherein: each L ^a is independently -NR ¹¹⁰S(O)2-, -S(O)2NR ¹¹⁰-, -NR -OC(O)O-, -C(O)O-, C _1-12 alkylene, C _2-12 alkenylene, C _2-12 alkynylene, C6-12 arylene, C _3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- membered heteroarylene, each independently optionally 15 substituted with one or more substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, and 5- to 12- membered heterocyclyl; each R ¹¹⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; 20 each R ¹²⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and q is an integer from 0 to 20. In certain embodiments, L is of the formula: -Y ¹⁰-(CHR ¹³⁰) _n’-Y ²⁰-(CHR ¹⁴⁰) _n''-Y ³⁰-(CHR ¹⁵⁰) _m''-Y ⁴⁰- 25 wherein: each of Y ¹⁰, Y ²⁰, Y ³⁰, and Y ⁴⁰ are independently a bond, - , -O-, -S(O) _0-2-, -NR ¹¹⁰C(O)-, -C(O)NR ¹¹⁰-, -NR ¹¹⁰C(O)NR ¹¹⁰-, -NR ¹¹⁰S(O) ₂-, -S(O) ₂NR ¹¹⁰-, -NR ¹¹⁰S(O) ₂NR ¹¹⁰-, -CR ¹²⁰=N-NR ¹¹⁰-, -NR ¹¹⁰-N=CR ¹²⁰-, -C(O)-, -OC(O)-, -OC(O)O-, -(CH ₂CH ₂O) _1-5-, -C(O)O-, C _1-12 alkylene, C _2-12 alkenylene, C _2-12 alkynylene, C _6-12 arylene, C _3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- 30 membered heteroarylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each R ¹¹⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹²⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹³⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; 5 each R ¹⁴⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹⁵⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and n', n'', and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. 10 In certain embodiments, L is of the formula: -Y ¹⁰-(CHR ¹³⁰)n’-Y ²⁰-(CHR ¹⁴⁰)n''-Y ³⁰-(CHR ¹⁵⁰)m''-Y ⁴⁰- wherein: each of Y ¹⁰, Y ²⁰, Y ³⁰, and Y ⁴⁰ are independently a bond, -NR ¹¹⁰-, -O-, -S(O)0-2-, -NR ¹¹⁰C(O)-, -C(O)NR ¹¹⁰-, -NR ¹¹⁰C(O)NR ¹¹⁰-, -NR ¹¹⁰S(O)2-, -S(O)2NR ¹¹⁰-, -NR ¹¹⁰S(O)2NR ¹¹⁰-, -CR ¹²⁰=N-NR ¹¹⁰-, 15 -NR ¹¹⁰-N=CR ¹²⁰-, -C(O)-, -OC(O)-, -OC(O)O-, -(CH ₂CH ₂O)1-5-, -C(O)O-, C _1-12 alkylene, C _2-12 alkenylene, C _2-12 alkynylene, C6-12 arylene, C _3-12 cycloalkylene, or 5- to 12-membered heterocyclylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each R ¹¹⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, 20 C6-12 aryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹²⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C _6-12 aryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹³⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; 25 each R ¹⁴⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹⁵⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and n', n'', and m'' are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8. 30 In certain embodiments, L is of the formula: wherein: each of L ², L ³, and L ⁴ is independently a bond, C _1-12 alkylene, -NHC(=O)-, -C(=O)NH-, -C(=O)-O-, -O-C(=O) -, or C=O; 5 each of R ²⁰⁰ and R ²⁰¹ is independently halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, and 5- to 12-membered heterocyclyl; and each of s and s' is independently 0, 1, 2, 3, or 4. In certain embodiments, the linking moiety is of the Formula: ; 10 wherein ring C is a 3- to 12- membered cycloalkylene or 3- to 12- membered heterocyclylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each of Y ⁵⁰ and Y ⁶⁰ are independently a bond, -NR ¹¹⁰-, -O-, -S(O)0-2-, -NR ¹¹⁰C(O)-, -C(O)NR ¹¹⁰-, 15 -NR ¹¹⁰C(O)NR ¹¹⁰-, -NR ¹¹⁰S(O)2-, -S(O)2NR ¹¹⁰-, -NR ¹¹⁰S(O)2NR ¹¹⁰-, -CR ¹²⁰=N-NR ¹¹⁰-, -NR ¹¹⁰-N=CR ¹²⁰-, -C(O)-, -OC(O)-, -OC(O)O-, -(CH ₂CH ₂O)1-5-, -C(O)O-, C _1-12 alkylene, C _2-12 alkenylene, C _2-12 alkynylene, C6-12 arylene, C _3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- membered heteroarylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy; 20 each R ¹¹⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹²⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and wherein the “*”and the wavy line represent a covalent bond. 25 In certain embodiments, each C _1-12 alkylene, C _2-12 alkenylene, C _2-12 alkynylene, C _6-12 arylene, C _3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- membered heteroarylene of Y ⁵⁰ and Y ⁶⁰ is independently optionally substituted with one to five substituents independently selected from halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy. In certain embodiments, the linking moiety is of the Formula: ; wherein ring C is a 3- to 12- membered cycloalkylene or 3- to 12- membered heterocyclylene, each independently optionally substituted with one or more substituents independently selected from oxo, halo, 5 C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each of Y ⁵⁰ and Y ⁶⁰ are independently a bond, -NR ¹¹⁰-, -O-, -S(O)0-2-, -NR ¹¹⁰C(O)-, -C(O)NR ¹¹⁰-, -NR ¹¹⁰C(O)NR ¹¹⁰-, -NR ¹¹⁰S(O)2-, -S(O)2NR ¹¹⁰-, -NR ¹¹⁰S(O)2NR ¹¹⁰-, -CR ¹²⁰=N-NR ¹¹⁰-, -NR ¹¹⁰-N=CR ¹²⁰-, -C(O)-, -OC(O)-, -OC(O)O-, -(CH ₂CH ₂O)1-5-, -C(O)O-, C _1-12 alkylene, C _2-12 alkenylene, C _2-12 alkynylene, C6-12 arylene, C _3-12 cycloalkylene, 5- to 12-membered heterocyclylene, or 5- to 12- membered heteroarylene, 10 each independently optionally substituted with one or more substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, or C1-4 haloalkoxy; each R ¹¹⁰ is independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; each R ¹²⁰ is independently hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, 15 C _6-12 aryl, 5- to 12-membered heteroaryl, C _3-12 cycloalkyl, or 5- to 12-membered heterocyclyl; and wherein the “*”and the wavy line represent a covalent bond. In certain embodiments, L comprises a non-biocleavable moiety. In certain embodiments, L comprises an optionally substituted alkylene having 4-7 chain atoms, optionally substituted 4-7-membered heterocyclylene, or optionally substituted heteroalkylene having 4-7 20 chain atoms. In certain embodiments, L comprises an optionally substituted heterocyclylene or optionally substituted heteroalkylene. In certain embodiments, L comprises an optionally substituted heterocyclylene and optionally substituted heteroalkylene. In certain embodiments, L is optionally substituted C4-10 atom heteroalkylene. 25 In certain embodiments, L is a 1-12 chain atom alkylene or 2-12 chain atom heteroalkylene linking moiety, containing 0-3 optionally substituted cycloalkylene, 0-3 optionally substituted heterocyclylene, 0-3 optionally substituted heteroarylene, 0-3 optionally substituted arylene, and 0-2 C=O. In certain embodiments, L is a 1-12 chain atom alkylene or 2-12 chain atom heteroalkylene linking moiety, containing 0-3 cycloalkylene, 0-3 heterocyclylene, 0-3 heteroarylene, 0-3 arylene, and 0-2 C=O. In certain 30 embodiments, L is a 1-12 chain atom alkylene or 2-12 chain atom heteroalkylene linking moiety, containing 1-3 cycloalkylene, heterocyclylene, heteroarylene, or arylene rings, and 0-2 C=O. In certain embodiments, L is a 4-12 chain atom alkylene or 4-12 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently selected from NH, O, or S, and optionally one C=O. In certain embodiments, L is a 4-11 chain atom alkylene or 4-11 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently selected from 5 NH, O or S, and optionally one C=O. In certain embodiments, L is a 4-10 chain atom alkylene or 4-10 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently selected from NH, O or S, and optionally one C=O. In certain embodiments, L is a 4-9 chain atom alkylene or 4-9 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently selected from NH, O or S, and optionally one C=O. In certain embodiments, L is a 4-8 chain atom alkylene 10 or 4-8 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently selected from NH, O or S, and optionally one C=O. In certain embodiments, L is a 4-7 chain atom alkylene or 4-7 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently selected from NH, O or S, and optionally one C=O. In certain embodiments, L is a 4-6 chain atom alkylene or 4-6 chain atom heteroalkylene linking moiety containing CH ₂ and up to 2 heteroatoms each independently 15 selected from NH, O or S, and optionally one C=O. As used herein, “chain atoms” include only those atoms making up the linking chain, and do not include hydrogen atoms or any substituent on an atom in the chain. By way of example, each of the following are linking moieties comprising 5 chain atoms: In certain embodiments, the linking moiety (L) is of the formula: 20 25 n _^y-2633819 5 10 n _^y-2633819 5 10 , n _^y-2633819 5 10 n _^y-2633819 5 n _^y-263 5 , , wherein the “*”and the wavy or dashed line represent a covalent bond. It is understood that either * or the wavy or dashed line can be connected to A ¹. In certain embodiments, the linking moiety (L) is of the formula: 10 n _^y-2633819 5 10 n _^y-2633819 5 n _^y-2633819 5 n _^y-2633819 ine represent a covalent bond to R ¹. It is understood that either * or the wavy or dashed line can be connected to A ¹. In certain embodiments, the linking moiety (L) is of the formula: 5 10 15 n _^y-2633819 5 “*”and the wavy line represent a covalent bond. It is understood that either * or the wavy or dashed line can be connected to R ¹. In certain embodiments, L is , , s is 1, 2, or 3; sƍ is 0 or 1; 10 G ¹, G ², G ³, and G ⁴ are each independently CH or N; and Lƍ and LƎ are each independently selected from a bond, CH ₂, CH ₂CH ₂, NHC(O), or C=O. In certain embodiments, , wherein Lƍ and L” are each independently selected from a bond, CH ₂, CH ₂CH ₂, NHC(O), or C=O; G ¹, G ², G ³, and G ⁴ are each independently CH or N; and s is 1, 2, or 3. In certain embodiments, s is 1 or 2. In certain 15 embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, , wherein Lƍ and L” are each independently selected from a bond, CH ₂, CH ₂CH ₂, NHC(O), or C=O; and s is 1, 2, or 3. In certain embodiments, s is 1 or 2. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. n _^y-2633819

5 , In certain embodiments, L is , wherein Lƍ and L” are each independently selected from a bond, CH ₂, CH ₂CH ₂, or C=O; s is 1, 2, or 3. In certain embodiments, s is 1 or 10 2. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, , wherein Lƍ and L” are each independently selected from a bond, CH ₂, CH ₂CH ₂, or C=O; and s’ is 0 or 1. In certain embodiments, s’ is 0. In certain embodiments, sƍ is 1. 5 , . , . ₁₀ , . In certain embodiments, Lƍ is a bond. In certain embodiments, Lƍ is CH ₂. In certain embodiments, Lƍ is CH ₂CH ₂. In certain embodiments, Lƍ is C=O. 5 , In certain embodiments, L” is a bond. In certain embodiments, L” is CH ₂. In certain embodiments, 10 L” is CH ₂CH ₂. In certain embodiments, L” is C=O.

. In certain embodiments, Lƍ is a bond. In certain embodiments, Lƍ is CH ₂. In certain embodiments, Lƍ is CH ₂CH ₂. In certain embodiments, Lƍ is C=O. ₅ . In certain embodiments, L” is a bond. In certain embodiments, L” is CH ₂. In certain embodiments, L” is CH ₂CH ₂. In certain embodiments, L” is C=O. In certain embodiments, the linking moiety L is of the formula:

5 10

5 o r ; where the “*”and the wavy line represent a covalent bond. It is understood that either * or the wavy or dashed line can be connected to R ¹. In certain embodiments, wherein the wavy 10 lines represent a covalent bond. It is understood that either end can be connected to R ¹. . Also provided is a compound as provided in Table 1, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. Table 1

In certain embodiments, the compound is not a compound selected from Table 1A, or a tautomer, stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog, or pharmaceutically acceptable salt thereof. Table 1A

Methods of Treatment Provided herein are compounds which can be used to treat, prevent, and/or delay the onset and/or development of cancer. Accordingly, in certain embodiments, provided is a method for the treatment of 5 cancer, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein. Certain embodiments provide a method of potentiation of cytotoxic cancer therapy in a subject in recognized need of such treatment comprising administering to the subject a therapeutically acceptable amount of a compound or composition described herein. It is contemplated that a patient having any cancer may benefit from being treated with the compounds and compositions described herein. Accordingly, in certain embodiments, the cancer is liver cancer, melanoma, Hodgkin’s disease, non-Hodgkin’s lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, 5 lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoides, head neck carcinoma, osteogenic sarcoma, 10 pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi’s sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, trophoblastic neoplasms, prostatic carcinoma, glioma, breast cancer, or prostate cancer. In certain embodiments, the cancer is bladder cancer, a blood 15 cancer, such as leukemia (e.g., chronic leukemia, chronic lymphocytic leukemia (CLL, etc.) or lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, low grade lymphoma, high grade lymphoma), lung cancer (e.g., small cell lung cancer), breast cancer, fallopian tube cancer, glioblastoma multiforme, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, testicular cancer, skin cancer (e.g., melanoma) or uterine cancer. In certain embodiments, the cancer is 20 bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer. In certain embodiments, the cancer is chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, non-Hodgkin lymphoma, Waldenström macroglobulinemia, polycythemia vera, trophoblastic neoplasms, and ovarian carcinoma. 25 In certain embodiments, the compounds and compositions as described herein are tailored to target cancers which overexpress a specific receptor, such as, but not limited to, androgen receptors, estrogen receptors, progesterone receptors, and/or glucocorticoid receptors by including an epitope which targets that specific nuclear receptor. The epitope can be derived from a steroid hormone or any non-steroidal drug which targets that particular receptor. 30 In certain embodiments, provided is a method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, prostate, breast, triple negative breast cancer, 35 bladder, or liver cancer. Also provided is a method of treating or preventing metastatic castration-resistant prostate cancer (mCRPC), comprising administering an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need thereof. In certain embodiments, provided is a method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically 5 acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof. In certain embodiments, the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer. In certain embodiments, the androgen receptor- targeting epitope comprises an androgen receptor agonist, a selective androgen-receptor modulator (SARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor 10 antagonist, a progestin, or an estrogen. In certain embodiments, the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, darolutamide, or an analog thereof. In certain embodiments, the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, 15 estramustine, ketoconazole, abiraterone, or an analog thereof. In certain embodiments, the nuclear payload comprises a PARP inhibitor. In certain embodiments, provided is a method of treating or preventing an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least 20 one estrogen and/or progesterone receptor-targeting epitope to an individual in need thereof. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, breast, uterine, or ovarian cancer. In certain embodiments, provided is a method of treating or preventing a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically 25 acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one glucocorticoid receptor-targeting epitope to an individual in need thereof. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, breast, uterine, or ovarian cancer. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, prostate, possibly breast, uterine, ovarian. 30 Compositions Compositions, including pharmaceutical compositions, of any of the compounds detailed herein are embraced by this disclosure. Thus, provided herein are pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions provided herein may take a form suitable 35 for oral, buccal, parenteral (e.g., intravenous, intramuscular, infusion or subcutaneous injection), nasal, topical or rectal administration, or a form suitable for administration by inhalation. Kits Kits for use to achieve anti-cancer effects comprising a compound or composition described herein are provided. In certain embodiments, the kit comprises a unit dose of a compound or composition described herein and instructions for administering the same. In certain aspects, the kit further comprises a 5 second drug suitable for anti-cancer therapy, or instructions for co-administering an additional anti-cancer therapy (such as radiation or gene therapy). In another aspect, kits for use to achieve anti-cancer effects comprise a low dose (e.g., less than about 500 mg/day, or less than about 400 mg/day, or less than about 300 mg/day, or less than about 200 mg/day) of a compound or composition described herein and a second drug suitable for anti-cancer therapy. In yet another variation, kits for use to achieve anti-cancer effects comprise 10 a high dose (e.g., greater than about 500 mg/day) of a compound or composition as described herein and a second drug suitable for anti-cancer therapy. Methods of Manufacturing a Medicament In a further aspect of the disclosure, use of the compounds and compositions described herein in the manufacture of a medicament is provided. In particular, the manufacture of a medicament for use in the 15 treatment of cancer, or diseases or conditions which can be mediated, at least in part, by blocking DNA repair and/or transcription activation, such as by inhibition of PARP, are provided. Further, pharmaceutical compositions of a compound described herein are also intended for use in the manufacture of a medicament for use in treatment of diseases or conditions which can be mediated, at least in part, by inhibition of PARP. EXAMPLES 20 The disclosure is further illustrated by the following examples. The examples below are non- limiting are merely representative of various aspects of the disclosure. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated. Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from 25 a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid 30 Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described. Exemplary protocols for specific compounds exemplified herein are shown in the following schemes. Scheme I illustrates a general methods which can be employed for the synthesis of compounds described herein, where each of A ¹, A ², A ³, A ⁴, R ², R ⁴, R ⁵, L, and R ¹ are each independently as defined herein, and LG is a leaving group (e.g., hydroxy, alkoxy, halo, etc.). Scheme I 5 In Scheme I, compounds of formula C-1 can be prepared from suitably substituted compound of formula A-1 by coupling with a suitable suitably substituted compound of formula B-1. Coupling of compound C-1 with an appropriately substituted compound of formula C provides compound D, which can then be taken on to provide a compound of formula I by coupling with a suitable L-R ¹ moiety, either 10 convergently or sequentially (i.e., either an L-R ¹ moiety or first a precursor for L followed by R ¹). Upon each reaction completion, each of the intermediate or final compounds can be recovered, and optionally purified, by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration and the like. Exemplary methods for the preparation of compounds of formula A-1 can be found in the literature (see, e.g., WO 2021/013735). 15 Additionally, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and 20 references cited therein. For example, protecting groups for alcohols, such as hydroxy, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF (tetra-n- butylammonium fluoride), HF-Py, or HF-NEt ₃. Other protecting groups for alcohols include acetyl, removed by acid or base, benzoyl, removed by acid or base, benzyl, removed by hydrogenation, 25 methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed by acid, methoxymethyl ether, removed by acid, tetrahydropyranyl or tetrahydrofuranyl, removed by acid, and trityl, removed by acid. Examples of protecting groups for amines include carbobenzyloxy, removed by hydrogenolysis p- methoxybenzyl carbonyl, removed by hydrogenolysis, tert-butyloxycarbonyl, removed by concentrated strong acid (such as HCl or CF ₃COOH), or by heating to greater than about 80 °C, 9- 30 fluorenylmethyloxycarbonyl, removed by base, such as piperidine, acetyl, removed by treatment with a base, benzoyl, removed by treatment with a base, benzyl, removed by hydrogenolysis, carbamate group, removed by acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis, 3,4-dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removed by ammonium cerium(IV) nitrate, tosyl, removed by concentrated acid (such as HBr or H ₂SO ₄) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide), troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid, 5 and sulfonamides (Nosyl & Nps), removed by samarium iodide or tributyltin hydride. Nomenclature was derived from ChemDraw Professional v18.2 and/or Chemdraw Professional v 21. If there are any structural ambiguities based on nomenclature, the corresponding structure shown in the scheme (and context of the synthetic scheme) should be referred to. SYNTHETIC EXAMPLES 10 Preparation of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cycl ohexyl)pyridazine-3- carboxamide (Int-A) Step-1: Preparation of tert-butyl ((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carb amate (Int-1) 15 To a stirred solution of (rel-trans)-4-aminocyclohexan-1-ol (SM-2, 10 g, 46.5 mmol, 1.0 eq.) in DMF (100 mL) under nitrogen atmosphere was added NaH (4.08 g, 102 mmol, 2.2 eq.) at 0 °C. The reaction mixture was warmed up to room temperature and stirred for 30 min. To this reaction mixture was added 2- chloro-4-fluoro-3-methylbenzonitrile (SM-1, 7.86 g, 46.51 mmol, 1.0 eq.) portion wise over a period of 10 min at room temperature and stirred for 3h. Progress of the reaction was monitored by TLC. After 20 completion of the reaction, ice cold water (100 mL) was added and the solid precipitate formed was filtered and dried to afford Int-1 (15 g, 88%). 1H NMR (400 MHz, DMSO-d6)δ7.73(d,J = 8.31 Hz, 1H), 7.22 (d, J = 8.80 Hz, 1H), 6.82 (s, 1H), 4.37 - 4.55 (m, 2H), 2.21 (s, 3H), 1.98 - 2.11 (m, 2H), 1.76 - 1.88 (m, 2H), 1.42 - 1.51 (m, 4H), 1.38 (s, 9H). LCMS: 309 [M-56+H] ⁺. Step-2: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chloro-3-methylbenzonit rile Hydrochloride (Int-2) To a flask charged with Int-1 (15 g), 4M HCl in 1,4-dioxane (75 mL) was added at 0 °C. The resulting mixture was allowed to warm up to RT and stir for 16h. After completion of the reaction, volatiles 5 were evaporated under reduced pressure and the resulting residue was triturated with diethyl ether (2 x 80 mL) and filtered to afford Int-2 (15 g, crude) which was used in the next step as is. 1H NMR (400 MHz, DMSO-d ₆) δ 8.30(brs s, 3H), 7.75 (d,J = 8.80 Hz, 1H), 7.28 (d, J = 8.80 Hz, 1H), 4.44 - 4.55 (m, 1H), 3.00 - 3.15 (m, 1H), 2.21 (s, 3H), 2.07 - 2.15 (m, 2H), 1.97 - 2.06 (m, 2H), 1.41 - 1.63 (m, 4H). LCMS: 264.75 [M+H] ⁺. 10 Step-3: Preparation of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cycl ohexyl)pyridazine- 3-carboxamide (Int-A) To A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chloro-3-methylbenzonit rile hydrochloride (Int-2, 15 g, 56.9 mmol, 1.0 eq.) and 6-chloropyridazine-3-carboxylic acid (SM-3, 9 g, 56.9 mmol, 1.0 eq.) in DMF (100 mL) were added HATU (32.4 g, 85.44 mmol, 1.5 eq.) and DIPEA (49 mL, 284 mmol, 5.0 eq.) 15 at 0 °C. Resulting reaction mixture was then allowed to stir at RT for 16h. Progress of the reaction was monitored by TLC. After reaction completion, volatiles were evaporated under reduced pressure and the residue was diluted with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extract was washed with water (400 mL) and brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product which was purified by column 20 chromatography eluting with 60-80% ethyl acetate in hexane to afford Int-A (6 g, 27%). 1H NMR (400 MHz, DMSO-d ₆) δ 9.12(d,J = 8.31 Hz, 1H), 8.22 (d, J = 8.80 Hz, 1H), 8.10 (d, J = 8.80 Hz, 1H), 7.77 (d, J = 8.80 Hz, 1H), 7.27 (d, J = 8.80 Hz, 1H), 4.43 - 4.57 (m, 1H), 3.85 - 4.01 (m, 1H), 2.23 (s, 3H), 2.08 - 2.17 (m, 2H), 1.86 - 1.96 (m, 2H), 1.64 - 1.77 (m, 2H), 1.49 - 1.62 (m, 2H). LCMS: 405.2 [M+H] ⁺.

Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B) Step-1: Preparation of ethyl 6-formyl-5-nitronicotinate (Int-1) A flask was charged with ethyl 6-methyl-5-nitronicotinate (SM-1, 50 g, 0.23 mol, 1.0 eq.), SeO ₂ 5 (39.6 g, 0.35 mol, 1.5 eq.) in 1,4-dioxane (250 mL, 5 vol) was allowed to stir under a nitrogen atmosphere at 110 °C until TLC indicated complete consumption of starting material. The reaction mixture was then cooled to ambient temperature, filtered through celite. The filtrate was concentrated under reduced pressure, purified by flash column over silica gel (60-120 mesh) eluting with 50-60 % ethyl acetate in hexane. The pure fractions combined and the solvent was evaporated under reduced pressure to obtain ethyl 6-formyl-5- 10 nitronicotinate (Int-1, 48 g, 90%). 1H NMR (400 MHz, DMSO-6d ₆) δ10.21 (s, 1H), 9.44 ( d, , 8.89 (d, J = 1.47 Hz, 1H), 4.42 (q, J = 7.01 Hz, 2H), 1.37 (t, J = 7.01 Hz, 3H). LCMS: 225.0 [M+H] ⁺. Step-2: Preparation of ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (Int-2) To a suspension of NaH (12.85 g, 0.32 mol, 2.0 eq., 60%) in dry THF (180 mL, 5 vol) was added a 15 solution of ethyl 2-(diethoxyphosphoryl)butanoate (SM-2, 60 g, 0.48 mol, 1.5 eq.) in dry THF (180 mL, 5 vol) dropwise at 0 °C under argon atmosphere, warmed up and stirred at 40 °C for 15 min. The reaction mixture was then cooled down to -78 °C and a solution of ethyl 6-formyl-5-nitronicotinate (Int-1, 36 g, 0.32 mol, 1.0 eq.) in dry THF (180 mL, 5 vol) was added dropwise at -78 °C under argon atmosphere and stirring was continued under argon atmosphere at same temperature until TLC indicated complete consumption of 20 starting material. After reaction completion, the mixture was quenched with saturated ammonium chloride solution (500 mL), extracted with ethyl acetate (2 x 500 mL), combined organic layer washed with brine solution (300 mL) and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure and the resulting crude product was purified by flash column (silica gel) eluting with 20-30 % ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure to obtain 5 ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (Int-2, 40 g, 77%) (E and Z isomers were observed). LCMS: 323.2 [M+H] ⁺. Step-3: Preparation of ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxy late (Int-3) A flask was charged with ethyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (Int-2, 40 10 g, 0.12 mmol, 1.0 eq.), 10% Pd/C (12 g, 30% w/w) and EtOAc (400 mL, 10 vol). The reaction mixture was then allowed to stir under hydrogen atmosphere (100 psi) at ambient temperature until TLC indicated complete consumption of starting material. The reaction mixture was then filtered through celite, the filtrate concentrated under reduced pressure and the residue was diluted with 4M HCl in 1,4-dioxane (200 mL, 5 vol) and allowed to stir for 2h at ambient temperature. After reaction completion, the reaction mixture was15 concentrated under reduced pressure, triturated with diethyl ether (100 mL), filtered and dried to get ethyl 7- ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxyla te (Int-3, 22 g, 73%). LCMS: 249.2 [M+H] ⁺. Step-4: Preparation of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (Int-4) A flask was charged with ethyl 7-ethyl-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxy late 20 (Int-3, 60 g, 0.24 mol, 1.0 eq.), SeO ₂ (39.9 g, 0.36 mol, 1.5 eq.) and AcOH (600 mL, 10 vol) and the reaction mixture was allowed to stir under a nitrogen atmosphere at 110 °C until TLC indicated complete consumption of starting material. The reaction mixture was then cooled to ambient temperature, quenched with saturated ammonium bicarbonate solution, and extracted with ethyl acetate (2 x 1L). The combined organic layer was washed with brine solution (500 mL) and dried over sodium sulfate, filtered, and 25 concentrated under reduced pressure to give ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3- carboxylate (Int-4, 25 g, 42%). 1H NMR (400 MHz, DMSO-d ₆) δ 12.04(brs,1H),8.86(s,1H),8.12(d,J = 3.91 Hz, 1H), 7.79 (s, 1H), 4.36 (q, J = 7.34 Hz, 2H), 2.55 (q, J = 7.17 Hz, 2H), 1.33 (t, J = 7.09 Hz, 2H), 1.15 (t, J = 7.09 Hz, 3H). LCMS: 247.2 [M+H] ⁺. Step-5: Preparation of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Int-5) To a solution of ethyl 7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (Int-4, 7 g, 28.45 mmol, 1.0 eq.) in dry THF (350 mL, 50 vol) was added a solution of 2M LiAlH ₄ in THF (28.4 mL, 56.8 mmol, 2.0 eq.) at 0 °C under nitrogen atmosphere. The resulting reaction mixture was allowed to stir under 5 nitrogen atmosphere at ambient temperature until TLC indicated complete consumption of starting material. The reaction mixture was then quenched with sodium sulfate solution, filtered and evaporated under reduced pressure to give 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Int-5, 4.1 g, 70%). LCMS: 205.1 [M+H] ⁺. Step-6: Preparation of 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B) 10 A flask was charged with 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Int-5, 4 g, 19.60 mmol, 1.0 eq.), SOCl2 (14 g, 117 mmol, 6.0 eq.), DMF (0.4 mL, 0.1 vol, catalytic amount) and DCM (120 mL, 30 vol) and the reaction mixture was allowed to stir under nitrogen atmosphere at ambient temperature until TLC indicated complete consumption of starting material. The reaction mixture was then diluted with water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layer was washed with 15 saturated bicarbonate solution (100 mL), brine solution (100 mL), dried over sodium sulfate and concentrated under reduced pressure to give 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 2 g, 46%). 1H NMR (400 MHz, DMSO-d6)δ12.23(br, s, 1H)8.556(s,1H),7.90(s,1H),7.82(s,1H),4.94(s, 2H), 2.55 (d, J = 7.34 Hz, 2H), 1.17 (t, J = 7.34 Hz, 3H). LCMS: 223.0 [M+H] ⁺. 20 Preparation of 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int-C) Step-1: Preparation of tert-butyl 4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)p iperazine- 1-carboxylate (Int-1) A flask was charged with 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 2.4 g, 9.30 mmol, 1.0 eq.), tert-butyl piperazine-1-carboxylate (SM-1, 1.7 g, 9.30 mmol, 1.0 eq.), DIPEA (8.5 mL, 46.5 5 mmol, 5.0 eq.), KI (166 mg, 1.8 mmol, 0.2 eq.) and acetonitrile (24 mL, 10 vol) and the reaction mixture was stirred under nitrogen atmosphere at 80 °C until TLC indicated complete consumption of starting material. The reaction mixture was then cooled to ambient temperature, concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with brine solution (100 mL), dried over sodium sulfate, filtered and concentrated under 10 reduced pressure. The crude obtained was purified by flash column over silica gel eluting with 0-3% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure to give tert-butyl 4- ((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pip erazine-1-carboxylate (Int-1, 1.7 g, 50%). 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 1.17 Hz, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 3.58 (s, 2H), 3.33 (s, 4H), 2.50 (d, J = 1.57 Hz, 2H), 2.34 (t, J = 4.30 Hz, 4H), 1.39 (s, 9H), 1.17 (t, J = 15 7.43 Hz, 3H). LCMS: 373.3 [M+H] ⁺. Step-2: Preparation of 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int- C) A flask was charged with tert-butyl 4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) piperazine-1-carboxylate (Int-1, 1.7 g, 4.56 mmol, 1.0 eq.), HCl (17 mL, 10 vol, 4 M in 1,4-dioxane) and 20 DCM (17 mL, 10 vol) and the reaction mixture was stirred under nitrogen atmosphere at ambient temperature until TLC indicated complete consumption of starting material. The reaction mixture was then concentrated under reduced pressure, triturated with diethyl ether (50 mL), filtered and dried to give 3-ethyl- 7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int-C, 1.37 g, 97%). 1H NMR (400 MHz, DMSO-d ₆^^į^^^^^^^^EU^V^^^+^^^^^^^^^EU^V^^^+^^^^^^^^^V^^^+^^^ ^^^^^^V^^^+^^^^^^^^ 25 (s, 1H), 4.56 (br s, 2H), 3.43 - 3.54 (m, 8H), 2.57 (q, J = 7.17 Hz, 2H), 1.18 (t, J = 7.34 Hz, 3H). LCMS: 273.2 [M+H] ⁺. Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1- yl)-2-fluorobenzoic acid (Int-D) Step-1: Preparation of 4-((2-carboxypropan-2-yl)amino)-2-fluorobenzoic acid (Int-1) 5 To a stirred solution of 4-bromo-2-fluorobenzoic acid (SM-1, 10.0 g, 45.66 mmol, 1.0 eq.) in DMF (100 mL, 10 vol) and water (10 mL, 1 vol), 2-amino-2-methylpropanoic acid (SM-2, 14.1 g, 136.98 mmol, 3.0 eq.), N,N-dimethylglycine (2.35 g, 22.83 mmol, 0.5 eq.), K ₂CO ₃ (31.5 g, 228.3 mmol, 5.0 eq.), Cu powder (575 mg, 9.13 mmol, 0.2 eq.) and copper iodide (1.73 g, 9.13 mmol, 0.2 eq.) were added at room temperature. The reaction mixture stirred at 110 °C until TLC indicated complete consumption of SM-1. The 10 reaction mixture was then diluted with ice cold water (500 mL) and acidified with 6 N HCl (pH ~4) and extracted with ethyl acetate (2 x 1L). The combined organic layer was washed with brine solution (300 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure, recrystallized with DCM, filtered and dried to obtain 4-((2-carboxypropan-2-yl)amino)-2-fluorobenzoic acid (Int-1, 6.2 g, 56%). 1H NMR (400 MHz, DMSO-d ₆^^į^^^^^^^^EU^V^^^+^^^^^^^^^W^^J = 8.79 Hz, 1H), 6.96 (s, 1H), 6.33 (dd,15 J = 8.79, 1.85 Hz, 1H), 6.15 (dd, J = 14.57, 1.62 Hz, 1H), 1.44 (s, 6H). LCMS: 242.15 [M+H] ⁺. Step-2: Preparation of methyl 2-fluoro-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)benzo ate (Int-2) To a stirred solution of 4-((2-carboxypropan-2-yl)amino)-2-fluorobenzoic acid (Int-1, 6.2 g, 25.72 mmol, 1.0 eq.) in DMF (70 mL, 10 vol), MeI (3.1 mL, 51.45 mmol, 2.0 eq.), K2CO3 (53.1 g, 385.5 mmol, 15.0 eq.) were added at room temperature. The reaction mixture was allowed to stir at ambient temperature 20 until TLC indicated complete consumption of starting material. The reaction mixture was then diluted with ice cold water (500 mL) and the resulting precipitate was filtered and dried to obtain methyl 2-fluoro-4-((1- methoxy-2-methyl-1-oxopropan-2-yl)amino)benzoate (Int-2, 4.82 g, 69%). 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^W^^J = 8.80 Hz, 1H), 7.11 (s, 1H), 6.29 (dd, J = 8.80, 2.45 Hz, 1H), 6.14 (dd, J = 14.67, 1.96 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H), 1.48 (s, 6H). LCMS: 270.10 [M+H] ⁺. Step-3: Preparation of methyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoate (Int-3) To a stirred solution of methyl 2-fluoro-4-((1-methoxy-2-methyl-1-oxopropan-2-yl)amino)benzo ate (Int-2, 4.8 g, 17.84 mmol, 1.0 eq.) in DMSO (7.2 mL, 1.5 vol), 4-isothiocyanato-2- 5 (trifluoromethyl)benzonitrile (SM-3, 8.5 g, 37.59 mmol, 2.1 eq.) was added at room temperature. The reaction mixture stirred at 90 °C until TLC indicated complete consumption of starting material. The reaction mixture was then diluted with ice cold water (500 mL) and extracted with ethyl acetate (2 x 1 L). The combined organic layer was washed with brine solution (300 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The crude obtained was purified by column (silica gel, 100-200 10 mesh), eluting with 20-30% ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure to obtain methyl 4-(3-(4-cyano-3-(trifluoromethyl)-phenyl)-5,5-dimethyl-4-oxo -2- thioxoimidazolidin-1-yl)-2-fluorobenzoate (Int-3, 5 g, 60%). 1H NMR (400 MHz, DMSO-d ₆) δ 8.41 (d, J = 8.31 Hz, 1H), 8.29 (d, J = 1.47 Hz, 1H), 8.06 - 8.11 (m, 2H), 7.51 (dd, J = 11.25, 1.96 Hz, 1H), 7.41 (dd, J = 8.31, 1.96 Hz, 1H), 3.90 (s, 3H), 1.55 (s, 6H). 15 LCMS: 466.50 [M+H] ⁺. Step-4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Int-D) A flask was charged with methyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoate (Int-3, 3 g, 6.45 mmol, 1.0 eq.), MeOH:THF:H2O (1:1:1, 30 mL, 20 10 vol) and LiOH (810 mg, 19.35 mmol, 3.0 eq.) at ambient temperature under argon atmosphere. The reaction mixture was stirred at ambient temperature until TLC indicated complete consumption of starting material. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), acidified with citric acid (pH ~3) and filtered the resulting precipitate and dried to obtain 4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazol idin-1-yl)-2-fluorobenzoic acid (Int-D, 2.6 g, 25 89%). 1H NMR (400 MHz, DMSO-d ₆) δ 8.40 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.94 (t, J = 8.07 Hz, 1H), 7.36 (d, J = 10.76 Hz, 1H), 7.29 (d, J = 8.31 Hz, 1H), 1.54 (s, 6H). LCMS: 452.20 [M+H] ⁺. Preparation of 6-(methylamino)hexan-1-ol trifluoroacetate (Int-E) 30 Step-1: Preparation of tert-butyl (6-((tert-butyldimethylsilyl)oxy)hexyl)carbamate (Int-1) A stirred solution of tert-butyl (6-hydroxyhexyl)carbamate (SM-1 (1.0 g, 4.60 mmol, 1 eq.) in dichloromethane (10 mL) was cooled to 0 °C followed by addition of triethylamine (0.83 mL, 5.98 mmol, 1.3 eq.) and tert-butyldimethylsilyl chloride (TBDMS, 765 mg, 5.06 mmol, 1.1 eq.). The reaction mixture 5 was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After complete consumption of SM-1, the reaction mixture was diluted with ice cold water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Int-1 (1.65 g, crude). 1H NMR (400 MHz, CDCl ₃) δ 4.50 (br s, 1H), (t, J = (t, 6.60 Hz, 2H), 3.11 (d, J = 6.36 Hz, 2H), 10 1.40 - 1.57 (m, 15H), 1.30 - 1.39 (m, 2H), 0.87 - 0.95 (m, 9H), 0.03 - 0.13 (m, 6H). LCMS: 332.38 [M+H] ⁺. Step-2: Preparation of tert-butyl (6-((tert-butyldimethylsilyl)oxy)hexyl)(methyl)carbamate (Int-2) A stirred solution of tert-butyl (6-((tert-butyldimethylsilyl)oxy)hexyl)carbamate (Int-1, 1.5 g, 4.53 mmol, 1 eq.) in DMF (10 mL) was added sodium hydride (283 mg, 6.79 mmol, 1.5 eq.) at 0 °C followed by addition of iodomethane (0.56 mL, 9.06 mmol, 2 eq.). The reaction mixture was allowed to warm up to room 15 temperature and stir for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Int-2 (1.38 g, crude). 1H NMR (400 MHz, CDCl3)= δ 3.61 (t, J 6.60 Hz, 2H), 3.18 - 3.10 (m, J = 5.38 Hz, 2H), 2.83 (s, 20 3H), 1.40 - 1.56 (m, 17H), 1.20 - 1.40 (m, 6H), 0.82 - 0.94 (m, 9H). Step-3: Preparation of 6-(methylamino)hexan-1-ol trifluoroacetate (Int-E) A stirred solution of tert-butyl (6-((tert-butyldimethylsilyl)oxy)hexyl)(methyl)carbamate (Int-2, 1.1 g, 3.18 mmol, 1 eq.) in dichloromethane (15 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (5 mL). The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of 25 the reaction was monitored by TLC. After complete consumption of Int-2, volatiles were evaporated and the crude obtained was filtered and washed with diethyl ether (2 x 50 mL) to afford Int-E (1.21 g, crude). 1H NMR (400 MHz, CDCl ₃) δ 8.26- 8.46 (m, 2H), 4.34 (t, J = 6.50 Hz, 2H), 2.95 - 3.10 (m, 3H), 2.75 (t, J = 5.00 Hz, 2H), 1.66 - 1.80 (m, 4H), 1.43 (d, J = 2.88 Hz, 4H). Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-hydroxyhexyl)(methy l)amino)phenyl)-13- methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-c yclopenta[a]phenanthren-17-yl acetate (Int-F) 5 Step-1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate (Int-1) To a stirred solution of SM-1 (10 g, 21 mmol, 1.0 eq.) in methanol (150 mL) and THF (150 mL) were added KOAc (20.6 g, 210 mmol, 10 eq.) and iodine (13.1 g, 105 mmol, 5 eq.) at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 3h. Progress of the reaction was monitored 10 by TLC. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate (Na ₂S ₂O ₃) solution (50 g in 30 mL water) and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford Int-1 (8.0 g, 82%). 1H NMR (400 MHz, DMSO-d ₆) δ11.91(brs,1H),6.91(d,J = 8.31 Hz, 2H), 6.44 (d, J = 8.31 Hz, 15 2H), 5.67 (s, 1H), 4.37 (m, 1H), 2.75 (s, 2H), 2.61 (d, J = 4.40 Hz, 3H), 2.30 - 2.40 (m, 1H), 2.07 - 2.16 (s, 5H), 1.99 (s, 6H), 1.63 - 1.77 (m, 2H), 1.21 - 1.45 (m, 5H), 0.86 (t, J = 6.60 Hz, 1H), 0.16 - 0.28 (m, 3H). LCMS: 462.28 [M+H] ⁺. Step-2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-hydroxyhexyl)(methy l)amino)phenyl)- 13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1 H-cyclopenta[a]phenanthren-17-yl acetate20 (Int-F) To a solution of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate (Int-9, 4 g, 8.67 mmol, 1.0 eq.) and 6-bromohexan-1-ol (SM-2, 7.81 g, 43.38 mmol, 5 eq.) in ethanol (40 mL) and water (40 mL) was added NaHCO3 (7.37 g, 86.76 mmol, 10 eq.) at room temperature. The reaction mixture was heated 25 to 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of celite bed and washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure, diluted with water (120 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 70% ethyl acetate in heptane to afford Int-F (2.6 g, 53%). 1H NMR (400 MHz, DMSO-d ₆) δ6.98(d,J = 7.89 Hz, 2H), 6.58 (d, J = 7.89 Hz, 2H), 5.67 (br s, 1H), 4.24 - 4.51 (m, 2H), 3.36 (d, J = 5.70 Hz, 2H), 3.23 (d, J = 6.58 Hz, 2H), 2.69 - 2.86 (m, 4H), 2.55 (s, 5 3H), 2.29 - 2.44 (m, 1H), 2.05 - 2.26 (m, 5H), 1.87 - 2.04 (m, 6H), 1.63 - 1.77 (m, 2H), 1.34 - 1.49 (m, 6H), 1.27 (br s, 6H), 0.23 (br s, 3H). LCMS: 562.40 [M+H] ⁺. Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (Int-G) Step-1: Preparation of tert-butyl 4-((1-((Benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine- 1-10 carboxylate (Int-1) To a stirred solution of benzyl 4-formylpiperidine-1-carboxylate (SM-1, 2.00 g, 8.08 mmol, 1.0 eq.) and tert-butyl piperazine-1-carboxylate (SM-1, 1.50 g, 8.08 mmol, 1.0 eq.) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (1.71 g, 8.08 mmol, 1.0 eq.) at 0 °C. The reaction mixture was warmed up to room temperature and stirred for 16h. Progress of the reaction was monitored by TLC. After 15 completion of the reaction, the reaction mixture was diluted with saturated aq. NaHCO3 (40 mL) and extracted with DCM (2 x 40 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 60% ethyl acetate in heptane to afford Int-1 (2 g, 59%). 1H NMR (400 MHz, DMSO-d6) δ 7.35(s,5H),5.05(s,2H),3.81- 4.06 (m, 2H), 3.24 - 3.29 (m, 20 4H), 2.68 - 3.06 (m, 2H), 2.26 (br s, 3H), 2.11 (d, J = 6.36 Hz, 2H), 1.60 - 1.88 (m, 4H), 1.38 (s, 9H), 0.96 (d, J = 11.25 Hz, 2H). LCMS: 418.53 [M+H] ⁺. Step-2: Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (Int-G) A solution of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine- 1-carboxylate (Int-1, 3.6 g, 8.6 mmol, 1.0 eq.) and 10% Pd/C (300 mg, 30% w/w) in ethanol (40 mL) was allowed to stir 25 under H2 atmosphere at 200 psi and room temperature for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of celite bed, washed with ethanol (100 mL) and the filtrate was concentrated under reduced pressure to afford Int-G (2.00 g, 83%). ¹H NMR (400 MHz, DMSO-d6)δ3.28(s,4H),3.14(d,J = 12.23 Hz, 2H), 2.71 (t, J = 11.98 Hz, 2H), 2.26 (d, J = 4.40 Hz, 4H), 2.11 (d, J = 6.36 Hz, 2H), 1.76 (d, J = 12.72 Hz, 2H), 1.39 (s, 9H), 1.10 - 1.25 (m, 4H). LCMS: 284.32 [M+H] ⁺. Preparation of 4-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-2-chlorobenzoni trile trifluoroacetate 5 (Int-A1) Step-1: Preparation of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)amino)cyclohexyl)carbama te (Int- 1) To a stirred solution of 2-chloro-4-fluorobenzonitrile (SM-1, 4 g, 25 mmol, 1.0 eq.) in DMSO (40 10 mL), tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (SM-1, 5.5 g, 25 mmol, 1.0 eq.) and K2CO3 (7.1 g, 51 mmol, 2 eq.) were added at room temperature. The reaction mixture was allowed to stir at 90 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL) and extracted with ethyl acetate (2 x 400 mL). The combined organic extract was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and 15 concentrated under vacuum. The crude obtained was purified by combi flash column eluting with 64% ethyl acetate in heptane to afford tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)amino)cyclohexyl)carbama te (Int-1, 7.1 g, 78%). 1H NMR (400 MHz, DMSO-d ₆) δ 7.48 (d,J = 8.80 Hz, 1H), 6.86 (d, J = 6.85 Hz, 1H), 6.80 (d, J = 6.85 Hz, 1H), 6.75 (s, 1H), 6.59 (d, J = 8.80 Hz, 1H), 3.20-3.23 (m, 2H), 1.91 (d, J = 11.25 Hz, 2H), 1.79 (d, 20 J = 10.76 Hz, 2H), 1.38 (s, 9H), 1.13 - 1.33 (m, 4H). Step-2: Preparation of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl ) carbamate (Int-2) To a stirred solution of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)amino)cyclohexyl)carbama te (Int-1, 5.5 g, 15 mmol, 1.0 eq.) in DMF (25 mL) under nitrogen atmosphere, NaH (63%, 500 mg, 21 mmol, 25 1.3 eq.) was added portion wise at 0 °C. The reaction mixture was allowed warm up to room temperature and stir for 30 min, cooled down to 0 °C and added methyl iodide (1.1 mL, 21 mmol, 1.3 eq.) dropwise at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 3h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer was concentrated under reduced 30 pressure and the crude obtained was purified by combi flash column eluting with 15% ethyl acetate in heptane to afford tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl )carbamate (Int- 2, 3.2 g, 55%). LCMS: 364.2 [M+H] ⁺. Step-3: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-2-chlorobenzoni trile 5 trifluoroacetate (Int-A1) To a stirred solution of tert-butyl ((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohexyl )- carbamate (Int-2, 1.1 g, 3 mmol, 1.0 eq.) in DCM (10 mL) under nitrogen atmosphere was added TFA (10 mL, 10 vol) at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were 10 evaporated under reduced pressure and the residue was triturated with diethyl ether (20 mL), filtered and dried under vacuum to afford 4-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-2-chlorobenzoni trile trifluoroacetate (Int-A1, 852 mg, 74%). LCMS: 264.1 [M+H] ⁺. Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chloro-3-methylbenzonit rile hydrochloride (Int-15 A2) Step-1: Preparation of tert-butyl ((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carb amate (Int-1) To a stirred solution of 2-chloro-4-fluoro-3-methylbenzonitrile (SM-1, 20 g, 93 mmol, 1.0 eq.) in20 DMF (200 mL), NaH (60%, 8.1 g, 204.6 mmol, 2.2 eq.) was added at room temperature followed by tert- butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (SM-2, 15.7 g, 93 mmol, 1.0 eq.). The reaction mixture was allowed to stir at ambient temperature for 3h. Progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was diluted with ice cold water (500 mL) and the precipitate was filtered, washed with water (500 mL), diethyl ether (500 mL) and dried to afford tert-butyl25 ((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)carb amate (Int-1, 32 g, 94%). 1H NMR (400 MHz, DMSO-d6 δ 7.74 (d, J = 8.80 Hz, 1H), 7.22 (d, J = 8.80 Hz, 1H), 6.84 (d, J = 7.34 Hz, 1H), 4.39 - 4.52 (m, 1H), 3.32 (s, 1H), 2.21 (s, 3H), 2.03 (d, J = 9.78 Hz, 2H), 1.81 (d, J = 10.27 Hz, 2H), 1.28 - 1.52 (m, 13H). LCMS: 309.16 [M+H-56] ⁺. Step-2: Preparation of 4-(((1r,4r)-4-aminocyclohexyl)oxy)-2-chloro-3-methylbenzonit rile hydrochloride (Int-A2) To a stirred solution of tert-butyl ((1r,4r)-4-(3-chloro-4-cyano-2- methylphenoxy)cyclohexyl)carbamate (Int-1, 5 g, 13.73 mmol, 1.0 eq.) in 1,4-dioxane (50 mL) under 5 nitrogen atmosphere was added HCl (4M in 1,4-dioxane, 25 mL) at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 2h. Progress of the reaction was monitored by TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure and the residue was triturated with diethyl ether (50 mL), filtered and dried under vacuum to afford 4-(((1r,4r)-4- aminocyclohexyl)oxy)-2-chloro-3-methylbenzonitrile hydrochloride (Int-A2, 3.7 g, 89%). 10 Preparation of 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one (Int-A3) Step-1: Preparation of 1-bromo-2,4-difluoro-3-nitrobenzene (Int-1) To a solution of H ₂SO ₄ (10 mL), TFA (50 mL) was added dropwise at 0 °C under argon atmosphere followed by portion wise addition of 1,3-difluoro-2-nitrobenzene (SM-1, 5.0 g, 31.46 mmol, 1.0 eq.) and 15 then NBS (6.15 g, 34.58 mmol, 1.1 eq.) while maintaining the temperature at 0 °C. The reaction mixture was allowed to warm up to ambient temperature and stir for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layer was washed with saturated bicarbonate solution (150 mL), brine solution (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under 20 reduced pressure. The crude obtained was purified by flash column and the pure fractions were combined and concentrated under reduced pressure to afford 1-bromo-2,4-difluoro-3-nitrobenzene (Int-1, 3.3 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 9.29 Hz, 1H), 7.54 (d, J = 9.54 Hz, 1H). Step-2: Preparation of methyl (4-bromo-3-fluoro-2-nitrophenyl)alaninate (Int-2) To a solution of 1-bromo-2,4-difluoro-3-nitrobenzene (Int-1, 4.6 g, 19.32 mmol, 1.0 eq.) in DMF (46 mL), methyl alaninate hydrochloride (SM-2, 3.2 g, 23.19 mmol, 1.2 eq.), DIPEA (8.4 mL, 48.31 mmol, 2.5 eq.) were added under argon atmosphere at ambient temperature. The resulting reaction mixture was allowed to stir at ambient temperature for 5h. Progress of the reaction was monitored by TLC. After 5 completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic layer was washed with water (150 mL), brine solution (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude obtained was purified by flash column and the pure fractions were combined and concentrated under reduced pressure to afford methyl (4-bromo-3-fluoro-2-nitrophenyl)alaninate (Int-2, 6.0 g, 96%). 10 LCMS: 321.11 [M+H] ⁺. Step-3: Preparation of methyl (2-Amino-4-bromo-3-fluorophenyl)alaninate (Int-3) To a solution of methyl (4-bromo-3-fluoro-2-nitrophenyl)alaninate (Int-2, 6.0 g, 18.75 mmol, 1.0 eq.) in MeOH:H2O (96 mL, 15:1), Zn powder (9.75 g, 150 mmol, 8.0 eq.), NH4Cl (8 g, 150 mmol, 8.0 eq.) were added at 0 °C and the resulting reaction mixture was allowed to warm up to ambient temperature and 15 stir for 6h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite pad, washed with MeOH (100 mL) and concentrated under reduced pressure. The obtained residue was diluted with water (200 mL), extracted with ethyl acetate (2 x 250 mL) and the combined organic layer was washed with water (150 mL), brine solution (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl (2-amino-4- 20 bromo-3-fluorophenyl)alaninate (Int-3, 6.0 g, crude). Step-4: Preparation of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-4) To a solution of methyl (2-amino-4-bromo-3-fluorophenyl)alaninate (Int-3, 6.0 g, 20.61 mmol, 1.0 eq.) in 1,4-dioxane (60 mL), HCl (4M in 1,4-dioxane, 60 mL) was added at 0 °C. The resulting reaction mixture was allowed to warm up to ambient temperature and stir for 2 h. Progress of the reaction was 25 monitored by TLC. After consumption of starting material, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether (40 mL), filtered and dried to afford 7- bromo-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-4, 5.0 g, crude). 1H NMR (400 MHz, DMSO-d ₆)δ10.42(s,1H),7.40(s,1H),7.28(s,1H),7.15(s,1H), 3.73-3.85 (m, 1H), 1.13 - 1.28 (m, 3H). LCMS: 259.1 [M+H] ⁺. 30 Step-5: Preparation of 7-bromo-8-fluoro-3-methylquinoxalin-2(1H)-one (Int-5) To a solution of 7-bromo-8-fluoro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-4, 1.0 g, 3.86 mmol, 1.0 eq.) in DCM (10 mL), DDQ (1.0 g, 4.63 mmol, 1.2 eq.) was added at 0 °C and the resulting reaction mixture was allowed to warm up to ambient temperature and stir for 2h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (100 mL), washed with saturated bicarbonate solution (50 mL), water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7-bromo-8-fluoro-3- 5 methylquinoxalin-2(1H)-one (Int-5, 800 mg, crude). LCMS: 257.14 [M+H] ⁺. Step-6: Preparation of methyl 5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Int-6) To a solution of 7-bromo-8-fluoro-3-methylquinoxalin-2(1H)-one (Int-5, 1.0 g, 3.8 mmol, 1.0 eq.) in MeOH (10 mL), Pd(dppf)Cl ₂.DCM (158 mg, 0.19 mmol, 0.05 eq.) and TEA (1 mL, 7.7 mmol, 2.0 eq.) 10 were added at RT in an autoclave and the resulting reaction mixture was allowed to stir at 80 °C under CO atmosphere for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite pad, washed with MeOH (50 mL) and concentrated under reduced pressure. The crude obtained was purified by flash column and the pure fractions were combined and concentrated under reduced pressure to afford methyl 5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline- 15 6-carboxylate (Int-6, 800 mg, 87%). 1H NMR (400 MHz, DMSO-d6)δ12.64(s,1H),7.54- 7.70 (m, 2H), 3.89 (s, 3H), 2.45 (s, 3H). LCMS: 237.3 [M+H] ⁺. Step-7: Preparation of 8-fluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (Int-7) To a solution of methyl 5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Int-6, 5.0 20 g, 21.18 mmol, 1.0 eq.) in THF (50 mL), LAH (21.1 mL, 42.2 mmol, 2.0 eq, 2M) solution was added at 0 °C under argon atmosphere and the resulting reaction mixture was allowed to warm up to ambient temperature and stir for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0 °C, quenched with saturated NH ₄Cl solution, filtered through celite pad and washed with MeOH (100 mL). The combined filtrate was concentrated under reduced pressure to afford 8- 25 fluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (Int-7, 4 g, 91%). LCMS: 209.35 [M+H] ⁺. Step-8: Preparation of 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one (Int-A3) A flask was charged with 8-fluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (Int-7, 1.0 g, 4.8 mmol, 1.0 eq.) and a cold solution of 47% HBr (50 mL) under argon atmosphere. The resulting reaction 30 mixture was allowed to warm up to room temperature and stir at 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, cooled to 0 °C, quenched with saturated NaHCO3 solution (pH ~7) and extracted with DCM (2 x 200 mL). The combined organic layer was washed with water (150 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 7-(bromomethyl)-8- fluoro-3-methylquinoxalin-2(1H)-one (Int-A3, 200 mg, 15%). 5 ¹H NMR (400 MHz, DMSO-d ₆)δ12.38- 12.68 (m, 1H), 7.50 (d, J = 8.31 Hz, 1H), 7.34 (t, J = 7.58 Hz, 1H), 4.78 (s, 2H), 2.40 (s, 3H). LCMS: 270.80 [M+H] ⁺. Preparation of 3-ethyl-7-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)-1 ,5-naphthyridin-2(1H)-one trifluoroacetate (Int-C1) 10 Step-1: Preparation of tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Int-1) To a solution of 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int-C, 2 g, 7.35 mmol, 1 eq.) in MeOH (20 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (SM-1, 1.56 g, 7.35 mmol, 1 eq.) and glacial acetic acid (0.2 mL) at room temperature, stirred for 1h and then 15 NaCNBH ₃ (2.37 g, 36.7 mmol, 5 eq.) was added at 0 °C. Progress of the reaction was monitored by TLC. The reaction mixture was allowed to warm up to room temperature and stir for 16h, quenched with water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layer was washed with water (100 mL), brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel flash column. The pure fractions were combined and20 evaporated under reduced pressure to afford tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Int-1, 2 g, 82%). 1H NMR (400 MHz, CDCl ₃)δ11.28- 11.56 (m, 1H), 8.49 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 4.03 – 4.13 (br s, 2H), 3.73 (s, 2H), 3.50 (s, 1H), 3.17 (q, J = 7.34 Hz, 2H), 2.70 – 2.74 (m, 8H), 1.75 – 1.79 (m, 3H), 1.45 (s, 9H), 1.34 (m, 6H), 1.09 - 1.23 (m, 2H). LCMS: 470.58 [M+H] ⁺. 25 Step-2: Preparation of 3-ethyl-7-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)-1 ,5-naphthyridin-2(1H)- one trifluoroacetate (Int-C1) To a solution of tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Int-1, 1.2 g, 2.55 mmol, 1 eq.) in DCM (12 mL), TFA (6 mL, 5 vol) was added at room temperature and the solution was allowed to stir for 2h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting solid was filtered, washed with diethyl ether (20 mL) and dried to afford 3-ethyl-7-((4-(piperidin-4-ylmethyl)piperazin-1-yl)methyl)-1 ,5-naphthyridin-2(1H)-one trifluoroacetate (Int-C1, 1.5 g, 82%). 5 ¹H NMR (400 MHz, DMSO-d ₆)δ12.01(s,1H),8.45(s,1H),8.31(br, s, 1H,7.77(s,1H,7.62 (s, 1H), 3.85 - 4.08 (m, 2H), 3.28 (d, J = 12.23 Hz, 2H), 3.05 - 3.18 (m, 4H), 2.77 - 2.92 (m, 4H), 2.54 - 2.60 (m, 2H), 1.98 (s, 2H), 1.83 (d, J = 13.69 Hz, 2H), 1.23 - 1.37 (m, 2H), 1.18 (m, 6H). Preparation of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (Int-E1) 10 Step-1: Preparation of tert-butyl 4-(6-(Methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (Int-1) To a Stirred solution of methyl 5-bromopyridine-2-carboxylate (SM-1, 200 mg, 0.92 mmol, 1.0 eq.) and tert-butyl piperazine-1-carboxylate (SM-2, 258 mg, 1.31 mmol, 1.5 eq.) in toluene (10 mL) was added cesium carbonate (60 mg, 1.8 mmol, 2 eq.) followed by BINAP (5.70 mg, 0.09 mmol, 0.1 eq.) and Pd ₂dba ₃ (8.40 mg, 0.092 mmol, 0.1 eq.) under N ₂ atmosphere at room temperature. Progress of the reaction was 15 monitored by TLC. The reaction mixture was stirred at 100 °C for 10h, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 50% EtOAc in heptane to afford Int-1 (130 mg). 20 LCMS: 322.2 [M+H] ⁺. Step-2: Preparation of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (Int-E1) A flask was charged with tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (Int-1, 250 mg, 0.78 mmol, 1 eq.), MeOH:THF:H2O (1:1:1, 15 mL) and LiOH (93 mg, 3.87 mmol, 5 eq.) at ambient temperature under argon atmosphere. The reaction mixture was stirred at ambient temperature until 25 TLC indicated complete consumption of starting material. The reaction mixture was concentrated under reduced pressure, diluted with water (10 mL), acidified with citric acid (pH ~3), filtered the resulting solid and dried to obtain 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (Int-E1, 90 mg, 39%). 1H NMR (400 MHz, DMSO-d ₆) δ 11.74 - 12.86 (br s, 1H), 8.34 (s, 1H), 7.86 (d, J = 8.80 Hz, 1H), 7.34 (d, J = 8.31 Hz, 1H), 3.45 (s, 4H), 3.35 (s, 4H), 1.41 (s, 9H). LCMS: 308.32 [M+H] ⁺. Example S1. Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-(4-((7- ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperaz ine-1-carbonyl)piperidin-1- yl)pyridazine-3-carboxamide (Compound No.1) 5 Step-1: Preparation of ethyl 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexy l)carbamoyl)- pyridazin-3-yl)piperidine-4-carboxylate (Int-1) To a stirred solution of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cycl ohexyl)- pyridazine-3-carboxamide (Int-A, 7 g, 17 mmol, 1.0 eq.) and ethyl piperidine-4-carboxylate (SM-1, 4 g, 25 mmol, 1.5 eq.) in DMF (70 mL) was added potassium carbonate (5.86 g, 42 mmol, 2.5 eq.) at room 10 temperature. The reaction mixture was allowed to stir at 80 °C for 12h. Progress of the reaction was monitored by TLC. After reaction completion, the reaction mixture was diluted with ice cold water (300 mL), stirred for 10 min and the precipitated solid was filtered and dried to afford Int-1 (6.0 g, 66%). 1H NMR (400 MHz, DMSO-d6)δ8.57(d, J = 7.82 Hz, 1H), 7.80 (d, J = 9.29 Hz, 1H), 7.75 (d, J = 8.80 Hz, 1H), 7.35 (d, J = 9.78 Hz, 1H), 7.24 (d, J = 8.80 Hz, 1H), 4.44 - 4.55 (m, 1H), 4.30 - 4.41 (m, 2H), 15 4.00 - 4.11 (m, 2H), 3.80 - 3.92 (m, 1H), 3.08 - 3.23 (m, 2H), 2.64 - 2.76 (m, 1H) 2.22 (s, 3H), 2.05 - 2.15 (m, 2H), 1.85 - 1.97 (m, 4H), 1.44 - 1.71 (m, 6H), 1.17 (t, J = 7.34 Hz, 3H). LCMS: 526.2 [M+H] ⁺. Step-2: Preparation of 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2- methylphenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidine -4-carboxylic acid (Int-2) To a solution of ethyl 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexy l)carbamoyl)- 20 pyridazin-3-yl)piperidine-4-carboxylate (Int-1, 6.0 g, 11.5 mmol, 1.0 eq.) in THF (20 mL) and water (5 mL) was added LiOH.H ₂O (2.49 g, 57.9 mmol, 5.0 eq.) at 0 °C and the resulting mixture was allowed to stir for 5 h. Progress of the reaction was monitored by TLC. Volatiles were then removed under reduced pressure, diluted with water (80 mL) and acidified with 1 N aq. HCl until pH 3 and extracted with ethyl acetate (3 x 80 mL). The combined organic extract was washed with water (200 mL), brine (200 mL), dried over 25 anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford Int-2 (5.4 g, 94%). LCMS: 498.37 [M+H] ⁺. Step-3: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-(4-((7-ethyl-6- oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1-ca rbonyl)piperidin-1-yl)pyridazine-3- carboxamide 5 To a stirred solution of 1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2- methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperidin e-4-carboxylic acid (Int-2, 250 mg, 0.503 mmol, 1.0 eq.) in DMF (3 mL) were added HATU (286 mg, 0.754 mmol, 1.5 eq.) and DIPEA (0.43 mL, 2.515 mmol, 5.0 eq.) at 0 °C and the reaction mixture was stirred for 5 min. To this mixture was added 3- ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int-C, 136 mg, 0.503 mmol, 1.0 10 eq.) at 0 °C and the reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. Upon reaction completion, the mixture was diluted with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extract was washed with water (60 mL), brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product which was purified by flash chromatography eluting with 1-4% methanol in dichloromethane to afford the 15 title compound (600 mg, 28%). 1H NMR (400 MHz, DMSO-d6)δ11.87(s,1H),8.58(brd, J = 8.00 Hz, 1H), 8.38 (s, 1H), 7.73 - 7.83 (m, 3H), 7.61 (s, 1H), 7.35 (br d, J = 9.51 Hz, 1H), 7.26 (br d, J = 8.88 Hz, 1H), 4.47 (br d, J = 13.38 Hz, 3H), 3.82 - 3.94 (m, 1H), 3.53 - 3.64 (m, 4H), 3.46 (br s, 2H), 2.96 - 3.15 (m, 3H), 2.52 - 2.58 (m, 2H), 2.29 - 2.46 (m, 3H), 2.24 (s, 3H), 2.07 - 2.15 (m, 2H), 1.90 (br d, J = 7.88 Hz, 2H), 1.48 - 1.76 (m, 9H), 1.18 20 (br t, J = 7.32 Hz, 3H). LCMS: 752.4 [M+H] ⁺. HPLC purity 93.8%.

Example S2. Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-(1-((7- ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperid ine-4-carbonyl)piperazin-1- yl)pyridazine-3-carboxamide (Compound No.4) 5 Step-1: Preparation of tert-butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyano-2- methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperazin e-1-carboxylate (Int-1) To a stirred solution of 6-chloro-N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cycl ohexyl)- pyridazine-3-carboxamide (Int-A, 900 mg, 2.2 mmol, 1.0 eq.) and tert-butyl piperazine-1-carboxylate (SM- 1, 622 mg, 3.3 mmol, 1.5 eq.) in DMF (10 mL) was added potassium carbonate (760 mg, 5.5 mmol, 2.5 eq.) 10 at room temperature. The reaction mixture was allowed to stir at 80 °C for 16h. Progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was diluted with ice cold water (60 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with water (40 mL), brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product which was purified by flash chromatography eluting with 30-35% ethyl acetate in 15 heptane to afford Int-1 (700 mg, 57%). 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 7.83 Hz, 1H), 7.82 (dd, J = 36.19, 10.27 Hz, 2H), 7.24-7.39 (m, 2H), 4.45 - 4.59 (m, 1H), 3.84 - 3.96 (m, 1H), 3.74-3.69 (m, 4H), 3.50-3.44 (m,4H), 2.24 (s, 3H), 2.12 (d, J = 10.76 Hz, 2H), 1.90 (d, J = 10.76 Hz, 2H), 1.49 - 1.74 (m, 4H), 1.43 (s, 9H). LCMS: 555.53 [M+H] ⁺. Step-2: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(piperazin-1- yl)pyridazine-3-carboxamide (Int-2) 5 To a solution of tert-butyl 4-(6-(((1r,4r)-4-(3-chloro-4-cyano-2- methylphenoxy)cyclohexyl)carbamoyl)-pyridazin-3-yl)piperazin e-1-carboxylate (Int-1, 700 mg, 1.2 mmol, 1 eq.) in 1,4-dioxane (7.0 mL) was added 4M HCl in1,4-dioxane (3.5 mL) at 0 °C and the resulting mixture was allowed to stir for 1h at RT. After consumption of starting material, the volatiles were evaporated under reduced pressure and the resulting residue was triturated with diethyl ether (2 x 20 mL), filtered and dried to 10 afford Int-2 (560 mg, crude) which was used as is in the next step. 1H NMR (400 MHz, DMSO-d6)δ9.11(s,1H),8.65(dd,J = 15.16, 8.31 Hz, 1H), 7.77 (d, J = 8.31 Hz, 1H), 7.33 - 7.49 (m, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.51 (s, 1H), 3.94 (s, 1H), 3.72 (s, 2H), 3.57 (s, 2H), 3.47 (s, 2H), 3.18 - 3.28 (m, 2H), 2.24 (s, 3H), 2.12 (d, J = 9.78 Hz, 2H), 1.90 (d, J = 10.27 Hz, 2H), 1.49 - 1.74 (m, 4H), 1.43 (s, 1H). LCMS: 455.36 [M+H] ⁺. 15 Step-3: Preparation of tert-butyl 4-(4-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cycloh exyl)- carbamoyl)pyridazin-3-yl)piperazine-1-carbonyl)piperidine-1- carboxylate (Int-3) To a stirred solution of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(piperazin- 1-yl)pyridazine-3-carboxamide (Int-2, 560 mg, 1.1 mmol, 1.0 eq.) and 1-(tert-butoxycarbonyl)piperidine-4- carboxylic acid (SM-2, 262 mg, 1.1 mmol, 1.0 eq.) in DMF (6 mL) were added HATU (652 mg, 1.6 mmol, 20 1.5 eq.) and DIPEA (0.6 mL, 3.4 mmol, 3.0 eq.) at 0 °C and the reaction mixture was allowed to stir at room temperature for 24h. Progress of the reaction was monitored by TLC. After starting material consumption, the reaction mixture was diluted with water (30 mL) and extracted with 10% methanol in DCM (3 x 30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product which was purified by flash 25 column chromatography eluting with 30-45% EtOAc in heptane to afford Int-3 (420 mg, 55%). 1H NMR (400 MHz, DMSO-d ₆)δ8.63(d,J = 8.31 Hz, 1H), 7.72 - 7.88 (m, 2H), 7.29 (s, 2H), 4.55 (s, 1H), 3.82 - 3.97 (m, 3H), 3.53 - 3.79 (m, 8H), 2.70 - 2.91 (m, 3H), 2.22 (s, 3H), 2.10 (d, J = 9.78 Hz, 2H), 1.88 (d, J = 4.89 Hz, 2H), 1.50 - 1.70 (m, 5H), 1.30 - 1.47 (m, 9H), 1.19 - 1.26 (m, 3H). LCMS: 666.64 [M+H] ⁺. 30 Step-4: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-(piperidine-4- carbonyl)piperazin-1-yl)pyridazine-3-carboxamide hydrochloride (Int-4) To a solution of Int-3 (420 mg, 0.63 mmol, 1 eq.) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4- dioxane (2 mL) at 0 °C and then allowed to stir for 2h at RT. After consumption of the starting material, the volatiles were evaporated under reduced pressure and the remaining residue was triturated with diethyl ether (2 x 20 mL) to afford Int-4 (250 mg, crude). 5 )δ8.83(d,J = 7.82 Hz, 1H), 8.63 (d, J = 7.83 Hz, 1H), 8.52 (s, 1H), 7.89 (d, J = 9.78 Hz, 1H), 7.41 (d, J = 9.29 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.51 (s, 1H), 3.89 (d, J = 4.89 Hz, 1H), 3.70 (s, 4H), 3.57 (s, 4H), 3.28 (d, J = 11.25 Hz, 2H), 2.86 - 3.07 (m, 2H), 2.24 (s, 3H), 2.12 (d, J = 10.27 Hz, 1H), 1.90 (s, 2H), 1.69 - 1.86 (m, 4H), 1.49 - 1.68 (m, 2H), 1.20 - 1.31 (m, 4H). LCMS: 566.3 [M+H] ⁺. 10 Step-5: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-(1-((7-ethyl-6- oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidine-4-ca rbonyl)piperazin-1-yl)pyridazine-3- carboxamide To a stirred solution of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4- (piperidine-4-carbonyl)piperazin-1-yl)pyridazine-3-carboxami de hydrochloride (Int-4, 250 mg, 0.45 mmol, 15 1.0 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one 100 mg, 0.45 mmol, 1 eq.) in DMF (2.5 mL) was added DIPEA (0.24 mL, 1.3 mmol, 3 eq.) at room temperature. The reaction mixture was allowed to stir at 80 °C for 6h. Progress of the reaction was monitored by TLC. After consumption of starting material, the reaction mixture was diluted with ice cold water (60 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried over 20 anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product obtained was purified by flash chromatography eluting with 4-6% methanol in dichloromethane to afford the title compound (75 mg, 22%). 1H NMR (400 MHz, DMSO-d ₆)δ11.82(s,1H),8.63(d,J = 7.82 Hz, 1H), 8.36 (s, 1H), 7.86 (d, J = 9.29 Hz, 1H), 7.71 - 7.80 (m, 2H), 7.61 (s, 1H), 7.36 (d, J = 9.78 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 4.51 (s, 25 1H), 3.89 (d, J = 8.31 Hz, 1H), 3.75 (s, 2H), 3.67 (s, 4H), 3.58 (s, 4H), 2.83 (d, J = 9.78 Hz, 2H), 2.66 (s, 1H), 2.24 (s, 3H), 2.10 (s, 4H), 1.48 - 1.71 (m, 9H), 1.23 (s, 3H), 1.18 (t, J = 7.34 Hz, 3H). LCMS: 751.8 [M+H] ⁺. HPLC purity 96.1%. Example S3. Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(4-(4- ((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)pip erazine-1-carbonyl)piperazin-1- yl)pyridazine-3-carboxamide (Compound No.7) 5 Step-1: Preparation of methyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridazine-3-carbox ylate (Int- 1) To a stirred solution of methyl 6-chloropyridazine-3-carboxylate (SM-1, 5 g, 29.06 mmol, 1.0 eq.) in 1,4-dioxane (50 mL), tert-butyl piperazine-1-carboxylate (SM-2, 5.4 g, 29.06 mmol, 1.0 eq.) and DIPEA (16 mL, 87 mmol, 3 eq.) were added at room temperature. The reaction mixture was allowed to stir at 90 °C 10 for 18h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL) and the resulting precipitate was filtered, washed with water (50 mL) and pentane (50 mL) and dried to obtain methyl 6-(4-(tert-butoxycarbonyl)piperazin-1- yl)pyridazine-3-carboxylate (Int-1, 85 g, 91%). 1H NMR (400 MHz, DMSO-d6^^į^^^^^^^G^^J = 9.29 Hz, 1H), 7.28 (d, J = 9.29 Hz, 1H), 3.87 (s, 3H), 15 3.75 (s, 4H), 3.47 (s, 4H), 1.43 (s, 9H). LCMS: 323.31 [M+H] ⁺. Step-2: Preparation of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridazine-3-carbox ylic acid (Int-2) To a stirred solution of methyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridazine-3-carbox ylate (Int-1, 3.5 g, 27.9 mmol, 1.0 eq.) in MeOH:THF:H ₂O (45 mL, 1:1:1, 5 vol), LiOH.H ₂O (3.5 g, 83.7 mmol, 3.0 eq.) was added at room temperature. The reaction mixture was allowed to warm up to room temperature 5 and stir for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with citric acid solution (pH ~5) and the resulting precipitate was filtered, washed with water (50 mL) and pentane (50 mL) and dried to obtain 6-(4-(tert-butoxycarbonyl)piperazin-1- yl)pyridazine-3-carboxylic acid (Int-2, 8 g, 93%). 1H NMR (400 MHz, DMSO-d ₆)δ7.85(d,J = 9.29 Hz, 1H), 7.29 (d, J = 9.29 Hz, 1H), 3.68 - 3.74 10 (m, 4H), 3.47 (s, 4H), 1.43 (s, 9H). LCMS: 309.27 [M+H] ⁺. Step-3: Preparation of tert-butyl 4-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cycl ohexyl)- carbamoyl)pyridazin-3-yl)piperazine-1-carboxylate (Int-3) To a stirred solution of 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridazine-3-carbox ylic acid (Int- 2, 3 g, 9.74 mmol, 1.0 eq.) in DMF (30 mL), 4-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)-2- 15 chlorobenzonitrile trifluoroacetate (Int-A1, 2.5 g, 9.74 mmol, 1.0 eq.), DIPEA (5.28 mL, 29.2 mmol, 3.0 eq.) and HATU (5.5 g, 14.55 mmol, 1.5 eq.) were added at room temperature. The reaction mixture was allowed to stir at ambient temperature under argon atmosphere for 3h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (200 mL), filtered and dried. The crude obtained was purified by combi flash column and the pure fractions20 were combined and concentrated under reduced pressure to afford tert-butyl 4-(6-(((1r,4r)-4-((3-chloro-4- cyanophenyl)(methyl)amino)cyclohexyl)carbamoyl)-pyridazin-3- yl)piperazine-1-carboxylate (Int-3, 2 g, 37%). 1H NMR (400 MHz, DMSO-d ₆)δ8.46- 8.54 (m, 1H), 7.82 - 7.88 (m, 1H), 7.59 (d, J = 8.80 Hz, 1H), 7.34 (d, J = 9.78 Hz, 1H), 6.93 (d, J = 1.96 Hz, 1H), 6.82 (d, J = 8.80 Hz, 1H), 3.70 (s, 4H), 3.46 (s, 25 4H), 2.91 (s, 2H), 2.80 - 2.87 (m, 3H), 1.91 (d, J = 7.83 Hz, 2H), 1.72 - 1.86 (m, 2H), 1.58 - 1.71 (m, 4H), 1.42 (s, 9H). Step-4: Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(piperazin- 1-yl)pyridazine-3-carboxamide trifluoroacetate (Int-4) To a stirred solution of tert-butyl 4-(6-(((1r,4r)-4-((3-chloro-4- 30 cyanophenyl)(methyl)amino)cyclohexyl)-carbamoyl)pyridazin-3- yl)piperazine-1-carboxylate (Int-3, 2 g, 3.61 mmol, 1.0 eq.) in DCM (20 mL), TFA (6 mL, 30 vol) was added at room temperature. The reaction mixture was allowed to stir at ambient temperature for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, triturated with diethyl ether (50 mL), filtered and dried to afford N-((1r,4r)-4-((3-chloro-4- cyanophenyl)(methyl)amino)cyclohexyl)-6-(piperazin-1-yl)pyri dazine-3-carboxamide trifluoroacetate (Int- 4, 1.5 g, 73%). 1H NMR (400 MHz, DMSO-d ₆)δ8.92(brs,2H),8.54(d,J = 7.82 Hz, 1H), 7.94 (d, J = 9.29 Hz, 5 1H), 7.60 (d, J = 8.80 Hz, 1H), 7.45 (d, J = 9.29 Hz, 1H), 6.94 (s, 1H), 6.82 (d, J = 8.31 Hz, 1H), 3.70 - 3.89 (m, 4H), 3.25 (s, 4H), 2.78 - 2.99 (m, 5H), 1.92 (d, J = 8.80 Hz, 2H), 1.59 - 1.88 (m, 6H). LCMS: 454.58 [M+H] ⁺. Step-5: Preparation of tert-butyl 4-(4-(6-(((1r,4r)-4-((3-chloro-4- cyanophenyl)(methyl)amino)cyclohexyl)-carbamoyl)pyridazin-3- yl)piperazine-1-carbonyl)piperazine- 10 1-carboxylate (Int-5) To a stirred solution of tert-butyl piperazine-1-carboxylate (SM-2, 1 g, 5.37 mmol, 1.0 eq.) in DCM (10 mL), pyridine (1 mL, 13.42 mmol, 2.5 eq.) and triphosgene solution (800 mg, 2.68 mmol, 0.5 eq.) in DCM (10 mL) were added at room temperature and the reaction mixture was allowed to stir at for 2h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was 15 diluted with DCM (200 mL) and washed with 1N HCl solution (2 x 200 mL). The organic layer was concentrated under reduced pressure and the obtained crude was used without purification. Separately, to a solution of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(piperazin-1-yl)pyridazine- 3-carboxamide trifluoroacetate (Int-4, 1.1 g, 1.93 mmol, 1.0 eq.) in DCM (10 mL), DIPEA (1.6 mL, 9.65 mmol, 5.0 eq.), DMAP (53 mg, 0.48 mmol, 0.25 eq.) and the crude in DCM solution obtained earlier was 20 added at RT under argon atmosphere. The resulting reaction mixture was allowed to stir at room temperature for 18h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (200 mL) and washed with water (2 x 200 mL). The organic layer was dried (Na ₂SO ₄), filtered, concentrated and the crude obtained was purified by combi flash column. The pure fractions were combined and concentrated under reduced pressure to afford tert-butyl 4-(4-(6-(((1r,4r)-4-((3-25 chloro-4-cyanophenyl)(methyl)amino)cyclohexyl)carbamoyl)pyri dazin-3-yl)piperazine-1- carbonyl)piperazine-1-carboxylate (Int-5, 1.2 g, 92%). 1H NMR (400 MHz, DMSO-d ₆)δ8.53(d,J = 8.31 Hz, 1H), 7.87 (d, J = 9.78 Hz, 1H), 7.60 (d, J = 8.80 Hz, 1H), 7.36 (d, J = 9.29 Hz, 1H), 6.94 (s, 1H), 6.82 (d, J = 8.31 Hz, 1H), 3.76 - 3.93 (m, 2H), 3.73 (s, 4H), 3.34 - 3.38 (m, 8H), 3.17 (s, 4H), 2.85 (s, 3H), 1.92 (d, J = 9.29 Hz, 2H), 1.58 - 1.82 (m, 6H), 1.41 (s, 30 9H). LCMS: 666.95 [M+H] ⁺. Step-6: Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(4- (piperazine-1-carbonyl)piperazin-1-yl)pyridazine-3-carboxami de trifluoroacetate (Int-6) To a stirred solution of tert-butyl 4-(4-(6-(((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)- cyclohexyl)carbamoyl)pyridazin-3-yl)piperazine-1-carbonyl)pi perazine-1-carboxylate (Int-5, 350 mg, 0.52 5 mmol, 1.0 eq.) in DCM (3.5 mL) TFA (1.05 mL, 3.0 vol) was added at room temperature. The reaction mixture was allowed to stir at ambient temperature for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, triturated with diethyl ether (50 mL), filtered and dried to afford N-((1r,4r)-4-((3-chloro-4- cyanophenyl)(methyl)amino)cyclohexyl)-6-(4-(piperazine-1-car bonyl)piperazin-1-yl)pyridazine-3- 10 carboxamide trifluoroacetate (Int-7, (300 mg, 84 %). Step-7: Preparation of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(4-(4-((7- ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperaz ine-1-carbonyl)piperazin-1-yl)pyridazine- 3-carboxamide To a stirred solution of N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(4- 15 (piperazine-1-carbonyl)piperazin-1-yl)pyridazine-3-carboxami de trifluoroacetate (Int-7, 350 mg, 0.51 mmol, 1.0 eq.) in DMF (3.5 mL), DIPEA (0.3 mL, 1.53 mmol, 3.0 eq.) and 7-(chloromethyl)-3-ethyl-1,5- naphthyridin-2(1H)-one (Int-7, 116 mg, 0.51 mmol, 1.0 eq.) were added at room temperature. The reaction mixture was allowed to stir at 80 °C for 3h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with 20 ethyl acetate (2 x 200 mL). The combined organic extract was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash column and the pure fractions were combined and concentrated under reduced pressure to afford N-((1r,4r)-4-((3-chloro-4-cyanophenyl)(methyl)amino)cyclohex yl)-6-(4-(4-((7-ethyl-6- oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1-ca rbonyl)piperazin-1-yl)pyridazine-3- 25 carboxamide (87 mg, 22%). 1H NMR (400 MHz, DMSO-d ₆)δ11.84(s,1H),83.53 (d,J = 7.82 Hz, 1H), 8.35 - 8.41 (m, 1H), 7.86 (d, J = 9.29 Hz, 1H), 7.74 (s, 1H), 7.56 - 7.64 (m, 2H), 7.35 (d, J = 9.29 Hz, 1H), 6.94 (s, 1H), 6.83 (d, J = 8.80 Hz, 1H), 3.72 (s, 6H), 3.61 (s, 2H), 3.32 (s, 4H), 3.22 (s, 4H), 2.85 (s, 3H), 2.52 - 2.60 (m, 2H), 2.41 (s, 4H), 1.92 (d, J = 8.80 Hz, 2H), 1.59 - 1.82 (m, 6H), 1.18 (t, J = 7.34 Hz, 3H). LCMS: 752.5 [M+H] ⁺. Example S4. Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-((4-((5- fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)pipe razin-1-yl)methyl)piperidin-1- yl)pyridazine-3-carboxamide (Compound No.12) 5 Step-1: Preparation of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (Int-1) To a stirred solution of methyl 6-chloropyridazine-3-carboxylate (SM-1, 5 g, 28 mmol, 1.0 eq.) and piperidin-4-ylmethanol (SM-2, 3.6 g, 31 mmol, 1.1 eq.) in acetonitrile (150 mL) was added triethylamine (6 mL, 43 mmol, 1.5 eq.) and the reaction mixture was allowed to stir at room temperature for 16h. After completion of the reaction, the volatiles were evaporated under reduced pressure and the crude obtained was10 purified by combi flash column eluting with 80% ethyl acetate in heptane to afford methyl 6-(4- (hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (Int-1, 5.9 g, 80%). 1H NMR (400 MHz, DMSO-d66) δ 7.79 (d, = 9.29 Hz, 1H), 7.27 (d, J = 9.78 Hz, 1H), 4.55 (s, 1H), 4.51 - 4.54 (m, 2H), 3.86 (s, 3H), 3.27 (t, J = 5.14 Hz, 2H), 3.00 (t, J = 11.98 Hz, 2H), 1.72-1.80 (m, 3H), 1.08 - 1.21 (m, 2H). LCMS: 251.95 [M+H] ⁺. Step-2: Preparation of methyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate (Int-2) To a stirred solution of methyl 6-(4-(hydroxymethyl)piperidin-1-yl)pyridazine-3-carboxylate (Int-2, 1 g, 3.98 mmol, 1.0 eq.) in DCM (50 mL) was added Dess-Martin periodinane (2.7 g, 5.97 mmol, 1.5 eq.) at 0 °C and the reaction mixture was allowed to warm up to room temperature and stir for 1h. Progress of the 5 reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated solution of Na ₂S ₂O ₃ (60 mL) and extracted with DCM (2 x 60 mL). The combined organic extract was washed with sat. NaHCO ₃ (60 mL), brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate (Int-2, 930 mg, crude). 10 ¹H NMR (400 MHz, DMSO-d ₆)δ9.63(s,1H),7.82(d,J = 9.78 Hz, 1H), 7.31 (d, J = 9.78 Hz, 1H), 4.34 (d, J = 13.69 Hz, 2H), 3.86 (s, 3H), 3.23 - 3.30 (m, 2H), 2.90 - 3.11 (m, 1H), 2.64 - 2.75 (m, 1H), 1.88 - 2.03 (m, 3H), 1.45 - 1.61 (m, 2H). LCMS: 250.2 [M+H] ⁺. Step-3: Preparation of methyl 6-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidi n-1- yl)pyridazine-3-carboxylate (Int-3) 15 To a stirred solution of methyl 6-(4-formylpiperidin-1-yl)pyridazine-3-carboxylate (Int-2, 900 mg, 3.61 mmol, 1.0 eq.) and tert-butyl piperazine-1-carboxylate (SM-3, 670 mg, 3.61 mmol, 1.0 eq.) in methanol (30 mL) was added triethylamine (1.5 mL, 10.83 mmol, 3 eq.) at room temperature. After 10 min, cat. Amount of acetic acid (0.4 mL) was added and the reaction mixture was allowed to stir for 1h. Sodium cyanoborohydride (450 mg, 7.22 mmol, 2.0 eq.) was then added at room temperature and allowed the 20 reaction mixture to stir for 16h. After completion of the reaction, water (100 mL) was added and the aqueous solution was extracted with DCM (2 x 100 mL). The combined organic extract was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude obtained was purified by combi flash column eluting with 80 % ethyl acetate in heptane to afford methyl 6-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidi n-1-yl)pyridazine-3-carboxylate (Int-3, 25 750 mg, 50%). 1H NMR (400 MHz, DMSO-d ₆)δ7.80(d,J = 9.78 Hz, 1H), 7.26 (d, J = 9.78 Hz, 1H), 4.51 (d, J = 13.21 Hz, 2H), 3.86 (s, 3H), 3.30-3.35 (m, 4H), 3.01 (t, J = 11.74 Hz, 2H), 2.20-2.29 (m, 4H), 2.15 (d, J = 7.34 Hz, 2 H,) 1.76 - 1.91 (m, 3H), 1.39 (s, 9H), 0.99 - 1.18 (m, 2H). LCMS: 420.4 [M+H] ⁺. Step-4: Preparation of 6-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidi n-1-yl)pyridazine-3- 30 carboxylic acid (Int-4) To a stirred solution of methyl 6-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidi n-1- yl)pyridazine-3-carboxylate (Int-3, 4 g, 9.54 mmol, 1.0 eq.) in MeOH:THF:H2O (40 mL, 1:1:1, 10 vol), LiOH.H2O (2.0 g, 47.7 mmol, 5.0 eq.) was added at room temperature. The reaction mixture was stirred at ambient temperature for 16h. After consumption of the starting material, the reaction mixture was acidified with citric acid solution (pH ~5) and the precipitate was filtered, washed with water (50 mL) and pentane (50 mL) and dried to give 6-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidi n-1-yl)pyridazine-3- carboxylic acid (Int-4, 3 g, 78%). 5 ¹H NMR (400 MHz, DMSO-d ₆) δ 7.79(d,J = 8.80 Hz, 1H), 7.27 (d, J = 9.29 Hz, 1H), 4.44 (d, J = 12.72 Hz, 2H), 3.30 (s, 4H), 2.96 (t, J = 12.23 Hz, 2H), 2.29 (s, 4H), 2.15 (d, J = 6.36 Hz, 2H), 1.89 - 2.00 (m, 1H), 1.80 (d, J = 13.20 Hz, 3H), 1.39 (s, 9H), 1.10 (d, J = 8.80 Hz, 2H). LCMS: 406.39 [M+H] ⁺. Step-5: Preparation of tert-butyl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclo hexyl)- carbamoyl)pyridazin-3-yl)piperidin-4-yl)methyl)piperazine-1- carboxylate (Int-5) 10 To a stirred solution of 6-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidi n-1- yl)pyridazine-3-carboxylic acid (Int-4, 750 mg, 1.85 mmol, 1.0 eq.) in DMF (7.5 mL), 4-(((1r,4r)-4- aminocyclohexyl)oxy)-2-chloro-3-methylbenzonitrile hydrochloride (Int-A2, 555 mg, 1.85 mmol, 1.0 eq.), DIPEA (0.95 mL, 5.55 mmol, 3.0 eq.) and HATU (1.05 g, 2.77 mmol, 1.5 eq.) were added under nitrogen atmosphere at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 16h. 15 After completion of the reaction, the reaction mixture was diluted with water (100 mL) and the resulting precipitate was filtered. The crude obtained was purified by flash column and the pure fractions were combined and concentrated under reduced pressure afford tert-butyl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano- 2-methylphenoxy)cyclohexyl)carbamoyl)pyridazin-3-yl)piperidi n-4-yl)methyl)piperazine-1-carboxylate (Int-5, 300 mg, 25%). 20 ¹H NMR (400 MHz, DMSO-d6)δ8.58(d,J = 7.83 Hz, 1H), 7.73 - 7.83 (m, 2H), 7.21 - 7.36 (m, 2H), 4.47 (m, 3H), 3.88 (s, 1H), 2.99 (t, J = 12.23 Hz, 2H), 2.89 (s, 1H), 2.67 - 2.77 (m, 1H), 2.20 - 2.32 (m, 8H), 2.15 (d, J = 6.85 Hz, 4H), 1.73 - 1.95 (m, 4H), 1.46 - 1.71 (m, 4H), 1.39 (s, 9H), 1.22 - 1.32 (m, 2H), 1.08 – 1.19 (m, 2H). LCMS: 652.65 [M+H] ⁺. Step-6: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-(piperazin-1- 25 ylmethyl)piperidin-1-yl)pyridazine-3-carboxamide trifluoroacetate (Int-6) To a stirred solution of tert-butyl 4-((1-(6-(((1r,4r)-4-(3-chloro-4-cyano-2- methylphenoxy)cyclohexyl)-carbamoyl)pyridazin-3-yl)piperidin -4-yl)methyl)piperazine-1-carboxylate (Int- 5, 300 mg, 0.53 mmol, 1.0 eq.) in DCM (3.5 mL) under nitrogen atmosphere was added TFA (1.75 mL) at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 4h. Progress of the 30 reaction was monitored by TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure and the residue was triturated with diethyl ether (20 mL), filtered and dried under vacuum to afford N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)-cyclohexyl)- 6-(4-(piperazin-1- ylmethyl)piperidin-1-yl)pyridazine-3-carboxamide trifluoroacetate (Int-6, 400 mg, crude). LCMS: 552.60 [M+H] ⁺. Step-7: Preparation of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-((4-((5- fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)pipe razin-1-yl)methyl)piperidin-1- yl)pyridazine-3-carboxamide 5 To a stirred solution of N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4- (piperazin-1-ylmethyl)piperidin-1-yl)pyridazine-3-carboxamid e trifluoroacetate (Int-6, 400 mg, 0.72 mmol, 1.0 eq.) in acetonitrile (4 mL), 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one (Int-A3, 196 mg, 0.72 mmol, 1.0 eq.), DIPEA (0.62 mL, 3.62 mmol, 5.0 eq.) was added under nitrogen atmosphere at 0 °C. The reaction mixture was allowed to warm up and stir at 80 °C for 5h. Progress of the reaction was 10 monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude obtained was purified by flash column and the pure fractions were combined and concentrated under reduced pressure to afford N-((1r,4r)-4-(3-chloro-4-cyano-2-methylphenoxy)cyclohexyl)-6 -(4-((4-((5-15 fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)pipe razin-1-yl)methyl)piperidin-1-yl)pyridazine- 3-carboxamide (70 mg, 13%). 1H NMR (400 MHz, DMSO-d6)δ12.37- 12.45 (m, 1H), 8.56 (d, J = 8.13 Hz, 1H), 7.74 - 7.81 (m, 2H), 7.50 (d, J = 8.25 Hz, 1H), 7.31 (d, J = 9.63 Hz, 1H), 7.21 - 7.27 (m, 2H), 4.40 - 4.55 (m, 3H), 3.82 - 3.93 (m, 1H), 3.61 (s, 2H), 2.98 (t, J = 11.76 Hz, 2H), 2.28 - 2.46 (m, 9H), 2.24 (s, 3H), 2.12 (d, J = 7.00 Hz, 20 4H), 1.72 - 1.95 (m, 5H), 1.47 - 1.70 (m, 5H), 0.98 - 1.20 (m, 3H). LCMS: 741.9 [ +H] ⁺.

Nuvation Ref.: NUVP-0051-PCT MoFo Ref.: 19369-20051.40 Example S5. Preparation of N-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)-5-(4-((7-e thyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)picolinamide (Compound No.2) 5 Step-1: Preparation of tert-butyl (6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)carbamate (Int-1) To a stirred soln. of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Int-D, 1 g, 2.21 mmol, 1.0 eq.) and tert-butyl N-(6- aminohexyl)carbamate (SM-1, 580 mg, 2.68 mmol, 1.2 eq.) in DMF (10 mL) were added N,N- 10 diisopropylethylamine (0.80 mL, 4.41 mmol, 2 eq.) and HATU (1.26 g, 3.31 mmol, 1.5 eq.) at room temperature. Progress of the reaction was monitored by TLC. The reaction mixture was stirred at room temperature for 16h, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium n _^ y-2633819 sulfate, filtered, and conc. under vacuum. The crude obtained was purified by combiflash chromatography eluting with 50% EtOAc in heptane to afford Int-1 (1.00 g, 98%). 1H NMR (400 MHz, DMSO-d ₆)δ8.50(s,1H),8.41(d,J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.75 (t, J = 7.34 Hz, 1H), 7.42 (d, J = 9.78 Hz, 1H), 7.28 - 7.36 (m, 1H), 6.77 (s, 1H), 3.25 (d, 5 J = 4.89 Hz, 2H), 2.90 (d, J = 5.87 Hz, 2H), 2.69 (s, 2H), 1.54 (s, 6H), 1.19 - 1.44 (m, 15H). LCMS: 650.45 [M+H] ⁺. Step-2: Preparation of N-(6-aminohexyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamide trifluoroacetate (Int-2) A flask was charged with tert-butyl (6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4- 10 oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)carba mate (Int-1, 1 g, 1.54 mmol, 1.0 eq.) in dichloromethane (50 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (1.00 mL). The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After complete consumption of Int-1, the volatiles were evaporated, and the crude obtained was filtered and washed with diethyl ether (2 x 25 mL) to afford the TFA salt of Int-2 (1.00 g, 15 crude). LCMS: 550.37 [M+H] ⁺. Step-3: Preparation of tert-butyl 4-(6-((6-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimet hyl-4-oxo- 2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)carbamoyl )pyridin-3-yl)piperazine-1-carboxylate (Int-3) 20 To a stirred solution of N-(6-aminohexyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5, 5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamide trifluoroacetate (Int-2, 1.00 g, 1.5 mmol, 0.1 eq.) and 5- (4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid (Int-E1, 449 mg, 1.5 mmol, 1 eq.) in DMF (15 mL), N,N-diisopropylethylamine (0.52 mL, 3.00 mmol, 2 eq.) and HATU (687 mg, 1.8 mmol, 1.2 eq.) were added at room temperature. Progress of the reaction was monitored by TLC. The reaction mixture was allowed to 25 stir for 16h, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 5% MeOH in DCM to afford Int-3 (760 mg, crude). 1H NMR (400 MHz, DMSO-d ₆)δ8.49(t,J = 5.38 Hz, 1H), 8.38 - 8.45 (m, 2H), 8.26 - 8.30 (m, 30 2H), 8.08 (dd, J = 8.07, 1.22 Hz, 1H), 7.84 (d, J = 8.31 Hz, 1H), 7.74 (t, J = 8.07 Hz, 1H), 7.38 - 7.44 (m, 2H), 7.32 (dd, J = 8.07, 1.71 Hz, 1H), 3.44 - 3.50 (m, 4H), 3.21 - 3.28 (m, 6H), 1.46 - 1.57 (m, 10H), 1.42 (s, 10H), 1.33 (t, J = 14.43 Hz, 5H). LCMS: 839.69 [M+H] ⁺. Step-4: Preparation of N-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)-5-(piperaz in-1-yl)picolinamide trifluoroacetate (Int-4) A stirred solution of tert-butyl 4-(6-((6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimet hyl-4- oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)carba moyl)pyridin-3-yl)piperazine-1-carboxylate 5 (Int-3, 760 mg, 9.06 mmol, 1 eq.) in dichloromethane (20 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (0.7 mL). The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After complete consumption of Int-3, the volatiles were evaporated and the crude obtained was filtered and washed with diethyl ether (2 x 25 mL) to afford the TFA salt of Int-4 (750 mg, crude). 10 ¹H NMR (400 MHz, DMSO-d ₆)δ8.74(brs,2H),8.37- 8.49 (m, 3H), 8.33 (s, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.89 (d, J = 8.80 Hz, 1H), 7.75 (t, J = 7.82 Hz, 1H), 7.48 (d, J = 8.31 Hz, 1H), 7.41 (d, J = 10.76 Hz, 1H), 7.32 (d, J = 7.83 Hz, 1H), 3.54 (s, 4H), 3.27 (s, 8H), 1.54 (s, 10H), 1.34 (br s, 4H). Step-5: Preparation of N-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2-15 thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)-5-(4-((7-e thyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)picolinamide To a stirred solution of N-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)-5-(piperaz in-1-yl)picolinamide trifluoroacetate (Int-4, 700 mg, 0.822 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 182 mg, 0. 20 822 mmol, 1 eq.) in DMF (7 mL) was added K2CO3 (227 mg, 1.6 mmol, 2 eq.). Progress of the reaction was monitored by TLC. The reaction mixture was allowed to stir at room temperature for 16h, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by prep. HPLC eluting with Mobile phase A: 0.1% FA in water 25 and Mobile phase B: acetonitrile to afford the title compound (180 mg, 23%). 1H NMR (400 MHz, DMSO-d ₆)δ11.84(s,1H),8.49(t,J = 5.38 Hz, 1H), 8.36 - 8.42 (m, 3H), 8.28 (dd, J = 9.44, 2.31 Hz, 2H),, 8.08 (dd, J = 8.25, 1.63 Hz, 1H), 7.83 (d, J = 8.88 Hz, 1H), 7.71 - 7.77 (m, 2H), 7.62 (d, J = 1.25 Hz, 1H), 7.37 - 7.43 (m, 2H), 7.32 (dd, J = 8.13, 1.75 Hz, 1H), 3.65 (s, 2H), 3.32 - 3.36 (m, 4H), 3.22 - 3.28 (m, 4H), 2.53 - 2.58 (m, 6H), 1.47 - 1.57 (m, 10H), 1.26 - 1.40 (m, 4H), 1.18 (t, J = 7.44 Hz, 30 3H). LCMS: 99.925.8 [M+H] ⁺. HPLC purity 99.1%. Example S6. Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-N-(2-(4-((7-ethyl-6-oxo-5,6-dihydro -1,5-naphthyridin-3-yl)methyl)piperazin- 1-yl)ethyl)-2-fluorobenzamide (Compound No.5) 5 Step-1: Preparation of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamido)ethyl)piperazine- 1-carboxylate (Int-1) To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Int-D, 500 mg, 1.10 mmol, 1 eq.) and tert-butyl 4-(2- aminoethyl)piperazine-1-carboxylate (SM-1, 280 mg, 1.2 mmol, 1.1 eq.) in DMF (2 mL) was added N,N- 10 diisopropylethylamine (0.4 mL, 2.21 mmol, 2 eq.) and HATU (632 mg, 1.66 mmol, 1.5 eq.). The reaction mixture was allowed to stir at room temperature for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (75 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was 15 purified by combiflash chromatography eluting with 67% EtOAc in heptane to afford Int-1 (615 mg, 83%). 1H NMR (400 MHz, DMSO-d ₆) δ 8.47 - 8.57 (m, 2H), 8.39 (s, 1H), 8.18 (d, J = 8.31 Hz, 1H), 7.89 (t, J = 8.07 Hz, 1H), 7.53 (dd, J = 10.52, 1.22 Hz, 1H), 7.44 (d, J = 7.83 Hz, 1H), 4.19 (d, J = 5.38 Hz, 4H), 3.35 - 3.55 (m, 4H), 2.41-2.58 (br s, 4H), 1.64 (s, 6H), 1.49 (s, 9H). LCMS: 663.54 [M+H] ⁺. Step-2: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-(2-(piperazin-1-yl)ethyl )benzamide trifluoroacetate (Int-2) A stirred solution of tert-butyl 4-(2-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo- 2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)ethyl)piperazin e-1-carboxylate (Int-1, 615 mg, 0.93 mmol, 1 5 eq.) in dichloromethane (6 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (1.0 mL). The reaction mixture was allowed to warm up to room temperature and stir for 3h. Progress of the reaction was monitored by TLC. After complete consumption of Int-1, the volatiles were evaporated and the crude obtained was triturated with n-heptane (50 mL) followed by diethyl ether (2 x 25 mL) to provide the TFA salt of Int-2 (630 mg, crude). 10 ¹H NMR (400 MHz, DMSO-d ₆) δ 8.74 (br s, 2H), 8.54 (s, 1H), 8.41 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.83 (t, J = 8.07 Hz, 1H), 7.46 (d, J = 10.76 Hz, 1H), 7.36 (d, J = 7.83 Hz, 1H), 3.51 (s, 2H), 3.22 (s, 4H), 2.81 - 3.14 (m, 6H), 1.55 (s, 6H). LCMS: 563.51 [M+H] ⁺. Step-3: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-N-(2-(4-((7-ethyl-6-oxo-5,6-dihydro -1,5-naphthyridin-3-yl)methyl)piperazin-1- 15 yl)ethyl)-2-fluorobenzamide A stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-(2-(piperazin-1-yl)ethyl )benzamide trifluoroacetate (Int-2, 500 mg, 0. 889 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 200 mg, 0.889 mmol, 1 eq.) in DMF (5 mL) was added K ₂CO ₃ (246 mg, 1.78 mmol, 2 eq.). The reaction mixture was allowed to stir 20 at room temperature for 4h and monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice cold water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude obtained was purified by combiflash chromatography eluting with 6% MeOH in DCM to afford the title compound (220 mg, 33%). 25 ¹H NMR (400 MHz, DMSO-d ₆) δ 11.82 (s, 1H), 8.34 - 8.43 (m, 3H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.78 (t, J = 7.83 Hz, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 10.76 Hz, 1H), 7.34 (d, J = 7.82 Hz, 1H), 3.57 (s, 2H), 3.38 (d, J = 5.38 Hz, 2H), 2.52 - 2.61 (m, 6H), 2.33 (s, 6H), 1.54 (s, 6H), 1.17 (t, J = 7.34 Hz, 3H). LCMS: 749.3 [M+H] ⁺. HPLC purity 99.3%. Example S7. Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-N-(6-(4-((7-ethyl-6-oxo-5,6-dihydro -1,5-naphthyridin-3-yl)methyl)piperazin- 1-yl)hexyl)-2-fluorobenzamide (Compound No.6) 5 Step-1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-(6-hydroxyhexyl)benzamid e (Int-1) To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Int-D, 700 mg, 1.55 mmol, 1 eq.) and 6-aminohexan-1-ol (SM-1 (218 mg, 1.86 mmol, 1.2 eq.) in DMF (3 mL), N,N-diisopropylethylamine (0.54 mL, 3.1 mmol, 2 eq.) 10 and HATU (884 mg, 2.32 mmol, 1.5 eq.) were added at room temperature. The reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. The reaction mixture was then diluted with ice cold water (50 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 15 65% EtOAc in heptane to afford Int-1 (450 mg, 53%). 1H NMR (400 MHz, DMSO-d ₆) δ 8.49 (t, J = 5.38 Hz, 1H), 8.40 (d, J = 8.26 Hz, 1H), 8.29 (d, J = 1.63 Hz, 1H), 8.08 (dd, J = 8.19, 1.69 Hz, 1H), 7.75 (t, J = 8.00 Hz, 1H), 7.42 (dd, J = 10.51, 1.75 Hz, 1H), 7.32 (dd, J = 8.13, 1.75 Hz, 1H), 4.33 (t, J = 5.13 Hz, 1H), 3.36 - 3.42 (m, 2H), 3.23 - 3.28 (m, 2H), 1.49 - 1.57 (m, 8H), 1.39 - 1.45 (m, 2H), 1.29 - 1.36 (m, 4H). LCMS: 551.31 [M+H] ⁺. Step-2: Preparation of N-(6-chlorohexyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5 ,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamide (Int-2) A solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1- yl)-2-fluoro-N-(6-hydroxyhexyl)benzamide (Int-1, 350 mg, 0.63 mmol, 1 eq.) in DCM (4 mL) was cooled to 5 0 °C followed by addition of thionyl chloride (SOCl ₂) dropwise and a catalytic amount of DMF (20µL). The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC/LCMS. After completion of reaction, volatiles were evaporated under reduced pressure to give the crude product Int-2 (222 mg, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 8.50 (s, 1H), 8.39 (dd, J = 11.49, 8.56 Hz, 2H), 8.27 (d, J = 17.12 10 Hz, 1H), 8.09 (t, J = 8.31 Hz, 1H), 7.73 (dt, J = 18.95, 8.13 Hz, 1H), 7.30 - 7.49 (m, 1H), 3.64 (t, J = 6.60 Hz, 2H), 3.26 (d, J = 5.87 Hz, 2H), 1.73 (quin, J = 6.73 Hz, 2H), 1.47 - 1.60 (m, 8H), 1.31 - 1.47 (m, 4H). LCMS: 569.29 [M+H] ⁺. Step-3: Preparation of tert-butyl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)piperazine- 1-carboxylate (Int-3) 15 A 100 mL sealed tube was charged with N-(6-chlorohexyl)-4-(3-(4-cyano-3- (trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazol idin-1-yl)-2-fluorobenzamide (Int-2, 380 mg, 0.667 mmol, 1 eq.), tert-butyl piperazine-1-carboxylate (SM-2, 150 mg, 0.801 mmol, 1.2 mmol), DIPEA (0.23 mL, 1.33 mmol, 2 eq.) and KI (111 mg, 0.667 mmol, 1 eq.) in acetonitrile (4 mL). The reaction mixture was purged with N ₂ gas and allowed to stir at 80 °C for 16h. Progress of the reaction was monitored 20 by TLC. The reaction mixture was then diluted with ice cold water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product Int- 3 (350 mg, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 8.49 (t, J = 5.50 Hz, 1H), 8.35 - 8.44 (m, 1H), 8.23 - 8.31 (m, 25 1H), 8.05 - 8.13 (m, 1H), 7.65 - 7.77 (m, 1H), 7.29 - 7.48 (m, 2H), 3.20 - 3.30 (m, 8H), 2.22 - 2.30 (m, 4H), 1.47 - 1.57 (m, 10H), 1.38 (s, 9H), 1.31 (br s, 4H). LCMS: 719.56 Step-4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-(6-(piperazin-1-yl)hexyl )benzamide trifluoroacetate (Int-4) A stirred solution of tert-butyl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo- 30 2-thioxoimidazolidin-1-yl)-2-fluorobenzamido)hexyl)piperazin e-1-carboxylate (Int-3, 330 mg, 0.459 mmol, 1 eq.) in dichloromethane (5 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (0.35 mL, 4.59 mmol, 10 eq.). The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After complete consumption of Int-3, volatiles were evaporated under reduced pressure. The crude obtained was triturated with n-heptane (50 mL) followed by diethyl ether (2 x 25 mL) to provide the TFA salt of Int-4 (280 mg, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 9.09 (s, 2H), 8.47 - 8.55 (m, 1H), 8.34 - 8.46 (m, 1H), 8.27 (d, J = 16.14 Hz, 1H), 8.08 (d, J = 7.34 Hz, 1H), 7.66 - 7.79 (m, 1H), 7.28 - 7.50 (m, 2H), 3.90 - 4.90 (m, 4H), 3.13 5 - 3.49 (m, 6H), 3.05 (s, 2H), 1.44 - 1.67 (m, 8H), 1.35 (s, 4H), 1.24 (s, 2H). LCMS: 619.47 [M+H] ⁺. Step-5: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-N-(6-(4-((7-ethyl-6-oxo-5,6-dihydro -1,5-naphthyridin-3-yl)methyl)piperazin-1- yl)hexyl)-2-fluorobenzamide To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- 10 thioxoimidazolidin-1-yl)-2-fluoro-N-(6-(piperazin-1-yl)hexyl )benzamide trifluoroacetate (Int-4, 280 mg, 0. 453 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 100 mg, 0.453 mmol, 1 eq.) in DMF (3 mL), K ₂CO ₃ (125 mg, 0.91 mmol, 2 eq.) was added. Progress of the reaction was monitored by TLC. The reaction mixture was allowed to stir at room temperature for 4h, diluted with ice cold water (75 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extract was washed with water (50 15 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude obtained was purified by prep. HPLC purification method eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford the title compound (37 mg, 12%). 1H NMR (400 MHz, DMSO-d ₆) δ 11.80 (s, 1H), 8.47 (t, J = 5.19 Hz, 1H), 8.40 (d, J = 8.25 Hz, 1H), 8.35 (d, J = 1.75 Hz, 1H), 8.29 (d, J = 1.75 Hz, 1H), 8.08 (dd, J = 8.19, 1.69 Hz, 1H), 7.71 - 7.75 (m, 2H), 20 7.57 (d, J = 1.25 Hz, 1H), 7.41 (dd, J = 10.51, 1.88 Hz, 1H), 7.32 (dd, J = 8.19, 1.81 Hz, 1H), 3.55 (s, 2H), 3.25 (d, J = 6.13 Hz, 2H), 2.53 (dd, J = 7.44, 0.94 Hz, 2H), 2.32 - 2.43 (m, 6H), 2.25 (t, J = 7.19 Hz, 2H), 1.49 - 1.56 (m, 9H), 1.38 - 1.44 (m, 2H), 1.27 - 1.34 (m, 5H), 1.17 (t, J = 7.44 Hz, 3H). LCMS: 805.5 [M+H] ⁺. HPLC purity 99.3%.

Example S8. Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-N-(6-(4-((7-ethyl-6-oxo-5,6-dihydro -1,5-naphthyridin-3-yl)methyl)piperazin- 1-yl)hexyl)-2-fluoro-N-methylbenzamide (Compound No.9) 5 Step-1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-(6-hydroxyhexyl)-N-methy lbenzamide (Int-1) To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Int-1, 800 mg, 1.77 mmol, 1 eq.) and the trifluoroacetate salt of 6-(methylamino)hexan-1-ol (Int-E, 651 mg, 2.66 mmol, 1.5 eq.) in DMF (6 mL), N,N- 10 diisopropylethylamine (0.92 mL, 5.31 mmol, 3 eq.) and HATU (1.34 g, 3.54 mmol, 2 eq.) were added at room temperature. The reaction mixture was allowed to stir at room temperature for 16h. Progress of the reaction was monitored by TLC. The reaction mixture was then diluted with ice cold water (75 mL) and extracted with ethyl acetate (2 x 75 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain Int-1 15 (1.28 g, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 8.40 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 7.83 Hz, 1H), 7.74 (t, J = 7.82 Hz, 1H), 7.42 (d, J = 9.78 Hz, 1H), 7.33 (d, J = 7.82 Hz, 1H), 4.24 - 4.42 (m, 2H), 3.39 - 3.52 (m, 1H), 3.10 - 3.28 (m, 1H), 2.94 - 3.02 (m, 1H), 2.68 (s, 3H), 1.54 (s, 6H), 1.20 - 1.45 (m, 8H). LCMS: 565.45 [M+H] ⁺. 20 Step-2: Preparation of N-(6-chlorohexyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5 ,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (Int-2) A solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2-thioxoimidazolidin-1- yl)-2-fluoro-N-(6-hydroxyhexyl)-N-methylbenzamide (Int-1, 1.0 g, 1.77 mmol, 1 eq.) in DCM (20 mL) was cooled to 0 °C followed by addition of thionyl chloride (SOCl ₂) dropwise (0.4 mL, 5.31 mmol, 3 eq.) and a catalytic amount of DMF (10 µL) and allowed to warm up to room temperature and stir for 16h. Progress of 5 the reaction was monitored by TLC/LCMS. After reaction completion, the volatiles were evaporated under reduced pressure to give the desired product Int-2 (680 mg, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 8.39 - 8.41 (d, J = 7.82 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 7.82 Hz, 1H), 7.66 - 7.80 (m, 1H), 7.42 (d, J = 9.29 Hz, 1H), 7.33 (d, J = 6.85 Hz, 1H), 3.59 - 3.69 (m, 1H), 3.44 - 3.58 (m, 1H), 2.68 (s, 3H), 1.67 - 1.79 (m, 2H), 1.54 (s, 6H), 1.28 - 1.47 (m, 4H), 1.05 - 1.27 (m, 4H). 10 LCMS: 583.35 [M+H] ⁺. Step-3: Preparation of tert-butyl 4-(6-(4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo-2- thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamido)hexyl)pi perazine-1-carboxylate (Int-3) To a solution of N-(6-chlorohexyl)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5 ,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (Int-2, 600 mg, 1.03 mmol, 1 eq.) in acetonitrile (10 15 mL), tert-butyl piperazine-1-carboxylate (SM-1, 287 mg, 1.54 mmol, 1.5 eq.), DIPEA (0.35 mL, 2.06 mmol, 2 eq.) and KI (170 mg, 1.03 mmol, 1 eq.) were added. The resulting mixture was stirred at 80 °C for 16h. Progress of the reaction was monitored by TLC. The reaction mixture was then diluted with ice cold water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced 20 pressure to obtain Int-3 (365 mg, crude). LCMS: 733.40 [M+H] ⁺. Step-4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-methyl-N-(6-(piperazin-1 -yl)hexyl)benzamide Trifluoroacetate (Int- 4) 25 A stirred solution of tert-butyl 4-(6-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl- 4-oxo- 2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamido)hexyl) piperazine-1-carboxylate (Int-3, 350 mg, 0.478 mmol, 1 eq.) in dichloromethane (10 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (1.0 mL). The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After complete consumption of Int-3, the volatiles were evaporated 30 and the crude obtained was triturated with diethyl ether (3 x 25 mL), filtered and dried under reduced pressure to provide Int-4 (395 mg, crude). NMR (400 MHz, DMSO-d ₆) δ 8.97 - 9.18 (m, 2H), 8.41 (d, J = 8.31 Hz, 1H), 8.28 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.75 (t, J = 8.07 Hz, 1H), 7.43 (d, J = 10.27 Hz, 1H), 7.33 (d, J = 7.83 Hz, 1H), 4.44 - 5.37 (m, 3H), 4.27 - 4.42 (m, 1H), 3.21 - 3.45 (m, 5H), 3.03 - 3.19 (m, 2H), 2.96 - 3.03 (m, 1H), 2.85-3.01 (m, 3H), 1.45 - 1.75 (m, 9H), 1.36 (s, 4H), 1.05 - 1.17 (m, 1H). LCMS: 633.4 [ . Step-5: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-N-(6-(4-((7-ethyl-6-oxo-5,6-dihydro -1,5-naphthyridin-3-yl)methyl)piperazin-1- 5 yl)hexyl)-2-fluoro-N-methylbenzamide To a stirred solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluoro-N-methyl-N-(6-(piperazin-1 -yl)hexyl)benzamide trifluoroacetate (Int-4, 350 mg, 0. 552 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 147 mg, 0.663 mmol, 1.2 eq.) in DMF (4 mL) was added K2CO3 (152 mg, 1.104 mmol, 2 eq.). Progress of the 10 reaction was monitored by TLC. The reaction mixture was then allowed to stir at room temperature for 6h, diluted with ice cold water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude obtained was purified by prep. HPLC eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford the title compound (111 mg, 24%). 15 ¹H NMR (400 MHz, DMSO-d6) į 11.80 (s, 1H), 8.48 (q, J = 5.34 Hz, 1H), 8.38 - 8.42 (m, 1H), 8.32 - 8.36 (m, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.25 Hz, 1H), 7.71 - 7.75 (m, 1H), 7.54 - 7.61 (m, 1H), 7.39 - 7.46 (m, 1H), 7.32 (d, J = 8.25 Hz, 1H), 3.52 - 3.57 (m, 2H), 3.48 (t, J = 7.19 Hz, 1H), 3.35 - 3.43 (m, 1H), 3.25 (d, J = 6.13 Hz, 1H), 3.13 (t, J = 7.00 Hz, 1H), 2.85-3.00 (d, 3H), 2.53 (d, J = 7.38 Hz, 2H), 2.38 (s, 4H), 2.21 - 2.29 (m, 2H), 1.47 - 1.57 (m, 8H), 1.38 - 1.46 (m, 2H), 1.32 (d, J = 3.00 Hz, 4H), 1.17 (t, = 7.44 Hz, 20 3H), 1.07 (d, J = 3.00 Hz, 2H). LCMS: 819.2 [M+H] ⁺. HPLC purity 99.7%. Example S9. Preparation of 4-(3-(4-(4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-3-flu orophenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (Compound No.10) Step-1: Preparation of tert-butyl 4-((1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl -4-oxo-2- thioxoimidazolidin-1-yl)-2-fluorobenzoyl)piperidin-4-yl)meth yl)piperazine-1-carboxylate (Int-1) To a stirred solution 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo- 2- thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (Int-D, 557 mg, 1.23 mmol, 0.7 eq.) and tert-butyl 4- 5 (piperidin-4-ylmethyl)piperazine-1-carboxylate (Int-G, 500 mg, 1.76 mmol, 1 eq.) in DMF (5 mL), N,N- diisopropylethylamine (0.61 mL, 3.52 mmol, 2 eq.) and HATU (802 mg, 2.11 mmol, 1.2 eq.) were added at room temperature. Progress of the reaction was monitored by TLC. The reaction mixture was allowed to stir at room temperature for 16h, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium 10 sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 5% MeOH in DCM to afford Int-1 (2.71 g, crude). 1H NMR (400 MHz, DMSO-d6) į 8.41 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.31 Hz, 1H), 7.59 (t, J = 7.58 Hz, 1H), 7.43 (d, J = 9.29 Hz, 1H), 7.30-7.38 (m, 1H), 4.51 (d, J = 12.72 Hz, 1H), 3.42 (d, J = 12.72 Hz, 1H), 3.35-3.26 (m, 4H), 3.13-3.05 (m, 1H), 2.86-2.78 (m, 2H), 2.26-2.31 (m, 4H), 2.18-2.14 (m, 15 2H), 1.85-1.69 (m, 2H), 1.64-1.91 (m, 2H), 1.55 (s, 6H), 1.41 (s, 9H). LCMS: 717.2 [M+H] ⁺. Step-2: Preparation of 4-(3-(3-fluoro-4-(4-(piperazin-1-ylmethyl)piperidine-1-carbo nyl)phenyl)-4,4- dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile trifluoroacetate (Int-2) A stirred solution of tert-butyl 4-((1-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl -4-oxo- 2-thioxoimidazolidin-1-yl)-2-fluorobenzoyl)piperidin-4-yl)me thyl)piperazine-1-carboxylate (Int-5, 500 mg, 20 0.698 mmol, 1 eq.) in dichloromethane (10 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (1.2 mL). Progress of the reaction was monitored by TLC. The reaction mixture was allowed to warm up to room temperature and stir for 16h and the volatiles were evaporated. The crude obtained was washed with diethyl ether (2 x 25 mL) to afford the TFA salt of Int-2 (520 mg, crude). 1H NMR (400 MHz, DMSO-d ₆) į 8.79 - 9.24 (m, 2H), 8.41 (d, J = 8.31 Hz, 1H), 8.29 (s, 1H), 8.02 - 25 8.11 (m, 1H), 7.59 (t, J = 7.58 Hz, 1H), 7.44 (d, J = 9.78 Hz, 1H), 7.34 (d, J = 8.31 Hz, 1H), 5.07 (s, 1H), 4.52 (d, J = 12.72 Hz, 1H), 3.57 (d, J = 4.40 Hz, 1H), 3.38 - 3.48 (m, 1H), 3.04 - 3.19 (m, 4H), 2.76 - 2.90 (m, 3H), 2.69 (s, 3H), 2.03 (s, 1H), 1.89 (d, J = 12.23 Hz, 1H), 1.73 (d, J = 11.25 Hz, 1H), 1.56 (s, 5H), 1.03 - 1.25 (m, 2H). LCMS: 617.56 [M+H] ⁺. Step-3: Preparation of 4-(3-(4-(4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-30 1-yl)methyl)piperidine-1-carbonyl)-3-fluorophenyl)-4,4-dimet hyl-5-oxo-2-thioxoimidazolidin-1-yl)-2- (trifluoromethyl)benzonitrile A stirred solution of 4-(3-(3-fluoro-4-(4-(piperazin-1-ylmethyl)piperidine-1-carbo nyl)phenyl)-4,4- dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl )benzonitrile trifluoroacetate (Int-2, 400 mg, 0.649 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 130 mg, 0.578 mmol, 0.7 eq.) in DMF (5 mL) was added K ₂CO ₃ (179 mg, 1.3 mmol, 2 eq.). Progress of the reaction was monitored by TLC. The reaction mixture was allowed to stir at room temperature for 16h, diluted with water (50 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with 5 water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by prep. HPLC eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford the title compound (135 mg, 26%). 1H NMR (400 MHz, DMSO-d6) į 11.81 (s, 1H), 8.40 (d, J = 8.13 Hz, 1H), 8.35 (d, J = 1.75 Hz, 1H), 8.29 (d, J = 1.75 Hz, 1H), 8.08 (dd, J = 8.25, 1.63 Hz, 1H), 7.73 (s, 1H), 7.55 - 7.61 (m, 2H), 7.42 (dd, 10 J = 9.88, 1.75 Hz, 1H), 7.32 (dd, J = 8.00, 1.75 Hz, 1H), 4.50 (d, J = 12.88 Hz, 1H), 3.55 (s, 2H), 3.41 (d, J = 13.01 Hz, 1H), 3.08 (t, J = 11.94 Hz, 1H), 2.77 - 2.85 (m, 1H), 2.52 - 2.57 (m, 2H), 2.38 (s, 7H), 2.15 (t, J = 6.25 Hz, 2H), 1.81 (d, J = 11.38 Hz, 2H), 1.64 - 1.74 (m, 1H), 1.55 (s, 6H), 1.17 (t, J = 7.44 Hz, 4H), 0.98 - 1.09 (m, 2H). LCMS: 803.3 [M+H] ⁺. Example S10. Preparation of 2-chloro-4-(3-(4-(4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naph thyridin-3-15 yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-4,4-d imethyl-5-oxo-2-thioxoimidazolidin-1- yl)benzonitrile (Compound No.3) Step-1: Preparation of (1-(4-nitrophenyl)piperidin-4-yl)methanol (Int-1) To a stirred solution of piperidin-4-ylmethanol hydrochloride (SM-1, 30 g, 197.8 mmol, 1.0 eq.) in 20 DMF (600 mL) and 1-fluoro-4-nitrobenzene (SM-2, 33.4 g, 237.4 mmol, 1.2 eq.), K2CO3 (81.9 g, 593.5 mmol, 3.0 eq.) was added at 0 °C under argon atmosphere. The resulting reaction mixture was allowed to stir at 90 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (1L) and the resulting precipitate was filtered, washed with water (500mL) and dried under vacuum to afford (1-(4-nitrophenyl)piperidin-4-yl)methanol (Int-1, 40 g, 87%). ¹H NMR (400 MHz, DMSO-d ₆) δ 8.02 (d, J = 9.65 Hz, 2H), 6.99 (d, J = 9.21 Hz, 2H), 4.50 (t, J = 5.26 Hz, 1H), 4.05 (d, J = 13.15 Hz, 2H), 3.27 (t, J = 5.48 Hz, 2H), 2.97 (t, J = 12.06 Hz, 2H), 1.62 - 1.78 (m, 3H), 1.10 - 1.22 (m, 2H). LCMS: 237.19 [M+H] ⁺. Step-2: Preparation of (1-(4-aminophenyl)piperidin-4-yl)methanol (Int-2) 5 To a stirred solution of (1-(4-nitrophenyl)piperidin-4-yl)methanol (Int-1, 10 g, 42.3 mmol, 1.0 eq.) in MeOH:EtOAc (1:1, 300 mL), 10% Pd/C (2 g, 20% w/w) was added at ambient temperature under argon atmosphere. The resulting reaction mixture was stirred at 100 psi under hydrogen atmosphere for 16h in an autoclave. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of celite, washed with MeOH (200 mL) and the filtrate was evaporated 10 under reduced pressure to afford (1-(4-aminophenyl)piperidin-4-yl)methanol (Int-2, 10 g, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 6.68 (d, J = 8.77 Hz, 2H), 6.47 (d, J = 8.33 Hz, 2H), 4.51 (br s, 2H), 4.43 (s, 1H), 3.28 - 3.34 (m, 4H), 2.44 (t, J = 11.62 Hz, 2H), 1.71 (d, J = 12.28 Hz, 2H), 1.40 (d, J = 4.82 Hz, 1H), 1.16 - 1.29 (m, 2H). LCMS: 207.14 [M+H] ⁺. Step-3: Preparation of ethyl 2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methy lpropanoate 15 (Int-3) o a stirred solution of (1-(4-aminophenyl)piperidin-4-yl)methanol (Int-2, 10 g, 48.54 mmol, 1.0 eq.) in DMF (200 mL), ethyl 2-bromo-2-methylpropanoate (SM-3, 11.35 g, 58.25 mmol, 1.2 eq.) and K2CO3 (20.09 g, 145.63 mmol, 3.0 eq.) were added at 0 °C under argon atmosphere. Progress of the reaction was monitored by TLC. The resulting reaction mixture was allowed to stir at 80 ^ for 16h, cooled down to room 20 temperature, diluted with water (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude obtained was purified with a flash column and the pure fractions were combined and concentrated under reduced pressure to provide ethyl 2-((4-(4- (hydroxymethyl)piperidin-1-yl)phenyl)amino)-2-methylpropanoa te (Int-3, 10 g, 64%). 25 ¹H NMR (400 MHz, DMSO-d ₆) į 6.71 (d, J = 8.33 Hz, 2H), 6.40 (d, J = 8.33 Hz, 2H), 5.28 (s, 1H), 4.43 (s, 1H), 4.05 (q, J = 6.58 Hz, 2H), 3.38 (d, J = 11.40 Hz, 2H), 3.28 (d, J = 5.26 Hz, 2H), 2.45 (t, J = 11.62 Hz, 2H), 1.71 (d, J = 11.84 Hz, 2H), 1.39 (s, 6H), 1.15 - 1.28 (m, 3H), 1.10 (t, J = 6.80 Hz, 3H). LCMS: 321.48 [M+H] ⁺. Step-4: Preparation of 2-chloro-4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4, 4-dimethyl-5-oxo- 30 2-thioxoimidazolidin-1-yl)benzonitrile (Int-4) To a stirred solution of ethyl 2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-2- methylpropanoate (Int-3, 30 g, 93.75 mmol, 1.0 eq.) in DMSO (120 mL), 2-chloro-4- isothiocyanatobenzonitrile (SM-4, 21.8 g, 112.5 mmol, 1.2 eq.) was added at 0 °C under argon atmosphere. Progress of the reaction was monitored by TLC. The resulting reaction mixture was allowed to stir at 80 °C for 4h, cooled down to room temperature and diluted with water (500 mL). The resulting precipitate was filtered, washed with water (500 mL) and diethyl ether (300 mL) and dried under vacuum to afford 2-chloro- 5 4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4,4-dimethy l-5-oxo-2-thioxoimidazolidin-1- yl)benzonitrile (Int-4, 35 g, 81%). 1H NMR (400 MHz, DMSO-d ₆) į 8.17 (d, J = 7.83 Hz, 1H), 8.01 (s, 1H), 7.71 (d, J = 7.34 Hz, 1H), 7.14 (d, J = 8.31 Hz, 2H), 7.03 (d, J = 8.31 Hz, 2H), 4.41 - 4.52 (m, 1H), 3.80 (d, J = 12.23 Hz, 2H), 3.26 - 3.29 (m, 2H), 2.72 (t, J = 11.74 Hz, 2H), 1.77 (d, J = 12.23 Hz, 2H), 1.46 (s, 6H), 1.14 - 1.31 (m, 3H). 10 LCMS: 469.47 [M+H] ⁺. Step-5: Preparation of (1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiox oimidazolidin-1- yl)phenyl)piperidin-4-yl)methyl methanesulfonate (Int-5) To a stirred solution of 2-chloro-4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4, 4-dimethyl-5- oxo-2-thioxoimidazolidin-1-yl)benzonitrile (Int-4, 10 g, 21.36 mmol, 1.0 eq.) in DCM (300 mL), MsCl 15 (1.81 mL, 23.5 mmol, 1.1 eq.), TEA (6 mL, 42.73 mmol, 2.0 eq.) were added at 0 °C under argon atmosphere. Progress of the reaction was monitored by TLC. The resulting reaction mixture was allowed to stir at RT for 1h, diluted with water (500 mL) and extracted with DCM (2 x 500mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiox oimidazolidin-1- 20 yl)phenyl)piperidin-4-yl)methyl methanesulfonate (Int-5, 11.7 g, crude). 1H NMR (400 MHz, CDCl ₃) į 7.75 - 7.84 (m, 1H), 7.68 (s, 1H), 7.52 (d, J = 8.33 Hz, 1H), 7.13 (d, J = 7.45 Hz, 2H), 6.99 (d, J = 7.45 Hz, 2H), 4.13 (d, = 5.26 Hz, 2H), 3.82 (d, J = 11.84 Hz, 2H), 3.03 (s, 3H), 2.77 - 2.94 (m, 2H), 1.91 (d, J = 13.15 Hz, 2H), 1.57 (s, 6H), 1.34 - 1.52 (m, 3H). LCMS: 547.46 [M+H] ⁺. 25 Step-6: Preparation of tert-butyl 4-((1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)methyl)piperaz ine-1-carboxylate (Int-6) To a stirred solution of (1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)methyl methanesulfonate (Int-5, 11.7 g, 21.48 mmol, 1.0 eq.) in acetonitrile (120 mL), tert-butyl piperazine-1-carboxylate (SM-5, 4 g, 21.48 mmol, 1.0 eq.), DIPEA (7.5 30 mL, 42.96 mmol, 2.0 eq.) and KI (350 mg, 2.14 mmol, 0.1 eq.) were added at 0 °C under argon atmosphere. Progress of the reaction was monitored by TLC. The resulting reaction mixture was allowed to stir at 80 °C for 16h, cooled down to room temperature, concentrated under reduce pressure, diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude obtained was purified with flash column and the pure fraction were combined and concentrated under reduced pressure to afford tert-butyl 4-((1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-th ioxoimidazolidin- 1-yl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Int-6, 10 g, 73%). 1H NMR (400 MHz, DMSO-d ₆) δ 8.17 (d, J = 8.29 Hz, 1H), 8.00 - 8.03 (m, 1H), 7.71 (dd, J = 8.35, 5 1.91 Hz, 1H), 7.10 (d, J = 8.81 Hz, 2H), 6.59 (d, J = 8.94 Hz, 2H), 3.46 (dd, J = 9.08, 7.63 Hz, 1H), 3.22 – 3.42 (m, 8H), 2.91 (t, J = 8.81 Hz, 1H), 2.24 - 2.39 (m, 6H), 1.54 - 1.70 (m, 3H), 1.45 (s, 6H), 1.39 (s, 9H). LCMS: 637.80 [M+H] ⁺. Step-7: Preparation of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(4-(4-(piperazin-1-ylmethyl )piperidin-1- yl)phenyl)-2-thioxoimidazolidin-1-yl)benzonitrile trifluoroacetate (Int-7) 10 To a stirred solution of tert-butyl 4-((1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)methyl)piperaz ine-1-carboxylate (Int-6, 5.2 g, 8.16 mmol, 1.0 eq.) in DCM (104 mL), TFA (26 mL, 5 vol) was added at 0 °C under argon atmosphere. Progress of the reaction was monitored by TLC. The resulting reaction mixture was stirred at RT for 16h, concentrated under reduced pressure, diluted with water (100 mL) and extracted with diethyl ether (2 x 100 mL). The 15 aqueous layer was basified with saturated bicarbonate solution (200 ml, pH ~8) and the resulting solid was filtered, washed with water (500 mL) and diethyl ether (300 mL) and dried under vacuum to afford 2-chloro- 4-(4,4-dimethyl-5-oxo-3-(4-(4-(piperazin-1-ylmethyl)piperidi n-1-yl)phenyl)-2-thioxoimidazolidin-1- yl)benzonitrile trifluoroacetate (Int-7, 4 g, 93%). 1H NMR (400 MHz, DMSO-d ₆) į 8.16 (d, J = 8.31 Hz, 1H), 8.01 (s, 1H), 7.71 (d, J = 8.31 Hz, 1H), 20 7.10 (d, J = 8.80 Hz, 2H), 6.59 (d, J = 8.31 Hz, 2H), 3.57 (s, 4H), 3.34 - 3.39 (m, 2H), 3.15 - 3.27 (m, 2H), 2.68 (s, 4H), 2.25 - 2.34 (m, 4H), 2.13 (d, J = 5.87 Hz, 2H), 1.55 - 1.70 (m, 2H), 1.45 (s, 6H). LCMS: 537.63 [M+H] ⁺. Step-8: Preparation of 2-chloro-4-(3-(4-(4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naph thyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-4,4-d imethyl-5-oxo-2-thioxoimidazolidin-1- 25 yl)benzonitrile To a stirred solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(4-(4-(piperazin-1-ylmethyl )piperidin-1- yl)phenyl)-2-thioxoimidazolidin-1-yl)benzonitrile trifluoroacetate (Int-7, 4 g, 7.46 mmol, 1.0 eq.) in DMF (40 mL), 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 1.4 g, 6.71 mmol, 0.9 eq.) and DIPEA (2.6 mL, 14.92 mmol, 2.0 eq.) were added at 0 °C under argon atmosphere. Progress of the reaction 30 was monitored by TLC. The resulting reaction mixture was stirred at ambient temperature for 16h, diluted with water (200 mL), the solid residue was filtered and washed with water (500 mL), diethyl ether (300 mL), acetonitrile (100 ml), DCM (200 mL) and dried under vacuum to afford 2-chloro-4-(3-(4-(4-((4-((7-ethyl-6- oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) methyl)piperidin-1-yl)phenyl)-4,4-dimethyl-5- oxo-2-thioxoimidazolidin-1-yl)benzonitrile (2.3 g, 42%). ¹H NMR (400 MHz, DMSO-d ₆) į 11.79 (s, 1H), 8.33 (s, 1H), 8.14 (d, J = 8.31 Hz, 1H), 7.99 (d, J = 1.47 Hz, 1H), 7.66 - 7.73 (m, 2H), 7.56 (s, 1H), 7.08 (d, J = 8.80 Hz, 2H), 6.57 (d, J = 8.80 Hz, 2H), 3.50 - 3.58 (m, 2H), 3.43 (t, J = 8.31 Hz, 1H), 3.31 - 3.36 (m, 1H), 3.19 - 3.26 (m, 2H), 2.88 (t, J = 8.56 Hz, 1H), 2.50 - 2.56 (m, 2H), 2.19 - 2.46 (m, 10H), 2.05 - 2.17 (m, 1H), 1.52 - 1.67 (m, 3H), 1.36 - 1.49 (m, 6H), 1.12 5 - 1.24 (m, 3H). LCMS: 723.3 [M+H] ⁺. Example S11. Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-((7-ethyl-6-oxo- 5,6-dihydro- 1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)hexyl)(methyl)am ino)phenyl)-13-methyl-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate formate (Compound No.14) 10 Step-1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-oxo hexyl)amino) phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate (Int-1) To a stirred solution of Int-F (500 mg, 0.891 mmol, 1 eq.) in ethyl acetate (40 mL) was added Dess- 15 Martin periodinane (DMP, 1.1 g, 2.67 mmol, 3 eq.) portion wise at 0 °C. The reaction mixture was heated to 80 °C for 2h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 50% aqueous Na2S2O3 solution (10 mL) and sat. NaHCO3 solution (15 mL) and the aqueous solution was extracted with ethyl acetate (2 x 25 mL). The combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum 20 to afford Int-1 (450 mg, 92%). 1H NMR (400 MHz, DMSO-d ₆) δ 9.64 (s, 1H), 6.98 (d, J = 8.31 Hz, 2H), 6.58 (d, J = 8.80 Hz, 2H), 5.67 (s, 1H), 4.39 (d, J = 5.87 Hz, 1H), 3.22 (t, J = 6.60 Hz, 2H), 2.55 - 2.80 (m, 5H), 2.51 – 2.54 (m, 2H), 2.40 (t, J = 7.09 Hz, 2H), 1.96 - 2.15 (m, 12H), 1.56-1.69 (m, 2H), 1.11 - 1.59 (m, 10H), 0.23 (s, 3H). LCMS: 560.4 [M+H] ⁺. 25 Step 2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-((7-ethyl-6-oxo- 5,6-dihydro-1,5- naphthyridin-3-yl)methyl)piperazin-1-yl)hexyl)(methyl)amino) phenyl)-13-methyl-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate formate ) To a solution of 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int-C, 0.5 g, 1.3 mmol, 1 eq.) in methanol (10 mL) were added (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-30 (methyl(6-oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14 ,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate (Int-1, 869 mg, 1.55 mmol, 1.2 eq.), triethylamine (0.18 mL, 1.29 mmol, 1 eq.) and acetic acid (0.7 mL) at room temperature and the mixture was allowed to stir for 2h. To this reaction mixture was added NaCNBH ₃ (160 mg, 2.59 mmol, 2 eq.) portion wise at 0 °C. The reaction mixture was warmed up to room temperature and allowed to stir for 16h. Progress of the reaction was 5 monitored by TLC. After completion of the reaction, cold water (50 mL) was added and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic extract was washed with water (60 mL), brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by prep. HPLC purification method eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford the formate salt of the title compound (100 mg, 9%). 10 ¹H NMR (400 MHz, DMSO-d6) į 11.81 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.61 (s, 1H), 6.92 (d, J = 8.31 Hz, 2H), 6.54 (d, J = 8.31 Hz, 2H), 5.65 (s, 1H), 4.33 (d, J = 6.36 Hz, 1H), 3.58 (s, 2H), 3.17 (s, 3H), 2.70 - 2.77 (m, 5H), 2.59 - 2.68 (m, 4H), 2.10 - 2.47 (m, 10H), 2.02 - 2.08 (m, 5H), 1.80 - 1.98 (m, 6H), 1.59 - 1.72 (m, 3H), 1.33 - 1.44 (m, 6H), 1.21 (s, 5H), 1.14 (t, J = 7.34 Hz, 3H), 0.17 (s, 3H). LCMS: 816.4 [M+H] ⁺. HPLC purity 92.1%. 15 Example S12. Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-((4-((7-ethyl-6- oxo-5,6- dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)methyl)p iperidin-1- yl)hexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11, 12,13,14,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate (Compound No.18) 20 Step-1: Preparation of tert-butyl 4-((1-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-m ethyl-3- oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a]phenanthren-11- yl)phenyl)(methyl)amino)hexyl)piperidin-4-yl)methyl)piperazi ne-1-carboxylate (Int-2) To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6- oxohexyl)amino)phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17- dodecahydro-1H-cyclopenta[a]phenanthren-25 17-yl acetate (Int-1, 100 mg, 0.35 mmol, 1.0 eq.) and tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1- carboxylate (Int-G, 240 mg, 0.42 mmol, 1.2 eq.) in methanol (5 mL) was added catalytic amount of acetic acid (0.5 mL) at room temperature and resulting mixture was allowed to stir for 4h. To this reaction mixture, NaCNBH ₃ (45 mg, 0.70 mmol, 2 eq.) was added portion wise at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. After 5 completion of the reaction, the reaction mixture was quenched with cold water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic extract was washed with water (30 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was triturated with n-pentane and diethyl ether to afford Int-2 (330 mg, 93%). 1H NMR (400 MHz, DMSO-d6) į 8.68 - 8.86 (m, 1H), 6.98 (d, J = 8.31 Hz, 2H), 6.59 (d, J = 7.82 10 Hz, 2H), 5.68 (s, 1H), 4.35-4.38 (m, 1H), 3.49 - 3.55 (m, 3H), 3.46 (d, J = 9.29 Hz, 1H), 3.35 - 3.42 (m, 6H), 3.14 - 3.26 (m, 4H), 2.91 - 3.13 (m, 3H), 2.67 - 2.90 (m, 8H), 2.55 - 2.66 (m, 3H), 2.19 - 2.43 (m, 6H), 2.04 - 1.83 (m, 21H), 1.16 - 1.52 (m, 9H), 0.29 - 0.55 (m, 3H). LCMS: 414.60 [M/2+H] ⁺. Step-2: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-(4- (piperazin-1- ylmethyl)piperidin-1-yl)hexyl)amino)phenyl)-3-oxo-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H- 15 cyclopenta[a]phenanthren-17-yl acetate trifluoroacetate (Int-3) A stirred solution tert-butyl 4-((1-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-m ethyl-3- oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a]phenanthren-11- yl)phenyl)(methyl)amino)hexyl)piperidin-4-yl)methyl)piperazi ne-1-carboxylate (Int-2, 220 mg, 0.26 mmol, 1 eq.) in dichloromethane (5 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (0.41 mL, 20 20 eq.). The reaction mixture was allowed to warm up to room temperature and stir for 2h. Progress of the reaction was monitored by TLC. After complete consumption of Int-2, the volatiles were evaporated under reduced pressure. The crude obtained was washed with n-heptane and diethyl ether to afford the TFA salt of Int-3 (500 mg, crude). 1H NMR (400 MHz, DMSO-d ₆) δ 8.68 - 8.99 (m, 2H), 7.68 - 7.73 (m, 1H), 7.48 (t, = 7.09 Hz, 25 1H), 7.24 (t, J = 6.85 Hz, 1H), 6.91 - 7.13 (m, 1H), 6.72 (s, 1H), 5.68 (s, 1H), 4.42 (d, J = 6.36 Hz, 1H), 3.49 (d, J = 10.76 Hz, 3H), 3.16 - 3.35 (m, 6H), 2.70 - 2.93 (m, 18H), 2.55 - 2.65 (m, 8H), 1.51-2.05 (m, 20H), 0.86 (t, J = 6.60 Hz, 3H). LCMS: 364.8 [M/2+H] ⁺. Step-3: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-((4-((7-ethyl-6- oxo-5,6-dihydro-1,5- naphthyridin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-y l)hexyl)(methyl)amino)phenyl)-13-methyl-3- 30 oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a]phenanthren-17-yl acetate A stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-(4- (piperazin-1- ylmethyl)piperidin-1-yl)hexyl)amino)phenyl)-3-oxo-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate trifluoroacetate (Int-3, 600 mg, 0.826 mmol, 1 eq.) and 7- (chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 130 mg, 0.578 mmol, 0.7 eq.) in acetonitrile (6 mL) was added DIPEA (0.58 mL, 3.30 mmol, 4 eq.) and the resulting reaction mixture was allowed to stir at room temperature for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, water (30 mL) was added and extracted with ethyl acetate (2 x 30 mL). The combined organic extract was 5 washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product obtained was purified by prep. HPLC eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford the title compound (45 mg, 7%). 1H NMR (400 MHz, DMSO-d ₆) δ 11.81 (s, 1H), 8.35 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 6.97 (d, J = 8.33 Hz, 2H), 6.58 (d, J = 8.33 Hz, 2H), 5.68 (s, 1H), 4.39 (d, J = 6.14 Hz, 1H), 3.56 (s, 2H), 3.24 (d, J = 10 7.02 Hz, 3H), 2.81 (s, 3H), 2.54 - 2.77 (m, 8H), 2.31 - 2.43 (m, 6H), 2.06 - 2.24 (m, 8H), 2.00 (s, 4H), 1.73 - 1.97 (m, 5H), 1.62 - 1.73 (m, 5H), 1.36 - 1.60 (m, 10H), 1.18 (t, J = 7.24 Hz, 9H), 0.20 - 0.26 (m, 3H). LCMS: 913.9 [M+H] ⁺. HPLC purity 95.1%. Example S13. Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-((4-((7-ethyl-6- oxo-5,6- dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)methyl)p iperidin-1-yl)-6-15 oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11, 12,13,14,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate (Compound No.16) Step-1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate (Int-1) 20 To a stirred solution of SM-1 (10 g, 21 mmol, 1.0 eq.) in methanol (150 mL) and THF (150 mL) were added KOAc (20.6 g, 210 mmol, 10 eq.) and iodine (13.1 g, 105 mmol, 5 eq.) at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 3h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with sodium thiosulfate (Na ₂S ₂O ₃) solution (50 g in 30 mL water) and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford Int-1 (8.0 g, 82%). 1H NMR (400 MHz, DMSO-d ₆) į 11.91 (br s, 1H), 6.91 (d, J = 8.31 Hz, 2H), 6.44 (d, J = 8.31 Hz, 5 2H), 5.67 (s, 1H), 4.37 (m, 1H), 2.75 (s, 2H), 2.61 (d, J = 4.40 Hz, 3H), 2.30 - 2.40 (m, 1H), 2.07 - 2.16 (s, 5H), 1.99 (s, 6H), 1.63 - 1.77 (m, 2H), 1.21 - 1.45 (m, 5H), 0.86 (t, J = 6.60 Hz, 1H), 0.16 - 0.28 (m, 3H). LCMS: 462.28 [M+H] ⁺. Step-2: Preparation of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3 -oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11- 10 yl)phenyl)(methyl)amino)hexanoic acid (Int-2) To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3- oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a]phenanthren-17-yl acetate (Int-1, 5 g, 10.83 mmol, 1.0 eq.) and 6-bromohexanoic acid (SM-2, 10.56 g, 54.13 mmol, 5 eq.) in ethanol (50 mL) and water (50 mL) was added NaHCO3 (7.37 g, 86.76 mmol, 10 eq.) at room temperature. The reaction mixture 15 was heated to 80 °C and stirred for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (120 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 80% ethyl acetate in heptane to afford Int-2 (0.90 g, 15%). 20 ¹H NMR (400 MHz, DMSO-d ₆) į 11.94 (br s, 1H), 6.98 (d, J = 7.83 Hz, 2H), 6.58 (d, J = 7.34 Hz, 2H), 5.67 (s, 1H),4.36 - 4.43 (m, 1H), 3.18 - 3.24 (m, 2H), 2.65 - 2.88 (m, 2H), 2.54 - 2.64 (m, 3H), 2.29 - 2.42 (m, 3H), 2.06 - 2.29 (m, 3H), 1.85 - 2.04 (m, 6H), 1.62 - 1.78 (m, 8H), 1.21 - 1.60 (m, 8H), 0.24 (s, 3H). LCMS: 576.67 [M+H] ⁺. Step-3: Preparation of tert-butyl 4-((1-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-m ethyl-3-25 oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta [a]phenanthren-11- yl)phenyl)(methyl)amino)hexanoyl)piperidin-4-yl)methyl)piper azine-1-carboxylate (Int-3) To a stirred solution of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3 -oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11- yl)phenyl)(methyl)amino)hexanoic acid (Int-2, 0.35 g, 0.61 mmol, 1 eq.) and tert-butyl 4-(piperidin-4-30 ylmethyl)piperazine-1-carboxylate (Int-G) in dichloromethane (10 mL) were added N,N- diisopropylethylamine (0.32 mL, 1.82 mmol, 3 eq.) and propylphosphonic anhydride (T3P, 0.45 mL 1.53 mmol, 2.5 eq.) at room temperature. Progress of the reaction was monitored by TLC. The reaction mixture was allowed to stir at room temperature for 16h, diluted with water (30 mL) and extracted with DCM (2 x 30 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by combiflash chromatography eluting with 70% ethyl acetate in heptane to afford Int-3 (0.25 g, 49%). 1H NMR (400 MHz, DMSO-d ₆) į 7.95 (s, 1H), 6.97 (d, = 8.31 Hz, 2H), 6.57 (d, J = 8.31 Hz, 2H), 5 5.66 (s, 1H), 4.28 - 4.41 (m, 1H), 3.93 - 4.17 (m, 1H), 3.59 - 3.84 (m, 4H), 3.28 (s, 6H), 3.21 (t, J = 6.85 Hz, 2H), 2.87 - 3.03 (m, 4H), 2.80 (s, 2H), 2.63 - 2.76 (m, 3H), 2.52 - 2.63 (m, 4H), 2.26 (s, 7H), 2.05 - 2.18 (m, 6H), 1.99 (s, 2H), 1.85 - 1.96 (m, 2H), 1.60 - 1.83 (m, 4H), 1.42 - 1.55 (m, 4H), 1.38 (s, 9H), 1.20 - 1.32 (m, 2H), 0.77 - 1.02 (m, 3H). LCMS: 841.07 [M+H] ⁺. Step-4: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-oxo -6-(4-(piperazin-1-10 ylmethyl)piperidin-1-yl)hexyl)amino)phenyl)-3-oxo-2,3,6,7,8, 11,12,13,14,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate trifluoroacetate (Int-4) A stirred solution of tert-butyl 4-((1-(6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-m ethyl- 3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopen ta[a]phenanthren-11- yl)phenyl)(methyl)amino)hexanoyl)piperidin-4-yl)methyl)piper azine-1-carboxylate (Int-3, 0.25 g, 0.30 15 mmol, 1 eq.) in dichloromethane (2 mL) was cooled to 0 °C followed by addition of trifluoroacetic acid (0.30 mL, 10 eq.). The reaction mixture was warmed to room temperature and stirred for 3h. Progress of the reaction was monitored by TLC. After complete consumption of the starting material, volatiles evaporated, and the crude obtained was triturated with diethyl ether to afford the TFA salt of Int-4 (0.25 g, crude). LCMS: 741.7 [M+H] ⁺. 20 Step-5: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-((4-((7-ethyl-6- oxo-5,6-dihydro-1,5- naphthyridin-3-yl)methyl)piperazin-1-yl)methyl)piperidin-1-y l)-6-oxohexyl)(methyl)amino)phenyl)-13- methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-c yclopenta[a]phenanthren-17-yl acetate To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methyl(6-oxo -6-(4- (piperazin-1-ylmethyl)piperidin-1-yl)hexyl)amino)phenyl)-3-o xo-2,3,6,7,8,11,12,13,14,15,16,17- 25 dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate trifluoroacetate (Int-4, 0.25 g, 0.34 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 0.75 mg, 0.34 mmol, 1 eq.) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.02 mmol, 3 eq.) at room temperature under inert atmosphere. The reaction mixture was stirred at 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted 30 with DCM (2 x 30 mL). The combined organic extract was washed with water (50 mL), brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by prep. HPLC eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford the title compound (30 mg, 9.6%). ¹H NMR (400 MHz, DMSO-d ₆) į 11.81 (s, 1H), 8.34 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 6.97 (d, J = 8.31 Hz, 2H), 6.57 (d, J = 8.31 Hz, 2H), 5.67 (s, 1H), 4.28 - 4.41 (m, 2H), 3.78 (d, J = 12.23 Hz, 1H), 3.55 (s, 2H), 3.21 (t, J = 7.09 Hz, 2H), 2.92 (t, J = 11.98 Hz, 1H), 2.80 (s, 3H), 2.63 - 2.77 (m, 2H), 2.61 (s, 1H), 2.53 (d, J = 7.83 Hz, 3H), 2.28 - 2.42 (m, 8H), 2.19 - 2.27 (m, 3H), 2.12 - 2.18 (m, 2H), 2.09 (s, 6H), 1.99 (s, 5 4H), 1.81 - 1.96 (m, 3H), 1.60 - 1.74 (m, 6H), 1.41 - 1.51 (m, 4H), 1.31 - 1.40 (m, 2H), 1.21 - 1.30 (m, 4H), 1.17 (t, J = 7.34 Hz, 3H), 0.77 - 0.99 (m, 3H). LCMS: 928.22 [M+H] ⁺. HPLC purity 99.8%. Example S14. Preparation of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3 -oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11- yl)phenyl)(methyl)amino)hexyl 4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- 10 yl)methyl)piperazine-1-carboxylate (Compound No.17) To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6- hydroxyhexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8 ,11,12,13,14,15,16,17-dodecahydro-1H- cyclopenta[a]phenanthren-17-yl acetate (Int-F, 500 mg, 0.89 mmol, 1 eq.) in dichloromethane (5 mL) was 15 added triethylamine (0.31 mL, 2.23 mmol, 2.5 eq.) and catalytic amount of DMAP (~1 mg, 0.025 eq.). The reaction mixture was cooled to 0 °C followed by addition of 4-nitrophenyl chloroformate (538 mg, 2.67 mmol, 3 eq.). The reaction mixture was warmed to room temperature and stirred for 2h. Progress of the reaction was monitored by TLC. After complete consumption of Int-F, an additional amount of triethylamine (0.1 mL, 0.89 mmol, 1 eq.) was added followed by 3-ethyl-7-(piperazin-1-ylmethyl)-1,5- 20 naphthyridin-2(1H)-one (Int-C, 367 mg, 1.33 mmol, 1.5 eq.) and the resulting reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, water (30 mL) was added, and the aqueous mixture was extracted with DCM (2 x 30 mL). The combined organic extract was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude obtained was purified by prep. HPLC 25 purification eluting with Mobile phase A: 0.1% FA in water and Mobile phase B: acetonitrile to afford Compound 17 (85 mg, 11%). 1H NMR (400 MHz, DMSO-d6) į 12.15 (s, 1H), 8.49 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.02 (d, J = 7.45 Hz, 2H), 6.57 - 6.74 (m, 2H), 5.68 (s, 1H), 4.41 (d, J = 6.14 Hz, 2H), 3.99 (t, J = 6.58 Hz, 4H), 3.21 - 3.29 (m, 3H), 2.91 - 3.18 (m, 4H), 2.84 (s, 3H), 2.57 (d, J = 7.02 Hz, 3H), 2.31 - 2.42 (m, 2H), 2.19 - 2.24 30 (m, 1H), 2.12 - 2.17 (m, 2H), 2.10 (s, 4H), 1.99 (s, 3H), 1.86 - 1.94 (m, 2H), 1.65 - 1.77 (m, 3H), 1.50 - 1.56 (m, 2H), 1.43 (d, J = 14.03 Hz, 4H), 1.26 (d, J = 17.98 Hz, 6H), 1.19 (t, J = 7.24 Hz, 5H), 0.22 (s, 3H). LCMS: 860.99 [M+H] ⁺. HPLC purity 95.7%. Example S15. Preparation of 3-ethyl-7-((4-((1-(6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13 -methyl-3- oxo-17-(prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodec ahydro-1H-cyclopenta[a]phenanthren-11- 5 yl)phenyl)(methyl)amino)hexyl)piperidin-4-yl)methyl)piperazi n-1-yl)methyl)-1,5-naphthyridin-2(1H)- one (Compound No.19) Step-1: Preparation of (8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-(4-(methylamino )phenyl)-17- (prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro- 3H-cyclopenta[a]phenanthren-3-one (Int- 10 1) To a stirred solution of (8S,11R,13S,14S,17S)-11-(4-(dimethylamino)phenyl)-17-hydroxy -13- methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-do decahydro-3H-cyclopenta[a]phenanthren-3- one (SM-1, 5 g, 11.63 mmol, 1.0 eq.) in MeOH:THF (1:1, 50 mL), KOAc (11.4 g, 111.6 mmol, 10.0 eq.) was added followed by a solution of I2 (8.8 g, 58.15 mmol, 3.0 eq.) in THF (25 mL) dropwise at 0 °C under 15 argon atmosphere and the resulting reaction mixture was allowed to stir at 0 °C for 1h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 5% sodium thiosulfate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (100 mL), brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was triturated with diethyl ether (2520 mL) and filtered to give (8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-(4-(methylamino )phenyl)-17- (prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro- 3H-cyclopenta[a]phenanthren-3-one (Int-1, 4 g, 82%). 1H NMR (400 MHz, DMSO-d6) į 6.99 (d, J = 7.82 Hz, 1H), 6.89 (d, J = 7.82 Hz, 1H), 6.75 (d, J = 7.82 Hz, 1H), 6.44 (d, J = 8.31 Hz, 1H), 5.64 (s, 1H), 5.41 (s, 1H), 4.18 - 4.40 (m, 1H), 2.83 - 2.92 (m, 2H), 25 2.69 - 2.80 (m, 3H), 2.52 - 2.66 (m, 2H), 2.28 - 2.45 (m, 2H), 2.04 - 2.27 (m, 3H), 1.90 - 2.04 (m, 2H), 1.72 - 1.90 (m, 3H), 1.59 (s, 2H), 1.19 - 1.37 (m, 2H), 1.09 (t, J = 6.85 Hz, 1H), 0.86 (t, J = 6.11 Hz, 1H), 0.42 (d, J = 2.93 Hz, 3H). LCMS: 416.62 [M+H] ⁺. Step-2: Preparation of (8S,11R,13S,14S,17S)-17-hydroxy-11-(4-((6- hydroxyhexyl)(methyl)amino)phenyl)-13-methyl-17-(prop-1-yn-1 -yl)-1,2,6,7,8,11,12,13,14,15,16,17- 5 dodecahydro-3H-cyclopenta[a]phenanthren-3-one (Int-2) To a stirred solution of (8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-(4-(methylamino )phenyl)- 17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahyd ro-3H-cyclopenta[a]phenanthren-3-one (Int- 1, 3 g, 7.22 mmol, 1.0 eq.) in EtOH:H2O (45 mL, 2:1) were added NaHCO3 (1.8 g, 21.65 mmol, 3.0 eq.) and 6-bromohexan-1-ol (4.72 mL, 36.09 mmol, 5.0 eq.) at room temperature. The reaction mixture was stirred at 10 80 °C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (100 mL), brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by silica gel flash column and the pure fractions were combined and concentrated under reduced pressure to afford 15 (8S,11R,13S,14S,17S)-17-hydroxy-11-(4-((6-hydroxyhexyl)(meth yl)amino)phenyl)-13-methyl-17-(prop-1- yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclo penta[a]phenanthren-3-one (Int-2, 1.4 g, 37%). 1H NMR (400 MHz, DMSO-d6) į 6.97 (d, J = 8.31 Hz, 2H), 6.60 (d, J = 8.80 Hz, 2H), 5.65 (s, 1H), 5.05 - 5.11 (m, 1H), 4.26 - 4.36 (m, 2H), 3.34 - 3.41 (m, 2H), 3.15 - 3.27 (m, 2H), 2.70 - 2.89 (m, 4H), 2.53 - 20 2.67 (m, 2H), 2.28 - 2.47 (m, 2H), 2.06 - 2.28 (m, 4H), 1.92 - 2.05 (m, 2H), 1.74 - 1.86 (m, 4H), 1.55 - 1.68 (m, 2H), 1.36 - 1.53 (m, 4H), 1.29 (d, J = 2.93 Hz, 6H), 0.36 - 0.46 (m, 3H). LCMS: 516.75 [M+H] ⁺. Step-3: Preparation of 6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(p rop-1-yn-1-yl)- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11- yl)phenyl)(methyl)amino)hexanal (Int-3) 25 To a solution of (8S,11R,13S,14S,17S)-17-hydroxy-11-(4-((6-hydroxyhexyl)(meth yl)amino)phenyl)- 13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17 -dodecahydro-3H-cyclopenta[a]phenanthren- 3-one (Int-2, 1.4 g, 2.71 mmol, 1.0 eq.) in EtOAc (14 mL) was added Dess–Martin periodinane (2.3 g, 5.43 mmol, 2.0 eq.) at room temperature and the reaction mixture was stirred at 80 °C under argon atmosphere for 1h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction 30 mixture was quenched with aq. sodium bicarbonate and aq. sodium thiosulfate solution (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (100 mL), brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(p rop-1-yn-1-yl)- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11- yl)phenyl)(methyl)amino)hexanal (Int-3, 1.6 g, crude). LCMS: 514.56 [M+H] ⁺. Step-4: Preparation of 3-ethyl-7-((4-((1-(6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13 -methyl-3-oxo-17- 5 (prop-1-yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro- 1H-cyclopenta[a]phenanthren-11- yl)phenyl)(methyl)amino)hexyl)piperidin-4-yl)methyl)piperazi n-1-yl)methyl)-1,5-naphthyridin-2(1H)- one To a solution of 6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(p rop-1-yn-1-yl)- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11-10 yl)phenyl)(methyl)amino)hexanal (Int-3, 1 g, 1.94 mmol, 1 eq.) in MeOH (10 mL), 3-ethyl-7-((4-(piperidin- 4-ylmethyl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one trifluoroacetate (Int-C1, 715 mg, 1.94 mmol, 1 eq.) and glacial acetic acid (0.1 mL) were added at room temperature and stirred for 2h. To this reaction mixture was added NaCNBH ₃ (609 mg, 9.7 mmol, 5 eq.) at 0 °C and the reaction mixture was allowed to warm up to room temperature and stir for 16h. Progress of the reaction was monitored by TLC. 15 After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layer was washed with water (100 mL), brine solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude obtained was purified by Prep.HPLC and the pure fractions were lyophilized to afford 3-ethyl-7-((4-((1-(6-((4- ((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1- yn-1-yl)-2,3,6,7,8,11,12,13,14,15,16,17-20 dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl )amino)hexyl)piperidin-4- yl)methyl)piperazin-1-yl)methyl)-1,5-naphthyridin-2(1H)-one (64 mg). 1H NMR (400 MHz, DMSO-d ₆) į 11.84 - 12.00 (m, 1H), 8.34 - 8.45 (m, 1H), 8.13 (s, 1H), 7.75 (s, 1H), 7.53 - 7.62 (m, 1H), 6.96 (d, J = 8.63 Hz, 2H), 6.52 (d, J = 8.63 Hz, 2H), 5.65 (s, 1H), 5.13 (s, 1H), 3.55 - 3.74 (m, 2H), 3.41 - 3.53 (m, 2H), 3.21 - 3.27 (m, 4H), 2.93 - 3.04 (m, 3H), 2.71 - 2.88 (m, 8H), 2.51 - 25 2.61 (m, 6H), 2.07 - 2.28 (m, 6H), 1.70 - 2.07 (m, 8H), 1.54 - 1.66 (m, 6H), 1.48 (s, 4H), 1.22 - 1.36 (m, 10H), 1.18 (t, J = 7.44 Hz, 2H), 0.41 (s, 3H). LCMS: 867.9 [M+H] ⁺. Example S16. Preparation of 3-ethyl-7-((4-(6-(((8S,13S,14S,17S)-13-methyl-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl)oxy)hexyl)piperazin- 1-yl)methyl)-1,5-naphthyridin-2(1H)-one (Compound No.21) 5 Step-1: Preparation of (8S,13S,14S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17- dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxola n]-17-ol (Int-1) To a stirred solution of (8S,13S,14S,17S)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14, 15,16,17- dodecahydro-3H-cyclopenta[a]phenanthren-3-one (SM-1, 1.0 g, 3.67 mmol, 1 eq.) in toluene (10 mL), PTSA (63 mg, 0.36 mmol, 0.1 eq.), ethylene glycol (SM-2, 1.12 mL, 18.35 mmol, 5 eq.) were added and 10 resulting reaction mixture allowed to stir at 100 °C for 3h. Progress of the reaction was monitored by TLC/LCMS. After completion of the reaction, the reaction was quenched with aqueous sat. NaHCO3 solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product obtained was purified by combiflash column chromatography eluting with 40% EtOAc in 15 heptane to afford Int-1 (600 mg, 52%). 1H NMR (400 MHz, DMSO-d6) į 5.47 - 5.53 (m, 1H), 4.55 (d, J = 3.29 Hz, 1H), 3.83 - 3.89 (m, 4H), 3.57 (t, J = 7.89 Hz, 1H), 2.31 - 2.44 (m, 1H), 2.16 (s, 2H), 2.03 - 2.12 (m, 3H), 1.72 - 1.94 (m, 4H), 1.59 - 1.71 (m, 4H), 1.34 - 1.45 (m, 1H), 1.00 - 1.10 (m, 3H), 0.62 (s, 3H). LCMS: 317.2 [M+H] ⁺. Step-2: Preparation of (8S,13S,14S,17S)-17-((6-chlorohexyl)oxy)-13-methyl-1,2,4,6,7 ,8,12,13,14,15,16,17- 20 dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxola ne] (Int-2) A stirred solution of (8S,13S,14S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17- dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxola n]-17-ol (Int-1, 1.0 g, 3.16 mmol, 1 eq.) and 1-bromo-6-chlorohexane (SM-3, 3.15 g, 15.82 mmol, 5 eq.) in DMF (10 mL) was cooled to 0 °C followed by addition of NaH (1.26 g, 31.6 mmol, 10 eq.). After complete addition, the reaction mixture was allowed to stir at 50 °C for 16h. Progress of the reaction was monitored by TLC/LCMS. The reaction mixture was then quenched with cold water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The crude obtained was purified by combiflash column chromatography eluting with 30% 5 EtOAc in heptane to afford Int-2 (640 mg, 46%). 1H NMR (400 MHz, DMSO-d ₆) į 5.47 (s, 1H), 3.86 (s, 4H), 3.37 - 3.45 (m, 2H), 3.28 (d, J = 4.25 Hz, 4H), 2.31 - 2.44 (m, 1H), 2.23 - 2.29 (m, 4H), 2.01 - 2.18 (m, 4H), 1.72 - 2.01 (m, 2H), 1.59 - 1.72 (m, 2H), 1.36 - 1.51 (m, 6H), 1.21 - 1.35 (m, 6H), 0.66 (s, 3H). LCMS: 435.55 [M+H] ⁺. Step-3: Preparation of tert-butyl 4-(6-(((8S,13S,14S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16 ,17-10 dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxola n]-17-yl)oxy)hexyl)piperazine-1- carboxylate (Int-3) To a stirred solution of (8S,13S,14S,17S)-17-((6-chlorohexyl)oxy)-13-methyl- 1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a] phenanthrene-3,2'-[1,3]dioxolane] (Int-2, 640 mg, 1.47 mmol, 1 eq.) in DMF (12 mL), N-Boc-piperazine (SM-6, 275 mg, 1.47 mmol, 1 eq.), Cs2CO3 (958 15 mg, 2.94 mmol, 2 eq.) and KI (122 mg, 0.735 mmol, 0.5 eq.) were added. The reaction mixture was allowed to stir at 80 °C for 16h. Progress of the reaction was monitored by TLC/LCMS. After completion of the reaction, the reaction mixture was diluted with ice cold water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (30 mL), brine (30 mL), dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The crude product was purified by combiflash column 20 chromatography eluting with 40% EtOAc in heptane to afford Int-3 (400 mg, 46%). 1H NMR (400 MHz, DMSO-d ₆) į 5.48 (s, 1H), 3.87 (s, 4H), 3.40 (t, J = 8.55 Hz, 2H), 3.23 - 3.30 (m, 6H), 2.22 - 2.28 (m, 6H), 2.00 - 2.21 (m, 8H), 1.61 - 1.71 (m, 3H), 1.39 - 1.51 (m, 8H), 1.38 (s, 9H), 1.21 - 1.35 (m, 6H), 0.66 (s, 3H). LCMS: 585.2 [M+H] ⁺. Step-4: Preparation of (8S,13S,14S,17S)-13-methyl-17-((6-(piperazin-1-yl)hexyl)oxy) - 25 1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]p henanthren-3-one trifluoroacetate (Int-4) To a stirred solution of tert-butyl 4-(6-(((8S,13S,14S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16 ,17- dodecahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxola n]-17-yl)oxy)hexyl)piperazine-1-carboxylate (Int-3, 400 mg, 0.684 mmol, 1.0 eq.) in DCM (5 mL) under nitrogen atmosphere, TFA (1.5 mL, 10 vol) was added at 0 °C. The reaction mixture was allowed to warm up to room temperature and stir for 4h. Progress 30 of the reaction was monitored by TLC. After completion of the reaction, the volatiles were evaporated under reduced pressure and the residue was triturated with diethyl ether (30 mL) to afford Int-4 (300 mg, 79%). ¹H NMR (400 MHz, DMSO-d ₆) į 8.98 - 9.40 (m, 2H), 5.58 (s, 1H), 3.96 - 5.28 (m, 2H), 3.31 - 3.42 (m, 5H), 2.92 - 3.14 (m, 4H), 2.86 (dt, J = 14.76, 5.19 Hz, 1H), 2.76 (dd, J = 16.01, 2.38 Hz, 1H), 1.67 – 2.48 (m, 12H), 1.19 – 1.65 (m, 14H), 0.83 (s, 3H). LCMS: 441.58 [M+H] ⁺. Step-5: Preparation of 3-ethyl-7-((4-(6-(((8S,13S,14S,17S)-13-methyl-3-oxo- 5 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl)oxy)hexyl)piperazin-1- yl)methyl)-1,5-naphthyridin-2(1H)-one To a stirred solution of (8S,13S,14S,17S)-13-methyl-17-((6-(piperazin-1-yl)hexyl)oxy) - 1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]p henanthren-3-one trifluoroacetate (Int-4, 200 mg, 0.453 mmol, 1 eq.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Int-B, 100 mg, 10 0.453 mmol, 1 eq.) in acetonitrile (2 mL), DIPEA (0.24 mL, 1.36 mmol, 3 eq.) and KI (37 mg, 0.22 mmol, 0.5 eq.) were added. The reaction mixture was allowed to stir at 80 °C for 4h. Progress of the reaction was monitored by TLC. After completion of the reaction, water (30 mL) was added, and the aqueous mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude 15 obtained was purified by combiflash column chromatography eluting with 17% MeOH in DCM to afford the title compound (45 mg, 20%). 1H NMR (400 MHz, DMSO-d ₆) δ 11.89 (s, 1H), 9.67 - 9.88 (m, 1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 5.57 (s, 1H), 3.57 - 3.70 (m, 2H), 3.36 - 3.48 (m, 3H), 3.26 - 3.30 (m, 1H), 2.85 (dt, J = 14.88, 5.19 Hz, 2H), 2.76 (dd, J = 16.07, 2.44 Hz, 1H), 2.52 - 2.58 (m, 2H), 2.40 - 2.47 (m, 3H), 2.34 - 2.40 (m, 2H), 20 2.27 - 2.34 (m, 3H), 2.23 (d, J = 11.13 Hz, 2H), 2.08 - 2.16 (m, 1H), 1.92 - 2.02 (m, 1H), 1.80 - 1.92 (m, 2H), 1.52 - 1.60 (m, 3H), 1.37 - 1.52 (m, 4H), 1.21 - 1.36 (m, 9H), 1.15 - 1.21 (m, 4H), 1.10 - 1.15 (m, 1H), 0.83 (s, 3H). LCMS: 627.94 [M+H] ⁺. HPLC purity 96.8%. Example S17. Preparation 2-chloro-4-(3-(4-(4-((4-((5-fluoro-2-methyl-3-oxo-3,4-dihydr oquinoxalin-6- yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-4,4-d imethyl-5-oxo-2-thioxoimidazolidin-1- 25 yl)benzonitrile (Compound No.22) ^

Step-1: Synthesis of (1-(4-nitrophenyl)piperidin-4-yl)methanol (Int-1) To a stirred solution of piperidin-4-ylmethanol. HCl (SM-1, 30 g, 197.8 mmol, 1.0 eq) in DMF (600 mL), 1-fluoro-4-nitrobenzene (SM-2, 33.4 g, 237.4 mmol, 1.2 eq), K ₂CO ₃ (81.9 g, 593.5 mmol, 3.0 eq) were 5 added at 0 ^oC under argon atmosphere. The resultant reaction mixture was stirred at 90 ^oC for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and diluted with water (1 L), filtered the obtained solids and washed with water (500mL), dried under vacuum to afford (1-(4-nitrophenyl)piperidin-4-yl)methanol (Int-1, 40 g, 87%) as a pale yellow solid. MS m/z calcd. For C ₁₂H ₁₆N ₂O ₃ ([M+H]+) 237.12; found 10 237.19. Step-2: Synthesis of (1-(4-aminophenyl) piperidin-4-yl) methanol (Int-2) To a stirred solution of (1-(4-nitrophenyl) piperidin-4-yl) methanol (Int-1, 10 g, 42.3 mmol, 1.0 eq) in MeOH:EtOAc (1:1, 300 mL), 10% Pd-C (2 g, 20% w/w) was added at ambient temperature under argon atmosphere. The resulting reaction mixture was stirred at 100PSI under Hydrogen atmosphere for 16 h 15 (Autoclave). Progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was filtered through celite bed and washed with MeOH (200 mL), filtrate was evaporated under reduced pressure to afford crude (1-(4-aminophenyl) piperidin-4-yl) methanol (Int- 2, 10 g, Crude) as a pale-yellow gummy. MS m/z calcd. For C ₁₂H ₁₈N ₂O ([M+H]+) 207.15; found 207.14. Step-3: Synthesis of ethyl 2-((4-(4-(hydroxymethyl) piperidin-1-yl)phenyl)amino)-2-20 methylpropanoate (Int-3)^ To a stirred solution of (1-(4-aminophenyl) piperidin-4-yl)methanol (Int-2, 10 g, 48.54 mmol, 1.0 eq) in DMF (200 mL), ethyl 2-bromo-2-methylpropanoate (SM-3, 11.35 g, 58.25 mmol, 1.2 eq), K ₂CO ₃ (20.09 g, 145.63 mmol, 3.0 eq) were added at 0 ^oC, under argon atmosphere. The resulting reaction mixture was stirred at 80 ^oC for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was cooled to room temperature and diluted with water (500 mL), extracted with ethyl acetate (2 x 500mL). The combined organic layer was washed with brine (200 mL), 5 dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to obtain crude compound, which was purified by flash column to obtain ethyl 2-((4-(4-(hydroxymethyl)piperidin-1- yl)phenyl)amino)-2-methylpropanoate (Int-3, 10 g, 64%) as a pale yellow solid. ESI MS m/z calcd. For C18H28N2O3 ([M+H]+) 321.21; found 321.48. Step-4: Synthesis of 2-chloro-4-(3-(4-(4-(hydroxymethyl) piperidin-1-yl)phenyl)-4,4-dimethyl-5-oxo-10 2-thioxoimidazolidin-1-yl)benzonitrile (Int-4)^ To a stirred solution of ethyl 2-((4-(4-(hydroxymethyl) piperidin-1-yl)phenyl)amino)-2-methylpropanoate (Int-3, 30 g, 93.75 mmol, 1.0 eq) in DMSO (120 mL), 2-chloro-4-isothiocyanatobenzonitrile (SM-4, 21.8 g, 112.5 mmol, 1.2 eq) was added at 0 ^oC under argon atmosphere. The resulting reaction mixture was stirred at 80 ^oC for 4 h. Progress of the reaction was monitored by TLC. After complete consumption of 15 starting material, the reaction mixture was cooled to room temperature and diluted with water (500 mL) and filtered the obtained solids, washed with water (500 mL) and diethyl ether (300 mL), dried under vacuum to afford 2-chloro-4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4, 4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)benzonitrile (Int-4, 35 g, 81%) as a pale yellow solid. ESI MS m/z calcd. For C24H25ClN4O2S ([M+H]+) 469.14; found 469.47. 20 Step-5: Synthesis of (1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiox oimidazolidin-1- yl) phenyl) piperidin-4-yl) methyl methane sulfonate (Int-5)^ To a stirred solution of 2-chloro-4-(3-(4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)-4, 4-dimethyl-5-oxo- 2-thioxoimidazolidin-1-yl)benzonitrile (Int-4, 10 g, 21.36 mmol, 1.0 eq) in DCM (300 mL), MsCl (1.81 mL, 23.5 mmol, 1.1 eq), TEA (6 mL, 42.73 mmol, 2.0 eq) were added at 0 ^oC under argon atmosphere. 25 The resulting reaction mixture was stirred at RT for 1 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was diluted with water (500 mL) and extracted with DCM (2 x 500mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulphate, filtered, evaporated under reduced pressure to afford crude (1-(4- (3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimida zolidin-1-yl)phenyl) piperidin-4- 30 yl)methyl methane sulfonate (Int-5, 11.7 g, Crude) as a yellow gummy semi-solid. ESI MS m/z calcd. For C25H27ClN4O4S2 ([M+H] +) 542.12; found 547.46. Step-6: Synthesis of tert-butyl 4-((1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl) phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (Int-6)^ To a stirred solution of (1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thiox oimidazolidin-1- 35 yl)phenyl) piperidin-4-yl)methyl methane sulfonate (Int-5, 11.7 g, 21.48 mmol, 1.0 eq) in Acetonitrile (120 mL), tert-butyl piperazine-1-carboxylate (SM-5, 4 g, 21.48 mmol, 1.0 eq), DIPEA (7.5 mL, 42.96 mmol, 2.0 eq) and KI (350 mg, 2.14 mmol, 0.1 eq) were added at 0 ^oC, under argon atmosphere. The resulting reaction mixture was stirred at 80 ^oC for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was cooled to room temperature 5 and evaporated under reduce pressure to obtain crude compound, which was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to obtain crude compound, which was purified by flash column to afford tert-butyl 4-((1-(4-(3-(3-chloro-4- cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)ph enyl)piperidin-4-yl)methyl) piperazine-1- 10 carboxylate (Int-6, 10 g, 73%) as an off white solid. ESI MS m/z calcd. For C33H41ClN6O3S ([M+H]+) 637.26; found 637.80. Step-7: Synthesis of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(4-(4-(piperazin-1-ylmethyl ) piperidin-1-yl) phenyl)-2-thioxoimidazolidin-1-yl) benzonitrile (Int-7)^^ To a stirred solution of tert-butyl 4-((1-(4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- 15 thioxoimidazolidin-1-yl)phenyl)piperidin-4-yl)methyl)piperaz ine-1-carboxylate (Int-6, 5.2 g, 8.16 mmol, 1.0 eq) in DCM (104 mL), TFA (26 mL, 5 vol) was added at 0 ^oC. under argon atmosphere. The resulting reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was evaporated under reduced pressure to obtain crude compound, which was diluted with water (100 mL) and washed with diethyl ether (2 X 20 100 mL), the aqueous layer was basified with saturated bicarbonate solution (200 ml, pH up to ~8) and filtered the obtained solid, washed with water (500 mL) and diethyl ether (300 mL), dried under vacuum to afford 2-chloro-4-(4,4-dimethyl-5-oxo-3-(4-(4-(piperazin-1-ylmethyl ) piperidin-1-yl) phenyl)-2- thioxoimidazolidin-1-yl) benzonitrile (Int-7, 4 g, 93%) as an off white solid. ESI MS m/z calcd. For C ₂₈H ₃₃ClN ₆OS ([M+H]+) 537.21; found 537.63. 25 Step-8: Synthesis of 2-chloro-4-(3-(4-(4-((4-((5-fluoro-2-methyl-3-oxo-3,4-dihydr oquinoxalin-6- yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-4,4-d imethyl-5-oxo-2-thioxoimidazolidin-1- yl)benzonitrile ^ To a stirred solution of 2-chloro-4-(4,4-dimethyl-5-oxo-3-(4-(4-(piperazin-1-ylmethyl )piperidin-1- yl)phenyl)-2-thioxoimidazolidin-1-yl)benzonitrile (Int-7, 0.15 g, 0.27 mmol) and 7-(bromomethyl)-8- 30 fluoro-3-methyl-1H-quinoxalin-2-one (Int-A3, 0.075 g, 0.27 mmol) in DMF (1.5 mL) was added DIPEA (0.097 mL, 0.55 mmol) and stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude compound, which was35 purified by prep-HPLC to afford 2-chloro-4-(3-(4-(4-((4-((5-fluoro-2-methyl-3-oxo-3,4- dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)methyl)piperidi n-1-yl)phenyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl)benzonitrile (Compound No.22, 33 mg, 16%) as an off-white solid. 1H NMR (400 MHz, DMSO-d ₆) į ppm 11.73 - 12.88 (br s, 1 H), 8.09 (d, J = 8.44 Hz, 1 H), 7.94 (d, J = 1.83 Hz, 1 H), 7.65 (dd, J = 8.31, 1.83 Hz, 1 H), 7.49 (d, J = 8.31 Hz, 1 H), 7.20 - 7.27 (m, 1 H), 7.07 (d, J = 5 8.80 Hz, 2 H), 6.55 (d, J = 9.05 Hz, 2 H), 3.61 (s, 2 H), 3.37 - 3.43 (m, 1 H), 3.13 - 3.23 (m, 2 H), 2.85 (t, J = 8.62 Hz, 1 H), 2.40 - 2.48 (m, 7 H), 2.39 (s, 3 H), 2.21 (dd, J = 8.19, 6.48 Hz, 1 H), 2.06 - 2.14 (m, 1 H), 1.58 (d, J = 6.36 Hz, 3 H), 1.41 (s, 6 H); ESI MS m/z calcd. For C ₃₈H ₄₀ClFN ₈O ₂S ([M+H]+) 727.2 found 727.2. Example S18. Preparation of 5-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3 -oxo-10 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-11- yl)phenyl)(methyl)amino)pentyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Compound No.23) ^ ^ Step-1: Synthesis of tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate To a stirred solution of 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int- 5 C, 1.0 g, 3.2 mmol, 1.0 eq) in methanol (20 mL) was added triethyl amine (323 mg, 3.5 mmol, 1.1 eq) at room temperature and stirred for 15 minutes. To this reaction mixture were added tert-butyl 4- formylpiperidine-1-carboxylate (SM-4, 760 mg, 3.5 mmol) and acetic acid (192 mg, 3.2 mmol, 1.0 eq) at room temperature and again stirred for 30 min at room temperature. To this reaction mixture was added NaCNBH3 (396 mg, 6.4 mmol, 2 eq) at 0 ^oC. The reaction mixture was allowed to room temperature and 10 stirred for 4 h. Progress of the reaction was monitored by TLC. After complete consumption of starting materials, solvents were evaporated under reduced pressure to obtain crude compound, which was triturated with diethyl ether (50 mL) and dried under vacuum to afford tert-butyl 4-((4-((7-ethyl-6-oxo- 5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)meth yl)piperidine-1-carboxylate (1.1 g, crude) as a colourless liquid which was used in next step without any further purification. ESI MS m/z calcd. For 15 C26H39N5O3 ([M+H] ⁺) 470.3; found 470.2. Step-2: Synthesis of 3-ethyl-7-((4-(piperidin-4-ylmethyl) piperazin-1-yl) methyl)-1,5-naphthyridin- 2(1H)-one hydrochloride salt To a stirred solution of tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (1.1 g, 2.3 mmol, 1.0 eq) in 1,4-dioaxne (10 20 mL) was added 4M HCl in 1,4-dioxane (3.5 mL, 3.0 eq) at 0 ^oC. The resultant reaction mixture was allowed to room temperature and stirred for 12 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the solvents were removed under reduced pressure to get crude compound, which was washed with diethyl ether (3 X 15 mL) and dried under vacuum to afford 3- ethyl-7-((4-(piperidin-4-ylmethyl) piperazin-1-yl) methyl)-1,5-naphthyridin-2(1H)-one hydrochloride salt 25 (900 mg, 94%) as an off white solid. ESI MS m/z calcd. For C ₂₁H ₃₂ClN ₅O ([M+H] ⁺) 370.2; found 370.4. Step-3: Synthesis of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-(dimethylamino)phenyl)- 13-methyl-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]p henanthren-17-yl acetate (SM-5, 10 g, 21 30 mmol, 1.0 eq) in methanol (150 mL) and THF (150 mL) were added KOAc (20.6 g, 210 mmol, 10 eq) and Iodine (13.1 g, 105 mmol, 5 eq) at 0 ^oC. The resultant reaction mixture was allowed to room temperature and stirred for 3 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was quenched with sodium thiosulfate (Na2S2O3) solution (50 g in 30 mL water) and extracted with ethyl acetate (2 X 200 mL). The combined organic extracts were washed with 35 brine (100 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo- 2,3,6,7,8,11,12,13,14, 15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (8.0 g, 82%) as an off-white solid, which was used in next step without any further purification. ESI MS m/z calcd. For C ₂₉H ₃₅NO ₄ ([M+H] ⁺) 462.26; found 462.28. 5 Step-4: Synthesis of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-hydroxyhexyl)(methy l)amino) phenyl)- 13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1 H-cyclopenta[a] phenanthren-17-yl acetate To a solution of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo- 2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a] phenanthren-17-yl acetate (4 g, 8.67 mmol, 10 1.0 eq) and 6-bromohexan-1-ol (SM-6, 7.81 g, 43.38 mmol, 5 eq) in ethanol (40 mL) and water (40 mL) was added NaHCO3 (7.37 g, 86.76 mmol, 10 eq) at room temperature. The resultant reaction mixture was heated to 80 ^oC and stirred for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was filtered through a pad of celite bed and washed with ethyl acetate (40 mL). Filtrate was concentrated under reduced pressure to obtain crude material, which was 15 diluted with water (120 mL) and extracted with ethyl acetate (2 X 200 mL). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude compound. Which was purified by Combiflash chromatography by eluting with 70% ethyl acetate in heptane to afford (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6- hydroxyhexyl)(methyl)amino) phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodec ahydro-1H- 20 cyclopenta[a] phenanthren-17-yl acetate (2.6 g, 53%) as an off-white solid. ESI MS m/z calcd. For C ₃₅H ₄₇NO ₅ ([M+H] ⁺) 562.35; found 562.40. Step-5: Synthesis of [(8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-[4-[methyl-[5-( 4- nitrophenoxy)carbonyloxypentyl]amino]phenyl]-3-oxo-1,2,6,7,8 ,11,12,14,15,16- decahydrocyclopenta[a]phenanthren-17-yl] acetate 25 To a stirred solution of [(8S,11R,13S,14S,17R)-17-acetyl-11-[4-[5-hydroxypentyl(methy l) amino]phenyl]- 13-methyl-3-oxo-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta [a] phenanthrene-17-yl] acetate (200 mg, 0.365 mmol, 1 eq) in DCM (10 mL) was added 4-nitrophenylchloroformate (SM-7, 114 mg, 0.547 mmol, 1.5 eq), DMAP (9 mg, 0.073 mmol, 0.2 eq) and triethyl amine (0.25 mL, 1.82 mmol, 5 eq) at 0 ⁰C. The resultant reaction mixture was allowed to stir at room temperature for 4 h. Progress of the reaction was 30 monitored by TLC and LCMS. After complete consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product, which was triturated with diethyl ether twice (2 x 20 mL) to afford [(8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-[4-[methyl-[5-( 4-nitrophenoxy) 35 carbonyloxypentyl]amino]phenyl]-3-oxo-1,2,6,7,8,11,12,14,15, 16-decahydrocyclopenta[a] phenanthren-17- yl] acetate (100 mg, 38% yield) as a light yellow colour solid. ESI MS m/z calcd. For C ₄₁H ₄₈N ₂O ₉ ([M+2) 712.8; found 713.1.^ Step-6: Synthesis of 5-[4-[(8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3- oxo- 1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-1 1-yl]-N-methyl-anilino]pentyl 4-[[4-[(7- 5 ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]m ethyl]piperidine-1-carboxylate To a stirred solution of [(8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-[4-[methyl-[5-( 4- nitrophenoxy)carbonyloxypentyl]amino]phenyl]-3-oxo-1,2,6,7,8 , 11,12,14,15,16- decahydrocyclopenta[a]phenanthren-17-yl] acetate (100 mg, 0.140 mmol, 1 eq) in dichloromethane (15 mL) was added 3-ethyl-7-[[4-(4-piperidylmethyl) piperazin-1-yl]methyl]-1H-1,5-naphthyridin-2- 10 one,hydrochloride (77 mg, 0.21 mmol, 1.5 eq), and DIPEA (0.12 mL, 0.701 mmol, 5 eq). The resultant reaction mixture was allowed to stir at room temperature for 16 h. Progress of the reaction was monitored by TLC and LCMS. After complete consumption of starting material, the reaction was diluted with water (20 mL) and extracted with 5% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude compound, which15 was purified by combiflash column chromatography and product was eluted in 100% ethyl acetate to get 5- [4-[(8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-ox o-1,2,6,7,8,11,12,14,15,16- decahydrocyclopenta[a]phenanthren-11-yl]-N-methyl-anilino]pe ntyl 4-[[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]methyl]piperidine-1- carboxylate (57 mg, 43%) as an off-white solid. 20 ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 11.82 (br s, 1 H) 8.35 (br s, 1 H) 7.74 (s, 1 H) 7.57 (s, 1 H) 6.97 (br d, J=8.63 Hz, 2 H) 6.51 - 6.60 (m, 2 H) 5.67 (s, 1 H) 4.39 (br d, J=7.00 Hz, 1 H) 3.82 - 4.01 (m, 4 H) 3.56 (br s, 2 H) 3.23 (br t, J=7.25 Hz, 2 H) 2.81 (s, 3 H) 2.64 - 2.77 (m, 4 H) 2.54 (br s, 4 H) 2.32 - 2.42 (m, 6 H) 2.05 - 2.24 (m, 9 H) 1.85 - 2.02 (m, 6 H) 1.60 - 1.77 (m, 5 H) 1.41 - 1.59 (m, 5 H) 1.22 - 1.39 (m, 5 H) 1.17 (t, J=7.38 Hz, 3 H) 0.57 - 0.97 (m, 3 H) 0.23 (s, 3 H) LCMS: 95.82 %; ESI MS m/z calcd. For 25 C ₅₆H ₇₄F ₃N ₆O ₇ ([M+H] +) 943.2; found 944.4 HPLC: 95.02 % Example S19. Preparation of N-((1r,4r)-4-((6-cyano-5-(trifluoromethyl)pyridin-3- yl)(methyl)amino)cyclohexyl)-6-(4-((4-((7-ethyl-6-oxo-5,6-di hydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3- carboxamide (Compound No.24) ^

Step-1: Synthesis of tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate To a stirred solution of 3-ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one hydrochloride (Int- 5 C, 1.0 g, 3.2 mmol, 1.0 eq) in methanol (20 mL) was added triethyl amine (323 mg, 3.5 mmol, 1.1 eq) at room temperature and stirred for 15 minutes. To this reaction mixture were added tert-butyl 4- formylpiperidine-1-carboxylate (SM-4, 760 mg, 3.5 mmol) and acetic acid (192 mg, 3.2 mmol, 1.0 eq) at room temperature and again stirred for 30 min at room temperature. To this reaction mixture was added NaCNBH3 (396 mg, 6.4 mmol, 2 eq) at 0 ^oC. The reaction mixture was allowed to room temperature and 10 stirred for 4 h. Progress of the reaction was monitored by TLC. After complete consumption of starting materials, solvents were evaporated under reduced pressure to obtain crude compound, which was triturated with diethyl ether (50 mL) and dried under vacuum to afford tert-butyl 4-((4-((7-ethyl-6-oxo- 5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)meth yl)piperidine-1-carboxylate (1.1 g, crude) as a colourless liquid which was used in next step without any further purification. ESI MS m/z calcd. For 15 C26H39N5O3 ([M+H] ⁺) 470.3; found 470.2. Step-2: Synthesis of 3-ethyl-7-((4-(piperidin-4-ylmethyl) piperazin-1-yl) methyl)-1,5-naphthyridin- 2(1H)-one hydrochloride salt To a stirred solution of tert-butyl 4-((4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (1.1 g, 2.3 mmol, 1.0 eq) in 1,4-dioaxne (10 mL) was added 4M HCl in 1,4-dioxane (3.5 mL, 3.0 eq) at 0 ^oC. The resultant reaction mixture was allowed to room temperature and stirred for 12 h. Progress of the reaction was monitored by TLC. After 5 complete consumption of starting material, the solvents were removed under reduced pressure to get crude compound, which was washed with diethyl ether (3 X 15 mL) and dried under vacuum to afford 3- ethyl-7-((4-(piperidin-4-ylmethyl) piperazin-1-yl) methyl)-1,5-naphthyridin-2(1H)-one hydrochloride salt (900 mg, 94%) as an off white solid. ESI MS m/z calcd. For C ₂₁H ₃₂ClN ₅O ([M+H] ⁺) 370.2; found 370.4. Step-3: Synthesis of tert-butyl N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]amino] 10 cyclohexyl]carbamate To a stirred solution of 4-amino-2-(trifluoromethyl)benzonitrile (SM-5, 1 g, 5.372 mmol, 1.0 eq) in DMF (30 mL) were added tert-butyl N-(4-oxocyclohexyl)carbamate (SM-6, 1.37 g, 6.447 mmol, 1.2 eq) and chlorotrimethylsilane (1.71 mL, 13.431 mmol, 2.5 eq) at 0 ^oC . The resultant reaction mixture was stirred for 10 min at 0 ^oC, followed by drop wise addition of BORANE-THF complex (1 mol/L) in THF (5.37 mL, 15 5.3726 mmol, 1 eq). The resultant reaction mixture was stirred at 0 ^oC for 2 h, allowed to room temperature and stirred at room temperature for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting materials, the reaction mixture was diluted with ice cold water (20 mL), saturated Na ₂CO ₃ solution and extracted with ethyl acetate (2 * 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over anhydrous sodium sulphate, filtered and 20 concentrated under reduced pressure to obtain crude compound, which was purified by reverse phase column by eluting with 0.1 % HCOOH in water, ACN to afford tert-butyl N-[4-[[6-cyano-5- (trifluoromethyl)-3-pyridyl]amino]cyclohexyl]carbamate (350 mg, 78% yield) as an off white solid. ESI MS m/z calcd. For C ₁₈H ₂₃F ₃N ₄O ₂ ([M-H] +) 384.3; found 383.2. Step-4: Synthesis of tert-butyl N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methyl- 25 amino]cyclohexyl]carbamate To a stirred solution of tert-butyl N-[4-[[6-cyano-5-(trifluoromethyl)-3- pyridyl]amino]cyclohexyl]carbamate (300 mg, 0.780 mmol, 1.0 eq) in DMF (15 mL) under nitrogen atmosphere was added 63% of NaH (21 mg, 0.780 mmol, 1.0 eq) portion wise at 0 ^oC. The reaction mixture was allowed to room temperature and stirred for 30 min then added methyl iodide (0.05 mL, 30 0.780 mmol, 1.0 eq) drop wise at 0 ^oC. The reaction mixture was allowed to room temperature and stirred for 3h. Progress of the reaction was monitored by TLC. After completion of the reaction, cold water (10 mL) was added and extracted with ethyl acetate (2 X 20 mL). Solvents were evaporated under reduced pressure to get crude compound which was purified by combiflash column by eluting with 15% ethyl acetate in heptane in to afford tert-butyl N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methyl- 35 amino]cyclohexyl]carbamate (180 mg, 58% yield) as an off white solid. ESI MS m/z calcd. For C ₁₉H ₂₅F ₃N ₄O ₂ ([M-H] +) 398.4; found 399.2. Step-5: Synthesis of 5-[(4-aminocyclohexyl)-methyl-amino]-3-(trifluoromethyl)pyri dine-2- carbonitrile;hydrochloride. HCl salt To a stirred solution of tert-butyl N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methyl- amino]cyclohexyl]carbamate (300 mg, 0.753 mmol, 1.0 eq) in DCM (10 mL) under nitrogen atmosphere 5 was added 4M hydrochloric acid (4 mol/L) in 1,4-dioxane (0.5 ml, 7.53 mmol, 4 mol/L, 10 eq) at 0 ^oC. The resultant reaction mixture was allowed to stir at room temperature for 16h. Progress of the reaction was monitored by TLC. After complete consumption of starting material, solvents were evaporated under reduced pressure to obtain crude material, which was washed with diethyl ether (20 mL) and dried under vacuum to afford 5-[(4-aminocyclohexyl)-methyl-amino]-3-(trifluoromethyl) pyridine-2-carbonitrile 10 hydrochloride salt (250 mg, crude) as an off white solid. ESI MS m/z calcd. For C ₁₄H ₁₇F ₃N ₄.ClH ([M-H] +) 334.7; found 334.8. Step-6: Synthesis of 6-chloro-N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methy l- amino]cyclohexyl]pyridazine-3-carboxamide To a stirred solution of 5-[(4-aminocyclohexyl)-methyl-amino]-3-(trifluoromethyl)pyri dine-2- 15 carbonitrile;hydrochloride. HCl salt (450 mg, 1.344 mmol, 1.0 eq) and 6-chloropyridazine-3-carboxylic acid (SM-7, 213 mg, 1.344 mmol, 1.0 eq) in DMF (15 mL) were added T3P (50% in ethylacetate) (0.85 mL, 2.688 mmol, 2.0 eq) and DIPEA (0.7 mL, 4.032 mmol, 3.0 eq) at room temperature and stirred for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting materials the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2 X 30 mL). The 20 combined organic extracts were washed with water (30 mL), brine (50 mL) and dried over anhydrous sodium sulphate. Filtered and concentrated under reduced pressure to obtain crude compound which was purified by combiflash column by eluting with 0-50% ethyl acetate in heptane to afford 6-chloro-N-[4- [[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methyl-amino]cycloh exyl] pyridazine-3-carboxamide (150 mg, 2 ^{5%) as an off white solid.ESI MS m/z calcd. For C} ₁₉ ^H ₁₈ ^ClF ₃ ^N ₆ ^{O ([M-H] +) 438.8; found 439.31.} 25 Step-15: Synthesis of N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methyl-amino]c yclohexyl]-6-[4-[[4- [(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1- yl]methyl]-1-piperidyl]pyridazine-3- carboxamide To a stirred solution of 6-chloro-N-[4-[[6-cyano-5-(trifluoro methyl)-3-pyridyl]-methyl- amino]cyclohexyl]pyridazine-3-carboxamide (140 mg, 0.319 mmol, 1.0 eq) in acetonitrile (10 mL) was 30 added 3-ethyl-7-[[4-(4-piperidylmethyl) piperazin-1-yl]methyl]-1H-1,5-naphthyridin-2-one (153 mg, 0.414 mmol, 1.3 eq) and K ₂CO ₃ (132 mg, 0.957 mmol, 3.0 eq) at room temperature. The reaction mixture was heated to 90 ^oC and stirred for 16 h. Progress of the reaction was monitored by TLC. After complete consumption of starting material the reaction was cooled to room temperature and diluted with cold water (20 mL), extracted with ethyl acetate (2 X 30 mL). The combined organic layer was washed with water (30 35 mL), brine (30 mL) and dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to obtain crude compound, which was purified by combi-flash column by eluting with 3-5% methanol in dichloromethane to afford N-[4-[[6-cyano-5-(trifluoromethyl)-3-pyridyl]-methyl- amino]cyclohexyl]-6-[4-[[4-[(7-ethyl-6-oxo-5H-1,5-naphthyrid in-3-yl)methyl]piperazin-1-yl]methyl]-1- piperidyl]pyridazine-3-carboxamide (Compound No.24, 100 mg, 40% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d ₆^^į^SSP 11.82 (s, 1 H), 8.52 (d, J=2.75 Hz, 1 H), 8.46 (d, J=7.38 Hz, 1 H), 5 8.36 (d, J=1.75 Hz, 1 H), 7.80 (d, J=9.63 Hz, 1 H), 7.74 (s, 1 H), 7.58 (d, J=1.13 Hz, 1 H), 7.42 (d, J=2.63 Hz, 1 H), 7.33 (d, J=9.76 Hz, 1 H), 4.47 (br d, J=13.26 Hz, 2 H), 4.15 - 4.21 (m, 1 H), 4.07 (br d, J=1.25 Hz, 1 H), 3.57 (s, 2 H), 2.94 - 3.08 (m, 5 H), 2.52 - 2.58 (m, 3 H), 2.40 (br d, J=1.63 Hz, 6 H), 2.14 (br d, J=6.88 Hz, 2 H), 1.75 - 1.98 (m, 10 H), 1.56 (br d, J=8.38 Hz, 2 H), 1.16 - 1.24 (m, 3 H), 1.09 (br d, J=10.01 Hz, 2 H); LCMS: 97.51 %; ESI MS m/z calcd. For C ₄₀H ₄₈F ₃N ₁₁O ₂ ([M+H] +) 772.8; found 772.4 HPLC: 96.64 % 10 Compound Nos.8, 11, 13, 15, and 20 were prepared similarly. Compound No.8 1H NMR (400 MHz, DMSO-d6)δ11.84(s,1H),8.34- 8.43 (m, 2H), 8.29 (s, 1H), 8.08 (d, J = 7.83 Hz, 1H), 7.74 (s, 1H), 7.58 (d, J = 6.85 Hz, 2H), 7.43 (d, J = 9.78 Hz, 1H), 7.33 (d, J = 4.40 Hz, 1H), 3.58 (d, J = 8.31 Hz, 2H), 3.37 - 3.51 (m, 5H), 3.14 (br s, 1H), 3.00 (s, 2H), 2.85 (s, 2H), 2.54 (s, 1H), 2.27 - 2.41 15 (m, 5H), 2.16 - 2.22 (m, 1H), 1.43 - 1.65 (m, 9H), 1.31 (d, J = 5.87 Hz, 2H), 1.17 (t, J = 7.34 Hz, 3H), 1.09 (d, J = 5.87 Hz, 1H); LCMS: 832.8 [ purity 96.8%. Compound No.11 (400 MHz, DMSO-d6) δ12.35- 12.46 (m, 1H), 8.46 (d, J = 8.38 Hz, 1H), 7.79 (d, J = 9.51 Hz, 1H), 7.60 (d, J = 9.01 Hz, 1H), 7.49 (d, J = 8.25 Hz, 1H), 7.31 (d, J = 9.76 Hz, 1H), 7.24 (t, J = 20 7.69 Hz, 1H), 6.94 (d, J = 2.25 Hz, 1H), 6.82 (dd, J = 9.13, 2.38 Hz, 1H), 4.45 (d, J = 13.13 Hz, 2H), 3.72 - 3.91 (m, 2H), 3.61 (s, 2H), 2.98 (t, J = 11.94 Hz, 2H), 2.85 (s, 4H), 2.32 - 2.47 (m, 9H), 2.12 (d, J = 6.88 Hz, 2H), 1.91 (d, J = 9.51 Hz, 2H), 1.59 - 1.82 (m, 9H), 1.01 - 1.14 (m, 3H). LCMS: 740.9 [M+H] ⁺. Compound No.13 1H NMR (400 MHz, DMSO-d ₆)δ12.43(s,1H),8.58(d,J = 8.25 Hz, 1H), 7.79 (dd, J = 16.26, 25 9.13 Hz, 2H), 7.51 (d, J = 8.25 Hz, 1H), 7.34 (d, J = 9.63 Hz, 1H), 7.23 - 7.29 (m, 2H), 4.43 - 4.55 (m, 3H), 3.82 - 3.94 (m, 1H), 3.66 (s, 2H), 3.42 - 3.59 (m, 4H), 3.09 (t, J = 11.76 Hz, 2H), 2.95 - 3.04 (m, 1H), 2.44 (s, 2H), 2.41 (s, 3H), 2.36 (s, 2H), 2.24 (s, 3H), 2.08 - 2.15 (m, 2H), 1.87 - 1.94 (m, 2H), 1.48 - 1.74 (m, 8H). LCMS: 755.7 [M+H] ⁺. Compound No.15 30 (400 MHz, DMSO-d ₆) δ11.81(s,1H),8.46(d,J = 8.31 Hz, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.80 (d, J = 9.29 Hz, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.31 (d, J = 9.78 Hz, 1H), 4.46 (d, J = 12.23 Hz, 2H), 3.80 - 3.94 (m, 2H), 3.57 (s, 2H), 2.99 (t, J = 11.98 Hz, 2H), 2.90 (s, 2H), 2.52 - 2.57 (m, 3H), 2.40 (s, 7H), 2.15 (d, J = 6.36 Hz, 2H), 1.59 - 1.96 (m, 12H), 1.18 (t, J = 7.34 Hz, 3H), 1.06 - 1.14 (m, 2H). LCMS: 738.4 [M+H] ⁺. Compound No.20 1H NMR (400 MHz, DMSO-d ₆^^į^^^^^^^^V^^^+^^^^^^^^^G^^J = 1.63 Hz, 1H), 8.14 (s, 1H), 7.74 (s, 5 1H), 7.57 (s, 1H), 6.95 (d, J = 8.50 Hz, 2H), 6.58 (d, J = 8.88 Hz, 2H), 6.53 (s, 2H), 5.64 (s, 1H), 5.11 (s, 1H), 4.29 - 4.34 (m, 1H), 3.56 (s, 2H), 3.20 - 3.25 (m, 2H), 2.81 (s, 3H), 2.70 - 2.78 (m, 2H), 2.34 - 2.44 (m, 7H), 2.25 - 2.31 (m, 3H), 2.16 - 2.24 (m, 3H), 2.13 (s, 1H), 2.05 - 2.11 (m, 1H), 1.90 - 2.04 (m, 2H), 1.67 - 1.87 (m, 5H), 1.53 - 1.66 (m, 2H), 1.33 - 1.51 (m, 5H), 1.22 - 1.32 (m, 7H), 1.17 (t, J = 7.44 Hz, 4H). LCMS: 770.2 [M+H] ⁺. 10 BIOLOGICAL ASSAYS Biological Example 1 AR binding assay: To assess AR binding, test compound (top dose 10 ^M, 4 fold serial dilution, 8 point dose response) and control (progesterone) were transferred to the assay plate. Cytosol from LnCaP cells was added to the plate, followed by addition of radiolabeled ³H-R1881 at a final concentration of 1 nM. 15 The plate was sealed, and the reaction was incubated at 300 rpm at 4 °C for 24 hrs. Radioligand absorption buffer (10 mM Tris-HCl, pH 7.4; 1.5 mM EDTA; 1 mM DTT; 0.25% charcoal; 0.0025% dextran) was then added to the plate, mixed, and incubated at 4 °C for 15 minutes. The plate was then centrifuged at 3000 rpm for 30 minutes at 4 °C. The supernatant was transferred to the scint-tube and Tri-carb was used for scintillation counting. The data was analyzed using GraphPadPrism v5.0 and binding IC50 was determined as 20 the concentration where 50% inhibition of radioligand binding was observed. GR binding assay: To assess GR binding, test compound (top dose 1 ^M, 4 fold serial dilution, 8 point dose response) and control (dexamethasone) are transferred to the assay plate. Cytosol from IM-9 cells is added to the plate, followed by addition of radiolabeled ³H-Dexamethasone at a final concentration of 1.5 nM. The plate is sealed, and the reaction incubated at 300 rpm at 4 °C for 24 hrs. Radioligand absorption 25 buffer (10 mM Tris-HCl, pH 7.4; 1.5 mM EDTA; 1 mM DTT; 0.25% charcoal; 0.0025% dextran) is then added to the plate, mixed, and incubated at 4 °C for 15 minutes. The plate is then centrifuged at 3000 pm for 30 minutes at 4 °C. The supernatant is transferred to the scint-tube and Tri-carb is used for scintillation counting. The data is analyzed using GraphPadPrism v5.0 and binding IC ₅₀ is determined as the concentration where 50% inhibition of radioligand binding is observed. 30 PR binding assay: Progesterone PR-B receptors from human breast carcinoma T47D cells are used in modified Na ₂HPO ₄/NaH ₂PO ₄ buffer pH 7.4. Compounds are screened at a range of doses (top dose 40 nM, 4 fold serial dilution, 8 point dose response) and are dispensed into the assay plate. Supernatant of 1.2 u 10 ⁵ cells aliquot is added to the assay plate and is incubated with 0.5 nM [ ³H]Progesterone for 20 hours at 4qC. Membranes are filtered and washed, the filters are then counted to determine [ ³H]Progesterone specifically bound. Binding IC50 is determined as the concentration where 50% inhibition of radioligand binding is observed. ER binding assay: (5Į^ELQGLQJ^is assessed using the LanthaScreen® TR-FRET ER Alpha Competitive Binding kit from ThermoFisherScientific. In this assay, a terbium-labeled anti-GST antibody is 5 used to indirectly label GST-tagged ER Alpha-ligand binding domain (LBD) by binding to its GST tag. Competitive binding to the ER Alpha-LBD (GST) is detected by a test compound’s ability to displace a fluorescent ligand (Fluormone™ ES2 Green tracer) from the ER Alpha-LBD (GST), which results in a loss of FRET signal between the Tb-anti-GST antibody and the tracer. To assess ER binding, test compound (top dose 10 ^M, 4 fold serial dilution, 8 point dose response) and controls (e.g. estradiol) are transferred to the 10 assay plate. The Fluormone™ ES2 Green tracer (3nM final concentration with assay buffer) is added to the assay plate. This is followed by addition of a mixture of the ER Alpha-LBD (GST) and terbium anti-GST antibody. After a 2h incubation period at room temperature, the plate is read on the Envision plate reader and the TR-FRET ratio of 520:495 emissions are calculated and used to determine the IC50 from a dose response curve of the compound. 15 AR antagonism assay: To evaluate AR antagonist activity, test compound was added to the assay plate (top dose 10 ^M, 3 fold serial dilution, 10 point dose response). HEK293 cells stably expressing the full-length androgen receptor were seeded at a density of 20000 cells/well in the assay plate. The assay plate was then incubated at room temperature for 10 minutes and at 37 °C, 5% CO2 for 20 minutes. Testosterone was added to the assay plate at 1 nM final concentration and the assay plate incubated at 37 °C, 5% CO2 for 20 20 h. After the incubation period, Steady-glo was added to the assay plate and mixed at room temperature for 20 minutes on an orbital shaker, before reading out on the EnVision plate reader. GR antagonism assay: To evaluate GR antagonist activity, test compound is added to the assay plate (top dose 5 ^M, 4 fold serial dilution, 8 point dose response). HEK293 cells stably expressing the ligand binding domain of the glucocorticoid receptor are seeded at a density of 40000 cells/well in the assay 25 plate. The assay plate is then incubated at 37 °C, 5% CO ₂ for 30 minutes. Dexamethasone is added to the assay plate at 1.5 nM final concentration and the assay plate incubated at 37 °C, 5% CO ₂ for 20 h. After the incubation period, Dual-glo luciferase reagent is added to the assay plate and mixed at room temperature for 20 minutes on an orbital shaker, before reading out on the EnVision plate reader. 50 ^L of Stop & Glo reagent is added to assay plate, mixed at room temperature for 20 minutes, and read on the Envision plate 30 reader. PR coactivator antagonist assay: Test compound (top dose 10 ^M, 4 fold serial dilution, 8 point dose response) and/or vehicle is incubated with the 2.5 nM Progesterone Receptor (PR)-LBD and coactivator peptide for 30 minutes at RT. Determination of the amount of complex formed is read spectrofluorimetrically (excitation: 337 nm, emission: 520/490 nm). Test compound-induced inhibition of 10 35 nM progesterone-induced fluorescence response by 50 percent or more (t50%) indicates receptor antagonist activity. ER antagonism assay: To evaluate ER antagonist activity, SK-BR-3 cells are seeded at a density of 30000 cells/well in the assay plate. The assay plate is then incubated at 37 °C, 5% CO ₂ for 24 h. A mixture of ERE plasmid and ER in opti-MEM media is incubated with lipofectamine 3000 in Opti-MEM media and incubated at room temperature for 15 minutes. 10 ^L of this transfection mix is added to each well of the 5 assay plate and the assay plate is incubated at 37 °C, 5% CO ₂ IRU^^^^K^^^^^^Q0^ȕ-Estradiol in 10 ^L medium or 10 ^L medium (control wells) is added to corresponding wells of aVVD\^SODWH^DQG^LQFXEDWHG^DW^^^^^^^^^ CO ₂ for 24 h. After the incubation period, 50 ^L of Dual-glo luciferase reagent is added to the assay plate and mixed at room temperature for 20 mins on an orbital shaker, before reading out on the EnVision plate reader. 50 ^L of Stop & Glo reagent is added to assay plate, mixed at room temperature for 20 minutes, and 10 read on the Envision plate reader. Cell viability assay: LNCap, 22Rv1, MDA-MB-436, MDA-MB-453, and IEC6 cells were seeded at a density of 500-2000 cells/well in 96 well plates, and a ‘T0’ (timepoint 0) was included along with the assay plate. The plates were then incubated at 37 °C, 5% CO2 in a cell culture incubator overnight. On the next day, the ‘T0’ plate was assayed using CellTiterGlo (Promega, Inc) according to the manufacturer’s 15 instructions. The appropriate compounds were diluted in DMSO and added to the assay plate (final DMSO concentration of 0.1-0.2%) on the next day. The assay plates were incubated for 6 days at 37 °C, 5% CO2. After the incubation period, the plates were assayed using CellTiterGlo (Promega, Inc) according to the manufacturer’s instructions and luminescence was read on the EnVision plate reader. Inhibition of the tested compounds was determined by the following formula: Inhibition rate (%) = (1– (RLU compound – RLU 20 day0) / (RLU control – RLU day0))*100%. GraphPadPrism was used to analyze the data and determine GI50/IC50 values. Data obtained for certain compounds disclosed herein in the assays described above in Biological Assay 2 are shown in Table 2 and Table 3. In Table 2, activity is provided as follows: A = IC50 ^100 nM; B = IC50 from >100 nM to ^1,000 25 nM; C = IC50 from >1,000 nM to ^10,000 nM; D = IC50 >10,000 nM; NT = Not tested. Table 2

In Table 3, activity is provided as follows: A = IC ₅₀ ^500 nM; B = IC ₅₀ from >500 nM to ^5,000 nM; C = IC50 from >5,000 nM to ^30,000 nM; D = IC50 >30,000 nM; NT = Not tested. Table 3

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