Macrocyclic panras inhibitors for the treatment of cancer

Abstract

The present invention relates to compounds of the formulae (I) or (XX) that are panRAS inhibitors for use in a method of treating cancer.

Description

[0001] PAT059646-WO-PCT 5 PANRAS INHIBITORS AND METHODS OF USE THEREOF TECHNICAL FIELD

[0001] The present disclosure relates to panRAS inhibitors. The disclosure further relates to methods and compositions useful in the treatment and / or diagnosis of cancers that express 10 RAS and / or are amenable to treatment by modulating panRAS expression and / or activity, as well as methods of making those compositions. BACKGROUND

[0002] Ras proteins (K-Ras, H-Ras and N-Ras) play an essential role in various human cancers 15 and are therefore appropriate targets for anticancer therapy. Indeed, mutations in Ras proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer. For example, activating mutations at codon 12 in Ras proteins function by 20 inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, enabling Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) of Ras are also responsible for 25 oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts against Ras during the last several decades, additional efforts are needed to uncover additional medicines for cancers driven by the various Ras mutations. SUMMARY 30

[0004] In one aspect, the present disclosure provides, 1 PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 20 each R1is independently selected from the group consisting of H, Halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, Halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-625 haloalkyl, NH2, and COR6, or R3is absent; PAT059646-WO-PCT 5 each R4is independently selected from the group consisting of H, halo, C1-6 alkyl, and C1-6 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 10 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 15 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; 20 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3. 25

[0005] In another aspect, the present disclosure provides,

[0002] PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 20 each R1is independently selected from the group consisting of H, Halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, Halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-625 haloalkyl, NH2, and COR6, or R3is absent; PAT059646-WO-PCT 5 each R4is independently selected from the group consisting of H, halo, C1-6 alkyl, and C1-6 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 10 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 15 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; 20 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3, 25 wherein at least one of the following is true: a) R9is oxetane or pyrrolidine, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. 30

[0006] In another aspect, the present disclosure provides,

[0003] PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 20 each R1is independently selected from the group consisting of H, Halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, Halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-625 haloalkyl, NH2, and COR6, or R3is absent; PAT059646-WO-PCT 5 each R4is independently selected from the group consisting of H, halo, C1-6 alkyl, and C1-6 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 10 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 15 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; 20 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3, 25 wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. . 30

[0007] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier. In yet another aspect, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective 35 amount of a compound of the disclosure, or a pharmaceutical composition comprising a compound of the disclosure. In yet another aspect, the disclosure provides methods of synthesis of a compound of the disclosure.

[0008] The disclosure provides, in part, novel compounds with biological activity against cancer 40 cells. The compounds may slow, inhibit, and / or reverse tumor growth in mammals, and / or may be useful for treating human cancer patients. The present disclosure more specifically relates, PAT059646-WO-PCT 5 in some embodiments, to panRAS inhibitor compounds that are capable of binding and killing cancer cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Fig.1 is a depiction of the 3-dimensional structure of Compound 101 derived from an X- 10 ray diffraction crystal study.

[0010] Fig.2 is a depiction of the PDB coordinates for Compound 101 derived from an X-ray diffraction crystal study. DETAILED DESCRIPTION 15

[0011] The disclosed compositions and methods may be understood more readily by reference to the following detailed description. Provided herein are compounds (e.g., compounds of formula (I) or other formulas disclosed herein), and pharmaceutically acceptable salts thereof, which are panRAS inhibitors.

[0012] In one aspect, the present disclosure provides. 20 A compound of formula (I*) or formula (XX*), or in some embodiments a compound of formula (I) or formula (XX), PAT059646-WO-PCT 5 wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 20 each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-625 haloalkyl, NH2, and COR6, or R3is absent; PAT059646-WO-PCT 5 each R4is independently selected from the group consisting of H, halo, C1-6 alkyl, and C1-6 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 10 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 15 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; 20 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3. 25

[0013] In one aspect, the present disclosure provides. A compound of formula (I*) or formula (XX*), or in some embodiments a compound of formula (I) or formula (XX), PAT059646-WO-PCT 5 10 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 15 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; 1 PAT059646-WO-PCT 5 ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C2-610 alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; 15 each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 20 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 25 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6alkyl, C3-6cycloalkyl, and C1-6haloalkyl; 30 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3, 35 wherein at least one of the following is true: a) R9is oxetane or pyrrolidine, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. PAT059646-WO-PCT 5

[0014] In another aspect, the present disclosure provides. A compound of formula (I*) or formula (XX*), or in some embodiments a compound of formula (I) or formula (XX), 10 PAT059646-WO-PCT 5 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 15 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6;20 R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-625 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; 30 each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; PAT059646-WO-PCT 5 R7is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted by C3-6 cycloalkyl, aryl, or 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; 10 each Rxis independently selected from H, C1-6alkyl, C3-6cycloalkyl, and C1-6haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and 15 n is 0, 1, 2, or 3, wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. 20

[0015] In another aspect, the present disclosure provides,

[0004] PAT059646-WO-PCT 5 A compound of formula (I*) or formula (XX*), wherein 10 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 20 each R1is independently selected from the group consisting of H, Halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; R3is selected from the group consisting of H, Halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-625 haloalkyl, NH2, and COR6, or R3is absent; PAT059646-WO-PCT 5 each R4is independently selected from the group consisting of H, halo, C1-6 alkyl, and C1-6 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 10 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 15 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; 20 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3, 25 wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. 30

[0016] In some embodiments, the present disclosure provides, A compound of formula (I) PAT059646-WO-PCT 5 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 15 each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; 20 each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 25 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 30 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; W is -COR9, wherein R9is C3-7 cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; 35 m is 0 or 1; and n is 0, 1, 2, or 3, wherein at least one of the following is true: a) R9is oxetane or pyrrolidine, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; 40 wherein R7is optionally further substituted. PAT059646-WO-PCT 5

[0017] In some embodiments, the present disclosure provides, A compound of formula (I) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 10 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; 15 ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-620 heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-625 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; 30 each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; PAT059646-WO-PCT 5 wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and 10 n is 0, 1, 2, or 3, wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. 15

[0018] In some embodiments, the present disclosure provides a compound of formula (I) 20 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 25 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and 30 ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; PAT059646-WO-PCT 5 R3is selected from the group consisting of H, halo, OH, CN, C1-10 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-310 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; 15 L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H or C1-6 alkyl; 20 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3, wherein at least one of the following is true: 25 a) m is 0; or b) R9is optionally substituted oxetane.

[0019] In some embodiments, the present disclosure provides a compound of formula (I) 30 PAT059646-WO-PCT 5 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 15 each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; 20 each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 25 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is 30 C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H or C1-6alkyl; W is -COR9, wherein R9is C3-7 cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; 35 m is 0 or 1; and n is 0, 1, 2, or 3, wherein at least one of the following is true: a) m is 0; or b) R9is optionally substituted 2-oxetanyl. 40 PAT059646-WO-PCT 5

[0020] In some embodiments, the compound is a compound of formula (II) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 15 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; 20 R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; 25 each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, 30 C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C1-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; PAT059646-WO-PCT 5 R8is H, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; n is 0, 1, 2, or 3; and wherein at least one of the following is true: 10 a) R9is oxetane or pyrrolidine, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. In some embodiments, the compound is a compound of compound of formula (I) 15 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 20 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 25 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; 30 R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; PAT059646-WO-PCT 5 each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3 alkyl, C1-3 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, 10 C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; 15 W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3; 20 wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. 25

[0021] In some embodiments, the compound is a compound of formula (II) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 30 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; PAT059646-WO-PCT 5 ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-610 heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-615 haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6 cycloalkyl; 20 each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C1-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; 25 wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; n is 0, 1, 2, or 3; and 30 wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted. 35

[0022] In some embodiments, the compound is a compound of formula (II) PAT059646-WO-PCT 5 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 10 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; 20 R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-325 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6 cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; 30 L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C1-6alkenyl, or C1-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H or C1-6alkyl; PAT059646-WO-PCT 5 W is -COR9, wherein R9is C3-7 cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, and R9is optionally substituted; and n is 0, 1, 2, or 3. 10

[0023] In some embodiments, the compound is a compound of formula (Iw) or formula (XXw) wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 15 N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 20 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; 25 R2is substituted pyridine or substituted phenyl; PAT059646-WO-PCT 5 R3is selected from the group consisting of H, halo, OH, CN, C1-10 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-310 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; 15 R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3.

[0024] In some embodiments, the compound is a compound of formula (Iw) 20 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 25 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 30 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; PAT059646-WO-PCT 5 R3is selected from the group consisting of H, halo, OH, CN, C1-10 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-310 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; 15 R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; m is 0 and n is 0; or m is 0 and n is 1. 20

[0025] In some embodiments, ring A is phenyl, pyridine, thiazole, triazole, oxazole, or oxadiazole, and ring A is substituted with 0-3 R10; wherein R10is selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6.

[0026] In some embodiments, ring A is 25

[0027] In some embodiments, ring A is

[0028] In some embodiments, R10is not H.

[0029] In some embodiments, ring B is optionally substituted pyrrole. 30

[0030] In some embodiments, ring C is optionally substituted phenyl. PAT059646-WO-PCT 5

[0031] In some embodiments, the BC ring system is indole, benzothiophene, benzoxazole, or indolizine, each of which optionally has 1-3 additional N ring atoms in its 6-membered ring, wherein each BC ring system is optionally substituted, for example wherein the BC ring system is optionally substituted with 1-3 R11, wherein each R11is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-610 heteroalkyl, C1-6haloalkyl, NH2, and COR6. In some embodiments, each R11is independently selected from the group consisting of H and halo. In some embodiments there are no R11substituents.

[0032] In some embodiments, the BC ring system is , wherein 15 X1is N, S, or O; X2is N or CR11; for example wherein either 0 or 1 of X2are N, and the remaining X2are CR11, for example wherein the BC ring system is , 20 wherein each R11is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6. In some embodiments, each R11is independently selected from the group consisting of H and halo. In some embodiments there are no R11substituents. In some embodiments, R11is not H.

[0033] In some embodiments, each R1is independently selected from the group consisting of 25 H, halo, C1-6alkyl, or C1-6haloalkyl; for example wherein each R1is H.

[0034] In some embodiments, R2is substituted pyridine. In some embodiments, R2is substituted 3-pyridyl.

[0035] In some embodiments, R2is 1 PAT059646-WO-PCT 5 , wherein R2ais C1-10alkyl, C3-6cycloalkyl, or C1-10heteroalkyl, and R2ais optionally substituted by 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, and COR6; for example, wherein R2ais C1-10optionally substituted heteroalkyl; 10 R2bis 5-6-membered heterocycloalkyl, with 1-3 ring atoms selected from the group consisting of N, O, P(O)xx, and S(O)xx, wherein xx is 0, 1, or 2, and R2bis optionally substituted, for example with 1-3 R2ba, wherein each R2bais independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, and COR6; and 15 wherein each phenyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of Halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl; and each R2cis independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, and C1-6heteroalkyl; for example, wherein each R2cis H. 20

[0036] In some embodiments, R2is , wherein R2ais C1-10alkyl, C3-6cycloalkyl, or C1-10heteroalkyl, and R2ais optionally substituted by 1-3 substituents independently selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; 25 for example, wherein R2ais C1-10optionally substituted heteroalkyl; R2bis 4-10-membered heterocycloalkyl, with 1-4 ring atoms selected from the group consisting of N, O, P(O)xx, and S(O)xx, wherein xx is 0, 1, or 2, and R2bis optionally substituted, for example with 1-3 R2ba, wherein each R2bais independently selected from the group consisting of H, halo, OH, CN, C1-6 alkyl, C1-306heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, COR6, and -(CH2)0-2- heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, P(O)xx, and S(O)xx, wherein xx is 0, 1, or 2, and wherein each phenyl, heterocycloalkyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and 35 C1-6heteroalkyl; PAT059646-WO-PCT 5 each R2cis independently selected from the group consisting of H, halo, OH, CN, C1-6 alkyl, and C1-6heteroalkyl; for example, wherein each R2cis H; and each Rxis independently selected from H, C1-6alkyl, C3-6cycloalkyl, and C1-6haloalkyl.

[0037] In some embodiments, R2bis 10 wherein X3is C, CRx, N, or P(O); is a single or double bond; and each Rxis independently selected from H, C1-6alkyl, C3-6cycloalkyl, and C1-6haloalkyl; for example, wherein R2bais H, C1-6alkyl, -(CH2)0-2phenyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, COR6,or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring 15 atoms selected from the group consisting of N, O, and S, and each phenyl, cycloalkyl, or heterocycloalkyl is optionally substituted.

[0038] In some embodiments, R2bis wherein X3is CH, N, or P(O); and 20 is a single or double bond; for example, wherein R2bais H, C1-6alkyl, -(CH2)0-2phenyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, COR6., or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S. 25

[0039] In some embodiments, R2bis PAT059646-WO-PCT 5 for example, wherein R2bais H, C1-6 alkyl, -(CH2)0-2 phenyl, C1-6 heteroalkyl, C1-6 haloalkyl, C3-6 cycloalkyl, COR6., or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S.

[0040] In some embodiments, R2ais 10 , wherein X4is O or N, and X5is CH; or X5is O or N, and X4is CH; and R2aais C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2aais absent or H; 15 R2abis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2abis absent or H; and R2acis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo or one OH, or R2acis absent or H.

[0041] In some embodiments, R2ais 20 , wherein X4is O or N, and X5is CH; or X5is O or N, and X4is CH; and R2aais C1-3alkyl optionally substituted with 1-3 halo, or R2aais absent or H; R2abis C1-3alkyl optionally substituted with 1-3 halo, or R2abis absent or H; and 25 R2acis C1-3alkyl optionally substituted with 1-3 halo or one OH.

[0042] In some embodiments, R2is PAT059646-WO-PCT 5 X3is C, CRx, N, or P(O); X4is O or N, and X5is CH; or X5is O or N, and X4is CH; and is a single or double bond R2aais C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2aais absent or 10 H; R2abis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2abis absent or H; R2acis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo or one OH; and R2bais H, C1-6alkyl, -(CH2)0-2phenyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, COR6., or 15 heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S, and each phenyl, cycloalkyl, or heterocyloalkyl is optionally substituted.

[0043] In some embodiments, R2is 20 , wherein X3is CH, N, or P(O); X4is O or N, and X5is CH; or X5is O or N, and X4is CH; and is a single or double bond 25 R2aais C1-3alkyl optionally substituted with 1-3 halo, or R2aais absent or H; R2abis C1-3alkyl optionally substituted with 1-3 halo, or R2abis absent or H; R2acis C1-3 alkyl optionally substituted with 1-3 halo or one OH; and R2bais H, C1-6alkyl, -(CH2)0-2phenyl, C1-6heteroalkyl, C1-6haloalkyl, or COR6. 30

[0044] In some embodiments, R2is PAT059646-WO-PCT 5 R2aais C1-3alkyl optionally substituted with 1-3 halo, or R2aais absent; 10 R2abis C1-3alkyl optionally substituted with 1-3 halo, or R2aais absent; R2acis C1-3alkyl optionally substituted with 1-3 halo; and R2bais H, C1-6 alkyl, -(CH2)0-2 phenyl, C1-6 heteroalkyl, C1-6 haloalkyl, C3-6 cycloalkyl, COR6., or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S, and each phenyl, cycloalkyl, or heterocycloalkyl is 15 optionally substituted.

[0045] In some embodiments, R2ais

[0046] In some embodiments, R2bais C1-6 alkyl. 20

[0047] In some embodiments, R3is selected from the group consisting of H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl, or R3is absent; for example, R3is C1-6alkyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is ethyl.

[0048] In some embodiments, each R4is independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; for example, each R4is H. 25

[0049] In some embodiments, each R5is independently selected from H and C1-6alkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl. In some embodiments, each R5is independently selected from H and C1-6alkyl; for example both R5are CH3.

[0050] In some embodiments, L is absent, or L is -COCHR7N(R8)-*, wherein * indicates the 30 point of attachment to W; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; PAT059646-WO-PCT 5 wherein R7is optionally further substituted by 1-3 substituents selected from the group consisting of halo, OH, C1-3haloalkyl, C1-3heteroalkyl, and C1-3alkyl; and R8is H or C1-3alkyl.

[0051] In some embodiments, R7is C1-6alkyl, C1-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, or C1-6alkyl substituted by C3-6cycloalkyl, wherein R7is optionally further substituted by 1-3 10 substituents selected from the group consisting of halo and C1-3alkyl. In some embodiments, R7is C1-6 alkyl, C2-6 alkenyl, or C3-6 cycloalkyl, wherein R7is optionally further substituted by 1-3 substituents selected from the group consisting of halo and C1-3alkyl.

[0052] In some embodiments, R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted by 1-3 substituents 15 selected from the group consisting of halo and C1-3alkyl.

[0053] In some embodiments, R7is 20

[0054] In some embodiments, R7is 25

[0055] In some embodiments, L is PAT059646-WO-PCT 5 r absent; for example, wherein R8is CH3. In some embodiments, L is 10 In some embodiments, L is

[0057] In some embodiments, 15 W is -COR9; R9is C3-7cycloalkyl or 4-6 membered heterocycloalkyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, wherein each R9is optionally substituted by 1-3 R9a, and optionally substituted with 1 R9bon a ring nitrogen atom, if present; each R9ais independently selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-620 heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, alkenyl, C1-6alkynyl, NH2, PAT059646-WO-PCT 5 COR6, NRxCOR6, and -(CH2)0-2 heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl.

[0058] In some embodiments, 10 W is -COR9; R9is C3-7cycloalkyl or 4-6 membered heterocycloalkyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, wherein each R9is optionally substituted by 1-3 R9a; each R9ais independently selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-615 heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, COR6, and -(CH2)0-2heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl. 20 In some embodiments, R9is oxetane or pyrrolidine, each optionally substituted. In some embodiments, R9is optionally substituted oxetane. In some embodiments, R9is oxetane optionally substituted with 1-3 R9a. In some embodiments, R9is 2-oxetanyl optionally substituted with 1-3 R9a. In some embodiments R9ais optionally substituted phenyl. 25

[0059] In some embodiments, W is PAT059646-WO-PCT 5 , wherein R9bis H, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, COR6, NRxCOR6, and -(CH2)0-2heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each 10 phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl, for example wherein R9bis H, C1-3alkyl, or NRxCO-C1-3alkyl.

[0060] In some embodiments, W is15 wherein R9bis H or C1-3alkyl.

[0061] In some embodiments, W is PAT059646-WO-PCT 5 wherein R9bis H or C1-3alkyl; for example wherein R9ais optionally substituted phenyl. In some embodiments, 10 each R9a’is independently selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, COR6, and -(CH2)0-2heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group 15 consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl. In some embodiments R9ais optionally substituted phenyl. In some embodiments, W is 20 PAT059646-WO-PCT 5 In some embodiments, W is . 10 In some embodiments, W is , 15 In some embodiments, W is PAT059646-WO-PCT 5

[0062] In some embodiments, the compound is a compound of formula (III), formula (XXIII), or formula (XXXIII) 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein n is 0 or 1; for example a compound of formula (IIIa) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H.

[0063] In some embodiments, the compound is a compound of formula (IV), formula (XXIV), or formula (XXXIV) 10 PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents; 10 for example, wherein the compound is a compound of formula (IVa) wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents. 15

[0064] In some embodiments, the compound is a compound of formula (V), formula (VI), formula (XXV), formula (XXVI), formula (XXXV), or formula (XXXVI)

[0005] PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; 15 for example, a compound of formula (V), formula (XXV), or formula (XXXV) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; for example, a compound of formula (VI), formula (XXVI), or formula (XXXVI) wherein R10is H.

[0065] In some embodiments, the compound is a compound of formula (Vw) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure, for example, wherein m is 0, and n is 0 or 1; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; 10 for example, a compound of formula (Vw) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H.

[0066] In some embodiments, the compound is a compound of formula (Va) or formula (VIa) 15 are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (Va) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; 20 for example, a compound of formula (VIa) wherein R10is H.

[0067] In some embodiments, the compound is a compound of formula (VII), formula (XXVII), or formula (XXXVII) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; 10 for example, wherein all R1are H.

[0068] In some embodiments, the compound is a compound of formula (Iy’) or formula (XXy’) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein m is 1 and n is 0 or 1. 10

[0069] In some embodiments, the compound is a compound of formula (Iy) or formula (XXy) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein m is 1 and n is 0 or 1.

[0070] In some embodiments, the compound is a compound of formula (Iyz) 10 wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H, for example wherein m is 1 and n is 0 or 1.

[0071] In some embodiments, the compound is a compound of formula (IIIy’), formula (XXIIIy’), 15 or formula (XXXIIIy’) PAT059646-WO-PCT 5 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein n is 0 or 1; for example a compound of formula (IIIya’) 1 PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H.

[0072] In some embodiments, the compound is a compound of formula (IIIy’), formula (XXIIIy’), 10 or formula (XXXIIIy’) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein n is 0 or 1; 10 for example a compound of formula (IIIya’) wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H. 15

[0073] In some embodiments, the compound is a compound of formula (IIIy), formula (XXIIIy), or formula (XXXIIIy) PAT059646-WO-PCT 5 ); 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein n is 0 or 1; for example a compound of formula (IIIya) 15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H.

[0074] In some embodiments, the compound is a compound of formula (IIIyz), formula (XXIIIyz), or formula (XXXIIIyz) PAT059646-WO-PCT 5 10 wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H, for example wherein n is 0 or 1; for example a compound of formula (IIIyza) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H.

[0075] In some embodiments, the compound is a compound of formula (IVy’), formula (XXIVy’), 10 or formula (XXXIVy’) 15 PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents; for example, wherein the compound is a compound of formula (IVya’) 10 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents.

[0076] In some embodiments, the compound is a compound of formula (IVy), formula (XXIVy), or formula (XXXIVy) 15 PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the 10 disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents; for example, wherein the compound is a compound of formula (IVya) 15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents.

[0077] In some embodiments, the compound is a compound of formula (IVyz), formula (XXIVyz), or formula (XXXIVyz) PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H; for example, wherein there are no R11substituents; for example, wherein the compound is a compound of formula (IVyza) PAT059646-WO-PCT 5 (IVyza); wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H; for example, wherein there are no R11substituents.

[0078] In some embodiments, the compound is a compound of formula (Vy’) or formula (VIy’), formula (XXVy’), formula (XXVIy’), formula (XXXVIy’) or formula (XXXVIy’) 10

[0006] PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; 1 PAT059646-WO-PCT 5 for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (Vy’), formula (XXVy’), or formula (XXXVy’) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; 10 for example, a compound of formula (VIy’), formula (XXVIy’), or formula (XXXVIy’) wherein R10is H. In some embodiments, the compound is a compound of formula (Vya’) or formula (Viya’) 15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein 20 there are no R11substituents; for example, a compound of formula (Vya’) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; for example, a compound of formula (Viya’) wherein R10is H.

[0079] In some embodiments, the compound is a compound of formula (Vy) or formula (VIy), 25 formula (XXVy), formula (XXVIy), formula (XXXVIy) or formula (XXXVIy)

[0007] PAT059646-WO-PCT 5 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the 10 disclosure; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (Vy), formula (XXVy), or formula (XXXVy) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; 15 for example, a compound of formula (VIy), formula (XXVIy), or formula (XXXVIy) wherein R10is H. In some embodiments, the compound is a compound of formula (Vya) or formula (VIya)

[0008] PAT059646-WO-PCT 5 (VIya); wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein 10 there are no R11substituents; for example, a compound of formula (Vya) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; for example, a compound of formula (VIya) wherein R10is H.

[0080] In some embodiments, the compound is a compound of formula (Vyz) or formula (VIyz), 15 formula (XXVyz), formula (XXVIyz), formula (XXXVyz), or formula (XXXVIyz) PAT059646-WO-PCT 5 10 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; PAT059646-WO-PCT 5 for example, wherein R9ais optionally subsituted phenyl; for example, a compound of formula (Vyz), formula (XXVyz), or formula (XXXVyz) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; for example, a compound of formula (VIyz), formula (XXVIyz), or formula (XXXVIyz) wherein 10 R10is H.

[0081] In some embodiments, the compound is a compound of formula (Vyz*) 15 for example, wherein m is 0 and n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, wherein R9ais optionally subsituted phenyl; 20 for example, wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H.

[0082] In some embodiments, the compound is a compound of formula (Vyza) or formula (VIyza) PAT059646-WO-PCT 5 embodiments of the disclosure, and R9ais not H; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, wherein R9ais optionally subsituted phenyl; 10 for example, a compound of formula (Vyza) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; for example, a compound of formula (VIyza) wherein R10is H.

[0083] In some embodiments, the compound is a compound of formula (VIIy), formula (VIIIy), 15 formula (XXVIIy), formula (XXVIIIy), formula (XXXVIIy), or formula (XXXVIIIy)

[0009] PAT059646-WO-PCT 5 10 PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H. 10

[0084] In some embodiments, the compound is a compound of formula (VIIyz) (VIIyz); wherein the variables are defined as in various embodiments of the disclosure, and R9ais not H; for example, wherein R9ais optionally subsituted phenyl; for example, wherein all R1are H. 15

[0085] In some embodiments, the compound is a compound of formula (Iw) or formula (XXw) PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure.

[0086] In some embodiments, the compound is a compound of formula (Iw*) or formula (XXw*) 10 1 PAT059646-WO-PCT 5 wherein the variables are defined as in various embodiments of the disclosure.

[0087] In some embodiments, L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W; 10 R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted; and R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; for example wherein R7is 15 for example wherein R7is for example wherein R7is .

[0088] In some embodiments, the compound is selected from the compounds disclosed in the 20 specification. In some embodiments, the compound is selected from the compounds in Table 20. In some embodiments, the compound is selected from the group consisting of the following compound numbers: 103, 106, 107, 109, 112, 116, 117, 122, 123, 124, 125, 126, 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 160, 161, and 162. In some embodiments, the compound is selected from the group 25 consisting of the following compound numbers: 103, 106, 107, 109, 112, 116, 117, 122, 123, PAT059646-WO-PCT 5 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 158, 159, 160, 161, and 162. In some embodiments, the compound is selected from the group consisting of the following compound numbers: 112, 116, 122, 123, 132, 133, 134, 135, 136, 137, 138, 139, 140, 147, 148, 149, 150, 151, 152, 153, 154, 155, 157, 159, 160, 161, and 162. 10

[0089] In some embodiments, any of the compounds disclosed herein may be in the form of a pharmaceutically acceptable salt.

[0090] In another aspect, disclosed is a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier.

[0091] In another aspect, disclosed is a method of treating cancer in a subject in need thereof, 15 the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutical composition of the disclosure.

[0092] In some embodiments, the cancer is a tumor or a hematological cancer, optionally, the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, 20 bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, 25 non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.

[0093] In some embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, colorectal cancer, melanoma, head and neck cancer, acute myeloid leukemia, and bladder cancer. 30

[0094] Throughout this text, the descriptions refer to compositions and methods of using the compositions. Where the disclosure describes or claims a feature or embodiment associated with a composition, such a feature or embodiment is equally applicable to the methods of using the composition. Likewise, where the disclosure describes or claims a feature or embodiment associated with a method of using a composition, such a feature or embodiment is equally 35 applicable to the composition.

[0095] When a range of values is expressed, it includes embodiments using any particular value within the range. Further, reference to values stated in ranges includes each and every value within that range. All ranges are inclusive of their endpoints and combinable. When values are expressed as approximations, by use of the antecedent “about,” it will be understood 40 that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of PAT059646-WO-PCT 5 “or” will mean “and / or” unless the specific context of its use dictates otherwise. All references cited herein are incorporated by reference for any purpose. Where a reference and the specification conflict, the specification will control.

[0096] It is to be appreciated that certain features of the disclosed compositions and methods, which are, for clarity, described herein in the context of separate embodiments, may also be 10 provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0097] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. lsotopically labeled compounds have structures 15 depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into compounds disclosed herein include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as3H,11C,13C,14C,15N,18F, and36Cl. Accordingly, it should be understood that the present disclosure includes compounds that incorporate one or more of 20 any of the aforementioned isotopes, including for example, radioactive isotopes, such as3H and 14C, or those into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or 25 substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically- labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, e.g., using an appropriate isotopically-labeled reagents in place of the non- labeled reagent previously employed. 30 Definitions

[0098] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein. 35

[0099] As used herein, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise. The terms “comprising”, “having”, “being of” as in “being of a chemical formula”, “including”, and “containing” are to be construed as open terms (i.e., meaning “including but not limited to”) unless otherwise noted. Additionally, whenever “comprising” or another open-ended term is used in an embodiment, it is to be understood that PAT059646-WO-PCT 5 the same embodiment can be more narrowly claimed using the intermediate term “consisting essentially of” or the closed term “consisting of”.

[0100] The term "about" or "approximately," when used in the context of numerical values and ranges, refers to values or ranges that approximate or are close to the recited values or ranges such that the embodiment may perform as intended, as is apparent to the skilled person from 10 the teachings contained herein. In some embodiments, about means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of a numerical amount. In one embodiment, the term “about” refers to a range of values which are 10% more or less than the specified value. In another embodiment, the term “about” refers to a range of values which are 5% more or less than the specified value. In another embodiment, the term “about” refers to a range of values which are 15 1% more or less than the specified value.

[0101] The term “agent” is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or a combination of two or more thereof. The term “therapeutic agent” or “drug” refers to an agent that is capable of modulating a biological process and / or has biological activity. The panRAS 20 inhibitors, as described herein, are exemplary therapeutic agents.

[0102] The term "chemotherapeutic agent" or “anti-cancer agent” is used herein to refer to all agents that are effective in treating cancer (regardless of mechanism of action). Inhibition of metastasis or angiogenesis is frequently a property of a chemotherapeutic agent. Chemotherapeutic agents include antibodies, biological molecules, and small molecules, and 25 encompass the panRAS inhibitors, as described herein. A chemotherapeutic agent may be a cytotoxic or cytostatic agent. The term “cytostatic agent” refers to an agent that inhibits or suppresses cell growth and / or multiplication of cells. The term "cytotoxic agent" refers to a substance that causes cell death primarily by interfering with a cell’s expression activity and / or functioning. 30

[0103] The term “Rat Sarcoma Virus (Ras)” or “panRAS,” as used herein, refers to any native form of the human Ras protein family (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras). The term encompasses full-length human K-Ras (Kristen Rat Sarcoma Virus), N-Ras (Neuroblastoma Rat Sarcoma Virus) as well as any form of human Ras that may result from cellular processing. The term also encompasses functional variants or 35 fragments of human Ras proteins, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biologic functions of human Ras proteins (i.e., variants and fragments are encompassed unless the context indicates that the term is used to refer to the wild-type protein only). Ras proteins can be isolated from human, or may be produced recombinantly or by synthetic methods. 40

[0104] The term "inhibit" or "inhibition" or “inhibiting,” as used herein, means to reduce a biological activity or process by a measurable amount, and can include but does not require PAT059646-WO-PCT 5 complete prevention or inhibition. In some embodiments, “inhibition” means to reduce the expression and / or activity of panRAS and / or one or more upstream modulators or downstream targets thereof.

[0105] The term “panRAS inhibitor,” as used herein, refers to an agent capable of reducing the expression and / or activity of panRAS (e.g., K-Ras (including splice variants KRAS4A and 10 KRAS4B), H-Ras and N-Ras) and / or one or more upstream modulators or downstream targets thereof. Other exemplary panRAS modulators (including exemplary inhibitors of panRAS) are described in WO2021 / 091956 or WO2022 / 060836.

[0106] The term “cancer,” as used herein, refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, 15 metastatic potential, rapid growth and proliferation rate, and / or certain morphological features. Often, cancer cells can be in the form of a tumor or mass, but such cells may exist alone within a subject, or may circulate in the blood stream as independent cells, such as leukemic or lymphoma cells. The term "cancer" includes all types of cancers and cancer metastases, including hematological cancers, solid tumors, sarcomas, carcinomas and other solid and non- 20 solid tumor cancers. Hematological cancers may include B-cell malignancies, cancers of the blood (leukemias), cancers of plasma cells (myelomas, e.g., multiple myeloma), or cancers of the lymph nodes (lymphomas). Exemplary B-cell malignancies include chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. Leukemias may include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), 25 chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. The terms “acute lymphoblastic leukemia” and “acute lymphocytic leukemia” can be used interchangeably to describe ALL. Lymphomas may include Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc. Other hematologic cancers may include myelodysplasia syndrome (MDS). Solid tumors may 30 include carcinomas such as adenocarcinoma, e.g., a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, 35 follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.

[0107] As used herein, the term “tumor” refers to any mass of tissue that results from excessive 40 cell growth or proliferation, either benign or malignant, including precancerous lesions. In some embodiments, the tumor is a breast cancer including ER positive breast cancer, multiple PAT059646-WO-PCT 5 myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant 10 prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.

[0108] The terms “tumor cell” and “cancer cell” may be used interchangeably herein and refer to individual cells or the total population of cells derived from a tumor or cancer, including both 15 non-tumorigenic cells and cancer stem cells. The terms “tumor cell” and “cancer cell” will be modified by the term “non-tumorigenic” when referring solely to those cells lacking the capacity to renew and differentiate to distinguish those cells from cancer stem cells.

[0109] The terms “subject” and “patient” are used interchangeably herein to refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., 20 mammals and non-mammals) such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is a human.

[0110] The term “a subject in need of treatment,” as used herein, refers to a subject that would 25 benefit biologically, medically, or in quality of life from a treatment (e.g., a treatment with any one or more of the exemplary compounds described herein).

[0111] As used herein, the term “treat,” “treating,” or “treatment” refers to any improvement of any consequence of disease, disorder, or condition, such as prolonged survival, less morbidity, and / or a lessening of side effects which result from an alternative therapeutic modality. In some 30 embodiments, treatment comprises delaying or ameliorating a disease, disorder, or condition (i.e., slowing or arresting or reducing the development of a disease or at least one of the clinical symptoms thereof). In some embodiments, treatment comprises delaying, alleviating, or ameliorating at least one physical parameter of a disease, disorder, or condition, including those which may not be discernible by the patient. In some embodiments, treatment comprises 35 modulating a disease, disorder, or condition, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In some embodiments, treatment comprises administration of a described compound or composition to a subject, e.g., a patient, to obtain a treatment benefit enumerated herein. The treatment can be to cure, heal, alleviate, delay, prevent, relieve, alter, remedy, ameliorate, palliate, improve, or 40 affect a disease, disorder, or condition (e.g., a cancer), the symptoms of a disease, disorder, or condition (e.g., a cancer), or a predisposition toward a disease, disorder, or condition (e.g., a PAT059646-WO-PCT 5 cancer). In some embodiments, in addition to treating a subject having a disease, disorder, or condition, a composition disclosed herein can also be provided prophylactically to prevent or reduce the likelihood of developing that disease, disorder, or condition.

[0112] As used herein, the term “prevent”, “preventing," or “prevention” of a disease, disorder, or condition refers to the prophylactic treatment of the disease, disorder, or condition; or 10 delaying the onset or progression of the disease, disorder, or condition.

[0113] As used herein, a "pharmaceutical composition" refers to a preparation of a composition, e.g., a panRAS inhibitor compound or composition, in addition to at least one other (and optionally more than one other) component suitable for administration to a subject, such as a pharmaceutically acceptable carrier, stabilizer, diluent, dispersing agent, suspending agent, 15 thickening agent, and / or excipient. The pharmaceutical compositions provided herein are in such form as to permit administration and subsequently provide the intended biological activity of the active ingredient(s) and / or to achieve a therapeutic effect. The pharmaceutical compositions provided herein preferably contain no additional components which are unacceptably toxic to a subject to which the formulation would be administered. 20

[0114] As used herein, the terms "pharmaceutically acceptable carrier" and "physiologically acceptable carrier," which may be used interchangeably, refer to a carrier or a diluent that does not cause significant irritation to a subject and does not abrogate the biological activity and properties of the administered compound or composition and / or any additional therapeutic agent in the composition. Pharmaceutically acceptable carriers may enhance or stabilize the 25 composition or can be used to facilitate preparation of the composition. Pharmaceutically acceptable carriers can include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as 30 would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The carrier may be selected to minimize adverse side effects in the subject, and / or to minimize degradation of the active ingredient(s). 35 An adjuvant may also be included in any of these formulations.

[0115] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Formulations for parenteral administration can, for example, contain excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or 40 hydrogenated napthalenes. Other exemplary excipients include, but are not limited to, calcium bicarbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, PAT059646-WO-PCT 5 gelatin, ethylene-vinyl acetate co-polymer particles, and surfactants, including, for example, polysorbate 20.

[0116] The term “pharmaceutically acceptable salt,” as used herein, refers to a salt which does not abrogate the biological activity and properties of the compounds disclosed herein, and does not cause significant irritation to a subject to which it is administered. Examples of such salts 10 include, but are not limited to: (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, 15 methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b) salts formed from elemental anions such as chlorine, bromine, and iodine. See, e.g., Haynes et al., “Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database,” J. Pharmaceutical Sciences, vol.94, no.10 (2005), and Berge et al., “Pharmaceutical Salts,” J. Pharmaceutical Sciences, vol.66, no.1 20 (1977), which are incorporated by reference herein.

[0117] In some embodiments, depending on their electronic charge, the compounds described herein can contain a monovalent anionic counterion M1-. Any suitable anionic counterion can be used. In certain embodiments, the monovalent anionic counterion is a pharmaceutically acceptable monovalent anionic counterion. In certain embodiments, the monovalent anionic 25 counterion M1- can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, formate, or the like. In some embodiments, the monovalent anionic counterion M1- is trifluoroacetate or formate.

[0118] As used herein, the term “therapeutically effective amount” or “therapeutically effective dose,” refers to an amount of a compound described herein, e.g., a compound or composition 30 described herein, to effect the desired therapeutic result (i.e., reduction or inhibition of an enzyme or a protein activity, amelioration of symptoms, alleviation of symptoms or conditions, delay of disease progression, a reduction in tumor size, inhibition of tumor growth, prevention of metastasis). In some embodiments, a therapeutically effective amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically effective amount 35 induces or causes side effects but only those that are acceptable by a treating clinician in view of a patient’s condition. In some embodiments, a therapeutically effective amount is effective for detectable killing, reduction, and / or inhibition of the growth or spread of cancer cells, the size or number of tumors, and / or other measure of the level, stage, progression and / or severity of a cancer. The term also applies to a dose that will induce a particular response in target cells, 40 e.g., a reduction, slowing, or inhibition of cell growth. A therapeutically effective amount can be determined by first administering a low dose, and then incrementally increasing that dose until PAT059646-WO-PCT 5 the desired effect is achieved. A therapeutically effective amount can also vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The specific amount may vary depending on, for example, the particular pharmaceutical 10 composition, the subject and their age and existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. In the case of cancer, a therapeutically effective amount of a compound may reduce the number of cancer cells, reduce 15 tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or relieve one or more symptoms.

[0119] As used herein, the term “prophylactically effective amount” or “prophylactically effective dose,” refers to an amount of a compound disclosed herein, e.g., a panRAS inhibitor compound or composition described herein, that is effective, at dosages and for periods of time necessary, 20 to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. In some embodiments, a prophylactically effective amount can prevent the onset of disease symptoms, including symptoms associated with a cancer. 25

[0120] The term "alkyl", as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. The term "C1-C6alkyl", as used herein, refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. Non-30 limiting examples of "C1-C6alkyl" groups include methyl (a C1alkyl), ethyl (a C2alkyl), 1- methylethyl (a C3alkyl), n-propyl (a C3alkyl), isopropyl (a C3alkyl), n-butyl (a C4alkyl), isobutyl (a C4alkyl), sec-butyl (a C4alkyl), tert-butyl (a C4alkyl), n-pentyl (a C5alkyl), isopentyl (a C5alkyl), neopentyl (a C5alkyl) and hexyl (a C6alkyl).

[0121] The term “alkenyl”, as used herein, refers to a straight or branched hydrocarbon chain 35 radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond. The term “C2-C6alkenyl”, as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to six carbon atoms, which is attached to the rest of the molecule by a single bond. Non-limiting examples of "C2-C6alkenyl" groups include ethenyl (a C2alkenyl), 40 prop-1-enyl (a C3alkenyl), but-1-enyl (a C4alkenyl), pent-1-enyl (a C5alkenyl), pent-4-enyl (a C5alkenyl), penta-1,4-dienyl (a C5alkenyl), hexa-1-enyl (a C6alkenyl), hexa-2-enyl (a C6alkenyl), PAT059646-WO-PCT 5 hexa-3-enyl (a C6alkenyl), hexa-1-,4-dienyl (a C6alkenyl), hexa-1-,5-dienyl (a C6alkenyl) and hexa-2-,4-dienyl (a C6alkenyl). The term “C2-C3alkenyl”, as used herein, refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to three carbon atoms, which is attached to the rest of the molecule by a single bond. Non-limiting examples of "C2-C3alkenyl" groups 10 include ethenyl (a C2alkenyl) and prop-1-enyl (a C3alkenyl).

[0122] The term "alkylene", as used herein, refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. The term "C1-C6alkylene", as used herein, refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no 15 unsaturation, having from one to six carbon atoms. Non-limiting examples of "C1-C6alkylene" groups include methylene (a C1alkylene), ethylene (a C2alkylene), 1-methylethylene (a C3alkylene), n-propylene (a C3alkylene), isopropylene (a C3alkylene), n-butylene (a C4alkylene), isobutylene (a C4alkylene), sec-butylene (a C4alkylene), tert-butylene (a C4alkylene), n- pentylene (a C5alkylene), isopentylene (a C5alkylene), neopentylene (a C5alkylene), and 20 hexylene (a C6alkylene).

[0123] The term “alkenylene”, as used herein, refers to a bivalent straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing at least one double bond. The term “C2-C6alkenylene”, as used herein, refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, 25 containing at least one double bond, and having from two to six carbon atoms. Non-limiting examples of "C2-C6alkenylene" groups include ethenylene (a C2alkenylene), prop-1-enylene (a C3alkenylene), but-1-enylene (a C4alkenylene), pent-1-enylene (a C5alkenylene), pent-4- enylene (a C5alkenylene), penta-1,4-dienylene (a C5alkenylene), hexa-1-enylene (a C6alkenylene), hexa-2-enylene (a C6alkenylene), hexa-3-enylene (a C6alkenylene), hexa-1-,4- 30 dienylene (a C6alkenylene), hexa-1-,5-dienylene (a C6alkenylene) and hexa-2-,4-dienylene (a C6alkenylene). The term “C2-C6alkenylene”, as used herein, refers to a bivalent straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to three carbon atoms. Non-limiting examples of "C2-C3alkenylene" groups include ethenylene (a C2alkenylene) and prop-1-enylene 35 (a C3alkenylene).

[0124] The term “cycloalkyl,” as used herein, refers to a non-aromatic, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system. In some embodiments, the cycloalkyl is a mono- or bi-cyclic saturated carbocyclic group containing from 3 to 10 ring members, which may include fused, bridged or spiro ring systems. Non-limiting examples of fused bicyclic or 40 bridged polycyclic ring systems include bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and 1 PAT059646-WO-PCT 5 adamantanyl. Non-limiting examples monocyclic C3-C8cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.

[0125] The term heteroarylene, cycloalkylene, heterocycloalkylene mean a divalent heteroaryl, cycloalkyl and heterocycloalkyl.

[0126] The term “haloalkyl,” as used herein, refers to a linear or branched alkyl chain 10 substituted with one or more halogen groups in place of hydrogens along the hydrocarbon chain. Examples of halogen groups suitable for substitution in the haloalkyl group include Fluorine, Bromine, Chlorine, and Iodine. Haloalkyl groups may include substitution with multiple halogen groups in place of hydrogens in an alkyl chain, wherein said halogen groups can be attached to the same carbon or to another carbon in the alkyl chain. 15

[0127] As used herein, the alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups may be optionally substituted by 1 to 4 groups selected from optionally substituted linear or branched (C1-C6)alkyl, optionally substituted linear or branched (C2- C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (C1-C6)alkoxy, optionally substituted (C1-C6)alkyl-S-, hydroxy, oxo 20 (or N-oxide where appropriate), nitro, cyano, -C(O)-OR0’, -O-C(O)-R0’, -C(O)-NR0’R0’’, -NR0’R0’’, -(C=NR0’)-OR0’’, linear or branched (C1-C6) haloalkyl, trifluoromethoxy, or halogen, wherein R0’ and R0’’ are each independently a hydrogen atom or an optionally substituted linear or branched (C1-C6)alkyl group, and wherein one or more of the carbon atoms of linear or branched (C1- C6)alkyl group is optionally deuterated. 25 Definitions for Terms in Drug Moieties

[0128] Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise 30 indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination.

[0129] Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. 35

[0130] Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such 40 stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of PAT059646-WO-PCT 5 the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0131] In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms 10 result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone – enol pairs, amide – imidic acid pairs, lactam – lactim pairs, amide – imidic acid pairs, enamine – imine 15 pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion. 20

[0132] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I and125I. Isotopically- 25 labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some 30 embodiments, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0133] Preparations of isotopically labelled compounds are known to those of skill in the art. For 35 example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0134] As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, 40 solvate). In some embodiments, compounds disclosed herein may be utilized in any such form, PAT059646-WO-PCT 5 including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.

[0135] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure includes each and every individual subcombination of the members of such groups 10 and ranges. For example, the term “C1-C6alkyl” is specifically intended to individually disclose methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl. Furthermore, where a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual 15 subcombination of members at each position.

[0136] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more “optionally 20 substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may 25 be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. For example, in the term “optionally substituted C1-C6alkyl-C2-C9heteroaryl,” the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The 30 term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0137] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group may be, independently, deuterium; halogen; -(CH2)0-4R°; -(CH2)0-4OR°; - 35 O(CH2)0-4Ro; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-4O(CH2)0-1Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R°; 4-8 membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; -(CH2)0-40 PAT059646-WO-PCT 5 (CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4-C(O)-N(R°)2; -(CH2)0-4-C(O)-N(R°)-S(O)2- R°; -C(NCN)NR°2; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OsiR°3; -(CH2)0-4OC(O)R°; -OC( O)(CH2)0-4SR°; -SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; - (CH2)0-4S(O)2R°; -( CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -10 N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; - P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°, -SiR°3; -(C1-4straight or branched alkylene)O-N(R°)2; or –(C1-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6aliphatic, -CH2Ph, - O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl ring), or a 3-6-membered saturated, partially 15 unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below. 20

[0138] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 25 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R*is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected 30 from nitrogen, oxygen, or sulfur.

[0139] Suitable substituents on the aliphatic group of R*include halogen, -R•, -(haloR•), -OH, - OR•, -O(haloR•), -CN, -C(O)OH, -C(O)OR•, -NH2, -NHR•, -NR•2, or -NO2, wherein each R•is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially 35 unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0140] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include - R†, -NR†2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2 C(NH)NR†2, or -N(R†)S(O)2R†; wherein each R†is independently hydrogen, C -6aliphatic which may 40 be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, PAT059646-WO-PCT 5 oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0141] Suitable substituents on an aliphatic group of R†are independently halogen, -R•, -(haloR•), - 10 OH, -OR•, -O(haloR•), -CN, -C(O)OH, -C(O)OR•, -NH2, -NHR•, -NR•2, or -NO2, wherein each R•is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R †include =O and =S. 15

[0142] The term “acetyl,” as used herein, refers to the group -C(O)CH3.

[0143] The term “alkoxy,” as used herein, refers to a -O-C1-C20alkyl group, wherein the alkoxy group is attached to the remainder of the compound through an oxygen atom.

[0144] The term “alkyl,” as used herein, refers to a saturated, straight or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons. In some 20 embodiments, an alkyl group is unbranched (i.e., is linear); in some embodiments, an alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0145] The term "heteroalkyl,” as used herein, refers to an "alkyl" group, as defined herein, in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom), 25 however the heteroalkyl group must contain at least one carbon atom after all replacements; for example, -NH-CH2-CH3, -CH2-NH-CH3, -CH2-N-(CH3)2, and -CH2-CH2-NH2are heteroalkyls but - NH2is not. When replacing a carbon with a heteroatom, an appropriate number of hydrogens are adjusted to fill out valences; for example, -CH2- can be replaced by groups such as -O, -S-, and -NH-, while -CH- can be replaced by groups such as -N-. The heteroatom may appear in 30 any part of the radical, for example in the middle or at either end of the radical. The number of carbons listed in the heteroalkyl refers to the number of carbons after all heteroatom replacements. For example, “C1-6heteroalkyl” means that there are between 1 and 6 carbon atoms in the heteroalkyl group, but there are also one or more heteroatoms; for example, -O- CH2-CH3 is a C2 heteroalkyl, not a C3 heteroalkyl. Heteroalkyl is thus inclusive of amines, 35 alkoxys, and thioethers, in addition to other groups. In some embodiments the heteroatoms in a heteroalkyl are selected from the group consisting of N, O and S.

[0146] The term “alkylene,” as used herein, represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term “Cx-Cy 40 alkylene” represents alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or PAT059646-WO-PCT 5 20 (e.g., C1-C6, C1-C10, C2-C20, C2-C6, C2-C10, or C2-C20 alkylene). In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

[0147] The term “alkenyl,” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1- 10 propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. The term “alkenylene,” as used herein, represents a divalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0148] The term “alkynyl,” as used herein, represents monovalent straight or branched chain 15 groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, and 1-propynyl.

[0149] The term “amino,” as used herein, represents -N(R†)2, e.g., -NH2and -N(CH3)2.

[0150] The term “aminoalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties. 20

[0151] The term “aryl,” as used herein, represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, wherein the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise 25 specified. In some embodiments, the aryl refers to a phenyl, nahthyl, biphenyl or indenyl group.

[0152] The term “C0,” as used herein, represents a bond. For example, part of the term - N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented by - N(C(O)-H)-.

[0153] The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to a monovalent, 30 optionally substituted C3-C12monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused or spirocyclic, in which all the rings are formed by carbon atoms and at least one ring is non-aromatic.

[0154] Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 35 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.

[0155] The term “carbonyl,” as used herein, represents a C(O) group, which can also be represented as C=O. 40

[0156] The term “carboxyl,” as used herein, means -CO2H, (C=O)(OH), COOH, or C(O)OH or the unprotonated counterparts. PAT059646-WO-PCT 5

[0157] The term “cyano,” as used herein, represents a -CN group.

[0158] The term “diastereomer,” as used herein, means stereoisomers that are not mirror images of one another and are non-superimposable on one another.

[0159] The term “enantiomer,” as used herein, means each individual optically active form of a compound disclosed herein, having an optical purity or enantiomeric excess (as determined by 10 methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

[0160] The term “haloalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same or different halogen moieties.

[0161] The term “halogen,” or “halo” as used herein, represents a halogen selected from 15 bromine, chlorine, iodine, and fluorine.

[0162] The term “heteroaryl,” as used herein, represents a monovalent, monocyclic or polycyclic ring structure that contains at least one fully aromatic ring: i.e., they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contains at least one ring heteroatom selected from N, O, or S in that aromatic ring. Exemplary unsubstituted heteroaryl 20 groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term “heteroaryl” incIudes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more, aryl or carbocyclic rings, e.g., a phenyl ring, or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, 25 tetrahydroquinolinyl, and 4-azaindolyl. A heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups. In some embodiments, the heteroaryl any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and 30 containing from 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogens).

[0163] The term “heterocycloalkyl,” as used herein, represents a monovalent monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused or spirocyclic, wherein at least one ring is non-aromatic and wherein the non-aromatic ring contains one, two, three, or four 35 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocycloalkyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.

[0164] The term “heterocycloalkyl” also represents a heterocyclic compound having a bridged 40 multicyclic structure in which one or more carbons or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term “heterocycloalkyl” includes PAT059646-WO-PCT 5 bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring.

[0165] Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4- 10 tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronapthyridinyl. A heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.

[0166] The term “hydroxy,” as used herein, represents a -OH group. 15

[0167] The term “hydroxyalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties.

[0168] The term “isomer,” as used herein, means any tautomer, stereoisomer, atropiosmer, enantiomer, or diastereomer of any compound disclosed herein. It is recognized that the compounds disclosed herein can have one or more chiral centers or double bonds and, 20 therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The chemical structures depicted herein, and therefore the compounds disclosed herein, encompass all the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric 25 mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of compounds disclosed herein can typically be resolved into their component enantiomers or stereoisomers by well- known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from 30 stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0169] The term “stereoisomer,” as used herein, refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric 35 forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds of the present disclosure may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

[0170] The term “sulfonyl” or "sulphonyl," as used herein, represents an -S(O)2- group.

[0171] The term “thiocarbonyl,” as used herein, refers to a -C(S)- group. 40 PAT059646-WO-PCT 5 Therapeutic Uses and Compositions

[0172] Disclosed herein are methods of using the compositions described herein, e.g., the disclosed panRAS inhibitor compounds and compositions, in treating a subject for a disorder, e.g., a cancer. Compositions, e.g., panRAS inhibitors, may be administered alone or in 10 combination with at least one additional inactive and / or active agent, e.g., at least one additional therapeutic agent, and may be administered in any pharmaceutically acceptable formulation, dosage, and dosing regimen. Treatment efficacy may be evaluated for toxicity as well as indicators of efficacy and adjusted accordingly. Efficacy measures include, but are not limited to, a cytostatic and / or cytotoxic effect observed in vitro or in vivo, reduced tumor volume, tumor 15 growth inhibition, and / or prolonged survival.

[0173] Methods of determining whether a panRAS inhibitor exerts a cytostatic and / or cytotoxic effect on a cell are known. For example, the cytotoxic or cytostatic activity of a panRAS inhibitor can be measured by, e.g., exposing mammalian cells to the panRAS inhibitor in a cell culture medium; culturing the cells for a period from about 6 hr to about 6 days; and measuring cell 20 viability (e.g., using a CellTiter-Glo® (CTG) or MTT cell viability assay). Cell-based in vitro assays may also be used to measure viability (proliferation), cytotoxicity, and induction of apoptosis (caspase activation) of the panRAS inhibitor.

[0174] For determining cytotoxicity, necrosis or apoptosis (programmed cell death) may be measured. Necrosis is typically accompanied by increased permeability of the plasma 25 membrane, swelling of the cell, and rupture of the plasma membrane. Apoptosis can be quantitated, for example, by measuring DNA fragmentation. Commercial photometric methods for the quantitative in vitro determination of DNA fragmentation are available. Examples of such assays, including TUNEL (which detects incorporation of labeled nucleotides in fragmented DNA) and ELISA-based assays, are described in Biochemica (1999) 2:34-7 (Roche Molecular 30 Biochemicals).

[0175] Apoptosis may also be determined by measuring morphological changes in a cell. For example, as with necrosis, loss of plasma membrane integrity can be determined by measuring uptake of certain dyes (e.g., a fluorescent dye such as, for example, acridine orange or ethidium bromide). A method for measuring apoptotic cell number has been described by Duke and 35 Cohen, Current Protocols in Immunology (Coligan et al., eds. (1992) pp.3.17.1-3.17.16). Cells also can be labeled with a DNA dye (e.g., acridine orange, ethidium bromide, or propidium iodide) and the cells observed for chromatin condensation and margination along the inner nuclear membrane. Apoptosis may also be determined, in some embodiments, by screening for caspase activity. In some embodiments, a Caspase-Glo® Assay can be used to measure 40 activity of caspase-3 and caspase-7. In some embodiments, the assay provides a luminogenic caspase-3 / 7 substrate in a reagent optimized for caspase activity, luciferase activity, and cell PAT059646-WO-PCT 5 lysis. In some embodiments, adding Caspase-Glo® 3 / 7 Reagent in an “add-mix-measure” format may result in cell lysis, followed by caspase cleavage of the substrate and generation of a “glow-type” luminescent signal, produced by luciferase. In some embodiments, luminescence may be proportional to the amount of caspase activity present, and can serve as an indicator of apoptosis. Other morphological changes that can be measured to determine apoptosis include, 10 e.g., cytoplasmic condensation, increased membrane blebbing, and cellular shrinkage. Determination of any of these effects on cancer cells indicates that a panRAS inhibitor is useful in the treatment of cancers.

[0176] Cell viability may be measured, e.g., by determining in a cell the uptake of a dye such as neutral red, trypan blue, Crystal Violet, or ALAMAR™ blue (see, e.g., Page et al. (1993) Intl J 15 Oncology 3:473-6). In such an assay, the cells are incubated in media containing the dye, the cells are washed, and the remaining dye, reflecting cellular uptake of the dye, is measured spectrophotometrically.

[0177] Cell viability may also be measured, e.g., by quantifying ATP, an indicator of metabolically active cells. In some embodiments, in vitro potency and / or cell viability of 20 prepared panRAS inhibitor compounds may be assessed using a CellTiter-Glo® (CTG) cell viability assay, as described in the examples provided herein. In this assay, in some embodiments, the single reagent (CellTiter-Glo® Reagent) is added directly to cells cultured in serum-supplemented medium. The addition of reagent results in cell lysis and generation of a luminescent signal proportional to the amount of ATP present. The amount of ATP is directly 25 proportional to the number of cells present in culture.

[0178] Cell viability may also be measured, e.g., by measuring the reduction of tetrazolium salts. In some embodiments, in vitro potency and / or cell viability of prepared panRAS inhibitor compounds may be assessed using an MTT cell viability assay, as described in the examples provided herein. In this assay, in some embodiments, the yellow tetrazolium MTT (3-(4, 5- 30 dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) is reduced by metabolically active cells, in part by the action of dehydrogenase enzymes, to generate reducing equivalents such as NADH and NADPH. The resulting intracellular purple formazan can then be solubilized and quantified by spectrophotometric means.

[0179] In certain aspects, the present disclosure features a method of killing, inhibiting or 35 modulating the growth of a cancer cell or tissue by disrupting the expression and / or activity of panRAS (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) and / or one or more upstream modulators or downstream targets thereof. The method may be used with any subject where disruption of panRAS (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) expression and / or activity provides a therapeutic 40 benefit. Subjects that may benefit from disrupting panRAS (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) expression and / or activity include, but are 1 PAT059646-WO-PCT 5 not limited to, those having or at risk of having a cancer such as a tumor or a hematological cancer. In some embodiments, the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal 10 cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer. 15

[0180] In some embodiments, the disclosed panRAS inhibitors may be administered in any cell or tissue that expresses EphA2, such as a EphA2-expressing cancer cell or tissue. An exemplary embodiment includes a method of killing a EphA2-expressing cancer cell or tissue. The method may be used with any cell or tissue that expresses EphA2, such as a cancerous cell or a metastatic lesion. Non-limiting examples of EphA2-expressing cancers include breast 20 cancer, non-small cell lung cancer, pancreatic cancer, esophageal cancer, head and neck cancer, gastric or stomach cancer, bladder cancer, and colorectal cancer.

[0181] In some embodiments, the disclosed panRAS inhibitors may be administered in any cell or tissue that expresses B7-H3 (CD276), such as a B7-H3 (CD276)-expressing cancer cell or tissue. An exemplary embodiment includes a method of killing a B7-H3 (CD276)-expressing 25 cancer cell or tissue. The method may be used with any cell or tissue that expresses B7-H3 (CD276), such as a cancerous cell or a metastatic lesion. Non-limiting examples of B7-H3 (CD276)-expressing cancers include colorectal cancer, pancreatic cancer, lymphoma, non-small cell lung cancer, small cell lung cancer, breast cancer including ER positive breast cancer, metastatic castration resistant prostate cancer, melanoma, bladder urothelial carcinoma, head 30 and neck cancer, and leukemia (e.g., acute myeloid leukemia).

[0182] Exemplary methods include the steps of contacting a cell with a panRAS inhibitor, as described herein, in an effective amount, i.e., an amount sufficient to kill the cell. The method can be used on cells in culture, e.g., in vitro, in vivo, ex vivo, or in situ. For example, cells that express EphA2 (e.g., cells collected by biopsy of a tumor or metastatic lesion; cells from an 35 established cancer cell line; or recombinant cells), can be cultured in vitro in culture medium and the contacting step can be affected by adding the panRAS inhibitor to the culture medium. The method will result in killing of cells expressing EphA2, including in particular cancer cells expressing EphA2. Alternatively, the panRAS inhibitor can be administered to a subject by any suitable administration route (e.g., intravenous, subcutaneous, or direct contact with a tumor 40 tissue) to have an effect in vivo. PAT059646-WO-PCT 5

[0183] The in vivo effect of a disclosed panRAS inhibitor therapeutic composition can be evaluated in a suitable animal model. For example, xenogeneic cancer models can be used, wherein cancer explants or passaged xenograft tissues are introduced into immune compromised animals, such as nude or SCID mice (Klein et al. (1997) Nature Med.3:402-8). Efficacy may be predicted using assays that measure inhibition of tumor formation, tumor 10 regression or metastasis, and the like.

[0184] In vivo assays that evaluate the promotion of tumor death by mechanisms such as apoptosis may also be used. In some embodiments, xenografts from tumor bearing mice treated with the therapeutic composition can be examined for the presence of apoptotic foci and compared to untreated control xenograft-bearing mice. The extent to which apoptotic foci are 15 found in the tumors of the treated mice provides an indication of the therapeutic efficacy of the composition.

[0185] Further provided herein are methods of treating a disorder, e.g., a cancer. The compositions described herein, e.g., the panRAS inhibitors disclosed herein, can be administered to a non-human mammal or human subject for therapeutic purposes. The 20 therapeutic methods include administering to a subject having or suspected of having a cancer a therapeutically effective amount of a composition comprising a panRAS inhibitor.

[0186] An exemplary embodiment is a method of treating a subject having or suspected of having a cancer, comprising administering to the subject a therapeutically effective amount of a composition disclosed herein, e.g., a panRAS inhibitor, composition, or pharmaceutical 25 composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow 30 cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, 35 prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.

[0187] In certain aspects, the present disclosure further provides methods of reducing or inhibiting growth of a tumor, comprising administering a therapeutically effective amount of a panRAS inhibitor or composition comprising a panRAS inhibitor. In some embodiments, the treatment is sufficient to reduce or inhibit the growth of the patient's tumor, reduce the number 40 or size of metastatic lesions, reduce tumor load, reduce primary tumor load, reduce invasiveness, prolong survival time, and / or maintain or improve the quality of life. In some PAT059646-WO-PCT 5 embodiments, the tumor is resistant or refractory to treatment with the panRAS inhibitor when administered alone.

[0188] An exemplary embodiment is a method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of an panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary 10 panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, 15 hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer. In some embodiments, the tumor is a gastric cancer. 20 In some embodiments, administration of the panRAS inhibitor, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to growth in the absence of treatment. 25

[0189] Another exemplary embodiment is a method of delaying or slowing the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the tumor is a breast cancer including ER positive breast cancer, multiple 30 myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant 35 prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer. In some embodiments, the tumor is a gastric cancer. In some embodiments, administration of the panRAS inhibitor, composition, or pharmaceutical composition delays or slows the growth of the tumor by at least about 10%, at least about 20%, 40 at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about PAT059646-WO-PCT 5 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to growth in the absence of treatment.

[0190] In certain aspects, the present disclosure further provides methods of reducing or slowing the expansion of a cancer cell population, comprising administering a therapeutically effective amount of a panRAS inhibitor or composition comprising a panRAS inhibitor. 10

[0191] An exemplary embodiment is a method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer cell population is from a tumor or a hematological cancer. In 15 some embodiments, the cancer cell population is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, 20 follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer. In some embodiments, administration of the panRAS inhibitor, composition, or pharmaceutical composition reduces the cancer cell 25 population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to the population in the absence of treatment. In some embodiments, administration of the panRAS inhibitor, composition, or pharmaceutical composition slows the expansion of the cancer cell population by at least about 30 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%, as compared to expansion in the absence of treatment.

[0192] Also provided herein are methods of determining whether a subject having or suspected of having a cancer will be responsive to treatment with the disclosed panRAS inhibitors and 35 compositions. An exemplary embodiment is a method of determining whether a subject having or suspected of having a cancer will be responsive to treatment with a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein) by providing a biological sample from the subject; contacting the sample with the panRAS inhibitor; and detecting binding 40 of the panRAS inhibitor to cancer cells in the sample. In some embodiments, the sample is a tissue biopsy sample, a blood sample, or a bone marrow sample. In some embodiments, the PAT059646-WO-PCT 5 method comprises providing a biological sample from the subject; contacting the sample with the panRAS inhibitor; and detecting one or more markers of cancer cell death in the sample (e.g., increased expression of one or more apoptotic markers, reduced expansion of a cancer cell population in culture, etc.).

[0193] Further provided herein are therapeutic uses of the disclosed panRAS inhibitors and 10 compositions. An exemplary embodiment is a panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein) for use in treating a subject having or suspected of having a cancer. Another exemplary embodiment is a use of an panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, 15 compositions, or pharmaceutical compositions disclosed herein) in treating a subject having or suspected of having a cancer. Another exemplary embodiment is a use of an panRAS inhibitor, composition, or pharmaceutical composition (e.g., any of the exemplary panRAS inhibitors, compositions, or pharmaceutical compositions disclosed herein) in a method of manufacturing a medicament for treating a subject having or suspected of having a cancer. 20

[0194] Moreover, panRAS inhibitors of the present disclosure may be administered to a non- human mammal for veterinary purposes or as an animal model of human disease. Regarding the latter, such animal models may be useful for evaluating the therapeutic efficacy of the disclosed panRAS inhibitors (e.g., testing of dosages and time courses of administration).

[0195] The therapeutic compositions used in the practice of the foregoing methods may be 25 formulated into pharmaceutical compositions comprising a pharmaceutically acceptable carrier suitable for the desired delivery method. An exemplary embodiment is a pharmaceutical composition comprising an panRAS inhibitor of the present disclosure and a pharmaceutically acceptable carrier, e.g., one suitable for a chosen means of administration, e.g., intravenous administration. The pharmaceutical composition may also comprise one or more additional 30 inactive and / or therapeutic agents that are suitable for treating or preventing, for example, a cancer (e.g., a standard-of-care agent, etc.). The pharmaceutical composition may also comprise one or more carrier, excipient, and / or stabilizer components, and the like. Methods of formulating such pharmaceutical compositions and suitable formulations are known in the art (see, e.g., “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA). 35

[0196] Suitable carriers include any material that, when combined with the therapeutic composition, retains the anti-tumor function of the therapeutic composition and is generally non- reactive with the patient’s immune system. Pharmaceutically acceptable carriers include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of 40 pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, mesylate salt, and the like, as well as combinations thereof. PAT059646-WO-PCT 5 In many cases, isotonic agents are included, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the panRAS inhibitor. 10

[0197] A pharmaceutical composition of the present disclosure can be administered by a variety of methods known in the art. The route and / or mode of administration may vary depending upon the desired results. In some embodiments, the therapeutic formulation is solubilized and administered via any route capable of delivering the therapeutic composition to the cancer site. Potentially effective routes of administration include, but are not limited to, parenteral (e.g., 15 intravenous, subcutaneous), intraperitoneal, intramuscular, intratumor, intradermal, intraorgan, orthotopic, and the like. In some embodiments, the administration is intravenous, subcutaneous, intraperitoneal, or intramuscular. The pharmaceutically acceptable carrier should be suitable for the route of administration, e.g., intravenous or subcutaneous administration (e.g., by injection or infusion). Depending on the route of administration, the 20 active compound(s), i.e., the panRAS inhibitor and / or any additional therapeutic agent, may be coated in a material to protect the compound(s) from the action of acids and other natural conditions that may inactivate the compound(s). Administration can be either systemic or local.

[0198] The therapeutic compositions disclosed herein may be sterile and stable under the conditions of manufacture and storage, and may be in a variety of forms. These include, for 25 example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended mode of administration and therapeutic application. In some embodiments, the disclosed panRAS inhibitors can be incorporated into a pharmaceutical composition suitable for parenteral administration. The injectable solution may30 be composed of either a liquid or lyophilized dosage form in a flint or amber vial, ampule, or pre- filled syringe, or other known delivery or storage device. In some embodiments, one or more of the panRAS inhibitors or pharmaceutical compositions is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted (e.g., with water or saline) to the appropriate concentration for administration to a subject. 35

[0199] Typically, a therapeutically effective amount or efficacious amount of a disclosed composition, e.g., a disclosed panRAS inhibitor, is employed in the pharmaceutical compositions of the present disclosure. The composition, e.g., one comprising an panRAS inhibitor, may be formulated into a pharmaceutically acceptable dosage form by conventional methods known in the art. Dosages and administration protocols for the treatment of cancers 40 using the foregoing methods will vary with the method and the target cancer, and will generally depend on a number of other factors appreciated in the art. PAT059646-WO-PCT 5

[0200] Dosage regimens for compositions disclosed herein, e.g., those comprising panRAS inhibitors alone or in combination with at least one additional inactive and / or active therapeutic agent, may be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus of one or both agents may be administered at one time, several divided doses may be administered over a predetermined period of time, or the dose of one or 10 both agents may be proportionally increased or decreased as indicated by the exigencies of the therapeutic situation. In some embodiments, treatment involves single bolus or repeated administration of the panRAS inhibitor preparation via an acceptable route of administration. In some embodiments, the panRAS inhibitor is administered to the patient daily, weekly, monthly, or any time period in between. For any particular subject, specific dosage regimens may be 15 adjusted over time according to the individual’s need, and the professional judgment of the treating clinician. Parenteral compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect 20 in association with the required pharmaceutical carrier.

[0201] Dosage values for compositions comprising a panRAS inhibitor and / or any additional therapeutic agent(s), may be selected based on the unique characteristics of the active compound(s), and the particular therapeutic effect to be achieved. A physician or veterinarian can start doses of the panRAS inhibitor employed in the pharmaceutical composition at levels 25 lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, effective doses of the compositions of the present disclosure, for the treatment of a cancer may vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is 30 prophylactic or therapeutic. The selected dosage level may also depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present disclosure employed, or the ester, salt, or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular 35 compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors. Treatment dosages may be titrated to optimize safety and efficacy.

[0202] Toxicity and therapeutic efficacy of compounds provided herein can be determined by standard pharmaceutical procedures in cell culture or in animal models. For example, LD50, 40 ED50, EC50, and IC50 may be determined, and the dose ratio between toxic and therapeutic effects (LD50 / ED50) may be calculated as the therapeutic index. The data obtained from in PAT059646-WO-PCT 5 vitro and in vivo assays can be used in estimating or formulating a range of dosage for use in humans. For example, the compositions and methods disclosed herein may initially be evaluated in xenogeneic cancer models (e.g., an NCI-H929 multiple myeloma mouse model).

[0203] In some embodiments, a panRAS inhibitor or composition comprising a panRAS inhibitor is administered on a single occasion. In other embodiments, a panRAS inhibitor or composition 10 comprising a panRAS inhibitor is administered on multiple occasions. Intervals between single dosages can be, e.g., daily, weekly, monthly, or yearly. Intervals can also be irregular, based on measuring blood levels of the administered agent (e.g., the panRAS inhibitor) in the patient in order to maintain a relatively consistent plasma concentration of the agent. The dosage and frequency of administration of a panRAS inhibitor or composition comprising a panRAS inhibitor 15 may also vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage may be administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively higher dosage at relatively shorter intervals is sometimes required until progression of the disease is reduced or terminated, and preferably 20 until the patient shows partial or complete amelioration of one or more symptoms of disease. Thereafter, the patient may be administered a lower, e.g., prophylactic regime.

[0204] The above therapeutic approaches can be combined with any one of a wide variety of additional surgical, chemotherapy, or radiation therapy regimens. In some embodiments, the panRAS inhibitors or compositions disclosed herein are co-formulated and / or co-administered 25 with one or more additional therapeutic agents, e.g., one or more chemotherapeutic agents, one or more standard-of-care agents for the particular condition being treated.

[0205] Kits for use in the therapeutic and / or diagnostic applications described herein are also provided. Such kits may comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) 30 comprising one of the separate elements to be used in a method disclosed herein. A label may be present on or with the container(s) to indicate that a panRAS inhibitor or composition within the kit is used for a specific therapy or non-therapeutic application, such as a prognostic, prophylactic, diagnostic, or laboratory application. A label may also indicate directions for either in vivo or in vitro use, such as those described herein. Directions and or other information may 35 also be included on an insert(s) or label(s), which is included with or on the kit. The label may be on or associated with the container. A label may be on a container when letters, numbers, or other characters forming the label are molded or etched into the container itself. A label may be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. The label may indicate that a panRAS inhibitor or 40 composition within the kit is used for diagnosing or treating a condition, such as a cancer a described herein. PAT059646-WO-PCT 5

[0206] In some embodiments, a kit comprises a panRAS inhibitor or composition comprising a panRAS inhibitor. In some embodiments, the kit further comprises one or more additional components, including but not limited to: instructions for use; other reagents, e.g., a therapeutic agent (e.g., a standard-of-care agent); devices, containers, or other materials for preparing the panRAS inhibitor for administration; pharmaceutically acceptable carriers; and devices, 10 containers, or other materials for administering the panRAS inhibitor to a subject. Instructions for use can include guidance for therapeutic applications including suggested dosages and / or modes of administration, e.g., in a patient having or suspected of having a cancer. In some embodiments, the kit comprises a panRAS inhibitor and instructions for use of the panRAS inhibitor in treating, preventing, and / or diagnosing a cancer. 15

[0207] It is known that elevated panRAS (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) expression correlates with resistance to radiation therapy and chemotherapy. PanRAS inhibitors that may not be sufficiently effective as monotherapy to treat cancer can be administered in combination with other therapeutic agents (including non- targeted and targeted therapeutic agents) or radiation therapy (including radioligand therapy) to 20 provide therapeutic benefit. Without wishing to be bound by theory, it is believed that the panRAS inhibitor s described herein sensitize tumor cells to the treatment with other therapeutic agents (including standard of care chemotherapeutic agents to which the tumor cells may have developed resistance) and / or radiation therapy. In some embodiments, panRAS inhibitors described herein, are administered to a subject having cancer in an amount effective to 25 sensitize the tumor cells. As used herein, the term “sensitize” means that the treatment with panRAS inhibitor increases the potency or efficacy of the treatment with other therapeutic agents and / or radiation therapy against tumor cells. COMBINATION THERAPIES 30

[0208] In some embodiments, the present disclosure provides methods of treatment wherein the panRAS inhibitors disclosed herein are administered in combination with one or more (e.g., 1 or 2) additional therapeutic agents. Exemplary combination partners are disclosed herein.

[0209] In certain embodiments, a combination described herein comprises a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is chosen from PDR001 (Novartis), Nivolumab (Bristol- 35 Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune). In some embodiments, the PD-1 inhibitor is PDR001. PDR001 is also known as Spartalizumab.

[0210] In certain embodiments, a combination described herein comprises a LAG-3 inhibitor. In 40 some embodiments, the LAG-3 inhibitor is chosen from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). PAT059646-WO-PCT 5

[0211] In certain embodiments, a combination described herein comprises a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is MBG453 (Novartis), TSR-022 (Tesaro), LY-3321367 (Eli Lily), Sym23 (Symphogen), BGB-A425 (Beigene), INCAGN-2390 (Agenus), BMS-986258 (BMS), RO-7121661 (Roche), or LY-3415244 (Eli Lilly).

[0212] In certain embodiments, a combination described herein comprises a PDL1 inhibitor. In 10 one embodiment, the PDL1 inhibitor is chosen from FAZ053 (Novartis), atezolizumab (Genentech), durvalumab (Astra Zeneca), or avelumab (Pfizer).

[0213] In certain embodiments, a combination described herein comprises a GITR agonist. In some embodiments, the GITR agonist is chosen from GWN323 (NVS), BMS-986156, MK-4166 or MK-1248 (Merck), TRX518 (Leap Therapeutics), INCAGN1876 (Incyte / Agenus), AMG 228 15 (Amgen) or INBRX-110 (Inhibrx).

[0214] In some embodiments, a combination described herein comprises an IAP inhibitor. In some embodiments, the IAP inhibitor comprises LCL161 or a compound disclosed in International Application Publication No. WO 2008 / 016893.

[0215] In an embodiment, the combination comprises an mTOR inhibitor, e.g., RAD001 (also20 known as everolimus).

[0216] In an embodiment, the combination comprises a HDAC inhibitor, e.g., LBH589. LBH589 is also known as panobinostat.

[0217] In an embodiment, the combination comprises an IL-17 inhibitor, e.g., CJM112.

[0218] In certain embodiments, a combination described herein comprises an estrogen receptor 25 (ER) antagonist. In some embodiments, the estrogen receptor antagonist is used in combination with a PD-1 inhibitor, a CDK4 / 6 inhibitor, or both. In some embodiments, the combination is used to treat an ER positive (ER+) cancer or a breast cancer (e.g., an ER+ breast cancer).

[0219] In some embodiments, the estrogen receptor antagonist is a selective estrogen receptor 30 degrader (SERD). SERDs are estrogen receptor antagonists which bind to the receptor and result in e.g., degradation or down-regulation of the receptor (Boer K. et al., (2017) Therapeutic Advances in Medical Oncology 9(7): 465-479). ER is a hormone-activated transcription factor important for e.g., the growth, development and physiology of the human reproductive system. ER is activated by, e.g., the hormone estrogen (17beta estradiol). ER expression and signaling 35 is implicated in cancers (e.g., breast cancer), e.g., ER positive (ER+) breast cancer. In some embodiments, the SERD is chosen from LSZ102, fulvestrant, brilanestrant, or elacestrant.

[0220] In some embodiments, the SERD comprises a compound disclosed in International Application Publication No. WO 2014 / 130310, which is hereby incorporated by reference in its entirety. 40

[0221] In some embodiments, the SERD comprises LSZ102. LSZ102 has the chemical name: (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3- PAT059646-WO-PCT 5 yl)oxy)phenyl)acrylic acid. In some embodiments, the SERD comprises fulvestrant (CAS Registry Number: 129453-61-8), or a compound disclosed in International Application Publication No. WO 2001 / 051056, which is hereby incorporated by reference in its entirety. In some embodiments, the SERD comprises elacestrant (CAS Registry Number: 722533-56-4), or a compound disclosed in U.S. Patent No.7,612,114, which is incorporated by reference in its10 entirety. Elacestrant is also known as RAD1901, ER-306323 or (6R)-6-{2-[Ethyl({4-[2- (ethylamino)ethyl]phenyl}methyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol. Elacestrant is an orally bioavailable, non-steroidal combined selective estrogens receptor modulator (SERM) and a SERD. Elacestrant is also disclosed, e.g., in Garner F et al., (2015) Anticancer Drugs 26(9):948-56. In some embodiments, the SERD is brilanestrant (CAS Registry 15 Number: 1365888-06-7), or a compound disclosed in International Application Publication No. WO 2015 / 136017, which is incorporated by reference in its entirety.

[0222] In some embodiments, the SERD is chosen from RU 58668, GW7604, AZD9496, bazedoxifene, pipendoxifene, arzoxifene, OP-1074, or acolbifene, e.g., as disclosed in McDonell et al. (2015) Journal of Medicinal Chemistry 58(12) 4883-4887. 20

[0223] Other exemplary estrogen receptor antagonists are disclosed, e.g., in WO 2011 / 156518, WO 2011 / 159769, WO 2012 / 037410, WO 2012 / 037411, and US 2012 / 0071535, all of which are hereby incorporated by reference in their entirety.

[0224] In certain embodiments, a combination described herein comprises an inhibitor of Cyclin-Dependent Kinases 4 or 6 (CDK4 / 6). In some embodiments, the CDK4 / 6 inhibitor is 25 used in combination with a PD-1 inhibitor, an estrogen receptor (ER) antagonist, or both. In some embodiments, the combination is used to treat an ER positive (ER+) cancer or a breast cancer (e.g., an ER+ breast cancer). In some embodiments, the CDK4 / 6 inhibitor is chosen from ribociclib, abemaciclib (Eli Lilly), or palbociclib.

[0225] In some embodiments, the CDK4 / 6 inhibitor comprises ribociclib (CAS Registry Number: 30 1211441-98-3), or a compound disclosed in U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety.

[0226] In some embodiments, the CDK4 / 6 inhibitor comprises a compound disclosed in International Application Publication No. WO 2010 / 020675 and U.S. Patent Nos.8,415,355 and 8,685,980, which are incorporated by reference in their entirety. 35

[0227] In some embodiments, the CDK4 / 6 inhibitor comprises ribociclib (CAS Registry Number: 1211441-98-3). Ribociclib is also known as LEE011, KISQALI®, or 7-cyclopentyl-N,N- dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0228] In some embodiments, the CDK4 / 6 inhibitor comprises abemaciclib (CAS Registry Number: 1231929-97-7). Abemaciclib is also known as LY835219 or N-[5-[(4-Ethyl-1-40 piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol- PAT059646-WO-PCT 5 6-yl]-2-pyrimidinamine. Abemaciclib is a CDK inhibitor selective for CDK4 and CDK6 and is disclosed, e.g., in Torres-Guzman R et al. (2017) Oncotarget 10.18632 / oncotarget.17778.

[0229] In some embodiments, the CDK4 / 6 inhibitor comprises palbociclib (CAS Registry Number: 571190-30-2). Palbociclib is also known as PD-0332991, IBRANCE® or 6-Acetyl-8- cyclopentyl-5-methyl-2-{[5-(1-piperazinyl)-2-pyridinyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. 10 Palbociclib inhibits CDK4 with an IC50 of 11nM, and inhibits CDK6 with an IC50 of 16nM, and is disclosed, e.g., in Finn et al. (2009) Breast Cancer Research 11(5):R77.

[0230] In certain embodiments, a combination described herein comprises an inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2). In some embodiments, the CXCR2 inhibitor is chosen from 6-chloro-3-((3,4-dioxo-2-(pentan-3-ylamino)cyclobut-1-en-1-yl)amino)-2-hydroxy-N- 15 methoxy-N-methylbenzenesulfonamide, danirixin, reparixin, or navarixin.

[0231] In some embodiments, the CSF-1 / 1R binding agent is chosen from an inhibitor of macrophage colony-stimulating factor (M-CSF), e.g., a monoclonal antibody or Fab to M-CSF (e.g., MCS110), a CSF-1R tyrosine kinase inhibitor (e.g., 4-((2-(((1R,2R)-2- hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide or BLZ945), a 20 receptor tyrosine kinase inhibitor (RTK) (e.g., pexidartinib), or an antibody targeting CSF-1R (e.g., emactuzumab or FPA008). In some embodiments, the CSF-1 / 1R inhibitor is BLZ945. In some embodiments, the CSF-1 / 1R binding agent is MCS110. In other embodiments, the CSF- 1 / 1R binding agent is pexidartinib.

[0232] In certain embodiments, a combination described herein comprises a c-MET 25 inhibitor. c-MET, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis. Inhibition of c-MET may induce cell death in tumor cells overexpressing c-MET protein or expressing constitutively activated c-MET protein. In some embodiments, the c-MET inhibitor is chosen from capmatinib (INC280), JNJ-3887605, AMG 337, LY2801653, 30 MSC2156119J, crizotinib, tivantinib, or golvatinib.

[0233] In certain embodiments, a combination described herein comprises a transforming growth factor beta (also known as TGF- TGF , TGFb, or TGF-beta, used interchangeablyherein) inhibitor. In some embodiments, the TGF- inhibitor is chosen from fresolimumab orXOMA 089. 35

[0234] In certain embodiments, a combination described herein comprises an adenosine A2a receptor (A2aR) antagonist (e.g., an inhibitor of A2aR pathway, e.g., an adenosine inhibitor, e.g., an inhibitor of A2aR or CD-73). In some embodiments, the A2aR antagonist is used in combination with a PD-1 inhibitor, and one or more (e.g., two, three, four, five, or all) of a CXCR2 inhibitor, a CSF-1 / 1R binding agent, LAG-3 inhibitor, a GITR agonist, a c-MET inhibitor, 40 or an IDO inhibitor. In some embodiments, the combination is used to treat a pancreatic cancer, a colorectal cancer, a gastric cancer, or a melanoma (e.g., a refractory melanoma). In some PAT059646-WO-PCT 5 embodiments, the A2aR antagonist is chosen from PBF509 (NIR178) (Palobiofarma / Novartis), CPI444 / V81444 (Corvus / Genentech), AZD4635 / HTL-1071 (AstraZeneca / Heptares), Vipadenant (Redox / Juno), GBV-2034 (Globavir), AB928 (Arcus Biosciences), Theophylline, Istradefylline (Kyowa Hakko Kogyo), Tozadenant / SYN-115 (Acorda), KW-6356 (Kyowa Hakko Kogyo), ST- 4206 (Leadiant Biosciences), or Preladenant / SCH 420814 (Merck / Schering). Without wishing to 10 be bound by theory, it is believed that in some embodiments, inhibition of A2aR leads to upregulation of IL-1b.

[0235] In certain embodiments, a combination described herein comprises an inhibitor of indoleamine 2,3-dioxygenase (IDO) and / or tryptophan 2,3-dioxygenase (TDO). In some embodiments, the IDO inhibitor is used in combination with a PD-1 inhibitor, and one or more15 (e.g., two, three, four, or all) of a TGF- inhibitor, an A2aR antagonist, a CSF-1 / 1R bindingagent, a c-MET inhibitor, or a GITR agonist. In some embodiments, the combination is used to treat a pancreatic cancer, a colorectal cancer, a gastric cancer, or a melanoma (e.g., a refractory melanoma). In some embodiments, the IDO inhibitor is chosen from (4E)-4-[(3- chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine (also known as epacadostat20 or INCB24360), indoximod (NLG8189), (1-methyl-D-tryptophan), -cyclohexyl-5H-Imidazo[5,1- a]isoindole-5-ethanol (also known as NLG919), indoximod, BMS-986205 (formerly F001287).

[0236] In certain embodiments, a combination described herein comprises a Galectin, e.g., Galectin-1 or Galectin-3, inhibitor. In some embodiments, the combination comprises a Galectin-1 inhibitor and a Galectin-3 inhibitor. In some embodiments, the combination 25 comprises a bispecific inhibitor (e.g., a bispecific antibody molecule) targeting both Galectin-1 and Galectin-3. In some embodiments, the Galectin inhibitor is used in combination with one or more therapeutic agents described herein. In some embodiments, the Galectin inhibitor is chosen from an anti-Galectin antibody molecule, GR-MD-02 (Galectin Therapeutics), Galectin- 3C (Mandal Med), Anginex, or OTX-008 (OncoEthix, Merck). 30 In some embodiments, a combination described herein comprises an inhibitor of the MAP kinase pathway including ERK inhibitors, MEK inhibitors and RAF inhibitors.

[0237] In some embodiments, a combination described herein comprises a MEK inhibitor. In some embodiments, the MEK inhibitor is chosen from Trametinib, selumetinib, AS703026, BIX 02189, BIX 02188, CI-1040, PD0325901, PD98059, U0126, XL-518, G-38963, or 35 G02443714.

[0238] In some embodiments, the MEK inhibitor is trametinib. Trametinib is also known as JTP-74057, TMT212, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide, or Mekinist (CAS Number 871700-17-3). 40

[0239] In some embodiments, the MEK inhibitor comprises selumetinib which has the chemical name: (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H- PAT059646-WO-PCT 5 benzimidazole-6-carboxamide. Selumetinib is also known as AZD6244 or ARRY 142886, e.g., as described in PCT Publication No. WO2003077914.

[0240] In some embodiments, the MEK inhibitor comprises AS703026, BIX 02189 or BIX 02188.

[0241] In some embodiments, the MEK inhibitor comprises 2-[(2-Chloro-4-iodophenyl)amino]-N- 10 (cyclopropylmethoxy)-3,4-difluoro-benzamide (also known as CI-1040 or PD184352), e.g., as described in PCT Publication No. WO2000035436).

[0242] In some embodiments, the MEK inhibitor comprises N-[(2R)-2,3-Dihydroxypropoxy]-3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide (also known as PD0325901), e.g., as described in PCT Publication No. WO2002006213). 15

[0243] In some embodiments, the MEK inhibitor comprises 2’-amino-3’-methoxyflavone (also known as PD98059) which is available from Biaffin GmbH & Co., KG, Germany.

[0244] In some embodiments, the MEK inhibitor comprises 2,3-bis[amino[(2- aminophenyl)thio]methylene]-butanedinitrile (also known as U0126), e.g., as described in US Patent No.2,779,780). 20

[0245] In some embodiments, the MEK inhibitor comprises XL-518 (also known as GDC-0973) which has a CAS No.1029872-29-4 and is available from ACC Corp.

[0246] In some embodiments, the MEK inhibitor comprises G-38963.

[0247] In some embodiments, the MEK inhibitor comprises G02443714 (also known as AS703206) 25

[0248] Additional examples of MEK inhibitors are disclosed in WO 2013 / 019906, WO 03 / 077914, WO 2005 / 121142, WO 2007 / 04415, WO 2008 / 024725 and WO 2009 / 085983, the contents of which are incorporated herein by reference. Further examples of MEK inhibitors include, but are not limited to, 2,3-Bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126 and described in US Patent No.2,779,780); (3S,4R,5Z,8S,9S,11E)-14-30 (Ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9, 19-tetrahydro-1H-2-benzoxacyclotetradecine- 1,7(8H)-dione] (also known as E6201, described in PCT Publication No. WO2003076424); vemurafenib (PLX-4032, CAS 918504-65-1); (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4- iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS 1035555- 63-5); pimasertib (AS-703026, CAS 1204531-26-9); 2-(2-Fluoro-4-iodophenylamino)-N-(2-35 hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); and 3,4- Difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinan-2- yl)methyl]benzamide (CH 4987655 or Ro 4987655).

[0249] In some embodiments, a combination described herein comprises a RAF inhibitor.

[0250] RAF inhibitors include, but are not limited to, Vemurafenib (or Zelboraf®, PLX-4032, 40 CAS 918504-65-1), GDC-0879, PLX-4720 (available from Symansis), Dabrafenib (or PAT059646-WO-PCT 5 GSK2118436), LGX 818, CEP-32496, UI-152, RAF 265, Regorafenib (BAY 73-4506), CCT239065, or Sorafenib (or Sorafenib Tosylate, or Nexavar®).

[0251] In some embodiments, the RAF inhibitor is Dabrafenib.

[0252] In some embodiments, the RAF inhibitor is LXH254.

[0253] In some embodiments, a combination described herein comprises an ERK inhibitor. 10

[0254] ERK inhibitors include, but are not limited to, LTT462, ulixertinib (BVD-523), LY3214996, GDC-0994, KO-947 and MK-8353.

[0255] In some embodiments, the ERK inhibitor is LTT462. LTT462 is 4-(3-amino-6- ((1S,3S,4S)-3-fluoro-4-hydroxy¬cyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2- (methylamino)¬ethyl)-2-fluorobenzamide and is the compound of the following structure: 15

[0256] The preparation of LTT462 is described in PCT patent application publication WO2015 / 066188. LTT462 is an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK 1 / 2).

[0257] In some embodiments, a combination described herein comprises a taxane, a vinca 20 alkaloid, a MEK inhibitor, an ERK inhibitor, or a RAF inhibitor.

[0258] In some embodiments, a combination described herein comprises at least two inhibitors selected, independently, from a MEK inhibitor, an ERK inhibitor, and a RAF inhibitor.

[0259] In some embodiments, a combination described herein comprises an anti-mitotic drug.

[0260] In some embodiments, a combination described herein comprises a taxane. 25

[0261] Taxanes include, but are not limited to, docetaxel, paclitaxel, or cabazitaxel. In some embodiments, the taxane is docetaxel.

[0262] In some embodiments, a combination described herein comprises a vinca alkaloid.

[0263] Vinca alkaloids include, but are not limited to, vincristine, vinblastine, and leurosine.

[0264] In some embodiments, a combination described herein comprises a topoisomerase 30 inhibitor.

[0265] Topoisomerase inhibitors include, but are not limited to, topotecan, irinotecan, camptothecin, diflomotecan, lamellarin D, ellipticines, etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, aurintricarboxylic acid, and HU-331. PAT059646-WO-PCT 5

[0266] In one embodiment, a combination described herein includes an interleukin-1 beta (IL- 1) inhibitor. In some embodiments, the IL-1 inhibitor is chosen from canakinumab,gevokizumab, Anakinra, or Rilonacept.

[0267] In certain embodiments, a combination described herein comprises an IL-15 / IL-15Ra complex. In some embodiments, the IL-15 / IL-15Ra complex is chosen from NIZ985 (Novartis), 10 ATL-803 (Altor) or CYP0150 (Cytune).

[0268] In certain embodiments, a combination described herein comprises a mouse double minute 2 homolog (MDM2) inhibitor. The human homolog of MDM2 is also known as HDM2. In some embodiments, an MDM2 inhibitor described herein is also known as a HDM2 inhibitor. In some embodiments, the MDM2 inhibitor is chosen from HDM201 or CGM097. 15

[0269] In an embodiment the MDM2 inhibitor comprises (S)-1-(4-chlorophenyl)-7-isopropoxy-6- methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1- yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one (also known as CGM097) or a compound disclosed in PCT Publication No. WO 2011 / 076786 to treat a disorder, e.g., a disorder described herein). In one embodiment, a therapeutic agent disclosed herein is used in 20 combination with CGM097.

[0270] In some embodiments, a combination described herein comprises a hypomethylating agent (HMA). In some embodiments, the HMA is chosen from decitabine or azacitidine.

[0271] In some embodiments, a combination described herein comprises a glucocorticoid. In some embodiments, the glucocorticoid is dexamethasone. 25

[0272] In some embodiments, a combination described herein comprises asparaginase.

[0273] In certain embodiments, a combination described herein comprises an inhibitor acting on any pro-survival proteins of the Bcl2 family. In certain embodiments, a combination described herein comprises a Bcl-2 inhibitor. In some embodiments, the Bcl-2 inhibitor is venetoclax (also known 30

[0274] In one embodiment, the Bcl-2 inhibitor is selected from the compounds described in WO 2013 / 110890 and WO 2015 / 011400. In some embodiments, the Bcl-2 inhibitor comprises navitoclax (ABT-263), ABT-737, BP1002, SPC2996, APG-1252, obatoclax mesylate (GX15- 070MS), PNT2258, Zn-d5, BGB-11417, or oblimersen (G3139). In some embodiments, the Bcl-35 2 inhibitor is N-(4-hydroxyphenyl)-3-[6-[(3S)-3-(morpholinomethyl)-3,4-dihydro-1H-isoquinoline- PAT059646-WO-PCT 5 2-carbonyl]-1,3-benzodioxol-5-yl]-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide, compound A1: (compound A1).

[0275] In some embodiments, the Bcl-2 inhibitor is (S)-5-(5-chloro-2-(3-(morpholinomethyl)-10 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide), compound A2: (compound A2).

[0276] In one embodiment, the panRAS inhibitors or combinations disclosed herein are suitable for the treatment of cancer in vivo. For example, the combination can be used to inhibit the 15 growth of cancerous tumors. The combination can also be used in combination with one or more of: a standard of care treatment (e.g., for cancers or infectious disorders), a vaccine (e.g., a therapeutic cancer vaccine), a cell therapy, a hormone therapy (e.g., with anti-estrogens or anti-androgens), a radiation therapy, surgery, or any other therapeutic agent or modality, to treat a disorder herein. For example, to achieve antigen-specific enhancement of immunity, the 20 combination can be administered together with an antigen of interest. A combination disclosed herein can be administered in either order or simultaneously. EXAMPLES 25 PAT059646-WO-PCT 5

[0277] The following examples provide illustrative embodiments of the disclosure. One of ordinary skill in the art will recognize the numerous modifications and variations that may be performed without altering the spirit or scope of the disclosure. Such modifications and variations are encompassed within the scope of the disclosure. The examples provided do not in any way limit the disclosure. 10 Example 1. Synthesis and Characterization of panRAS Inhibitors, and Precursors thereof

[0278] Exemplary panRAS inhibitors and intermediates were synthesized using exemplary methods described in this example. 15 Materials, Methods & General Procedures: Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. 20 Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. Analytical Methods, Materials, and Instrumentation 25 Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (1H NMR) spectra were acquired on Bruker AVANCE 400 MHz, 500 MHz or 600 MHz NMR spectrometers using ICON-NMR, under TopSpin program control unless otherwise noted. Spectra were measured at 298 K, unless indicated otherwise, and 30 were referenced relative to the solvent resonance. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide ( 2.50),methanol ( 3.31), chloroform ( 7.26) or other solvent as indicated in NMR spectral data. A smallamount of the dry sample (2 to 5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemDraw Professional v22 from PerkinElmer. 35 Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical and electron impact ionization methods from a range of instruments of the following configurations: Waters Acquity UPLC / SQD system, using a photodiode array detector and a single quadrupole mass detector; Agilent 1200 systems with G 6110 series mass detector; Agilent 40 1290 Infinity II with DAD (photodiode array detector) and single quadrupole mass detector with ESI and APCI ionization (multi-mode);Waters AcQuity UPLC with PDA (photodiode array PAT059646-WO-PCT 5 detector), ELSD and single quadrupole mass detector with ESI ionization; Waters AutoPurification System with PDA (photodiode array detector) and single quadrupole mass detector with ESI ionization; [M+H]+refers to protonated molecular ion of the chemical species; [M-H]- refers to molecular ion of the chemical species with loss of one proton; [M+Na]+refers to molecular ion of the chemical species with addition of one sodium ion; [M-Boc+H]+refers to protonated molecular 10 ion of the chemical species without a Boc protecting group; [M-tBu+2H]+refers to protonated molecular ion of the chemical species without a tert-butyl group. Abbreviations Some abbreviations used in the examples are as follows: 1,1-bis(di-tert-butylphosphino)-15 ferrocenedichloropalladium (II) (PdCl2(dtpf) or Pd(dtpf)Cl2); 1,1-bis(diphenylphosphino)- ferrocenedichloropalladium (II) (PdCl2(dppf) or Pd(dppf)Cl2); 1,1-carbonyldiimidazole (CDI);(1- cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU); 1-hydroxy-7-azabenzotriazole (HOAt); 2-(1H-7-azabenzotriazol- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU); 2,2'-bis-diphenylphospphanyl- 20 [1,1']binaphthalenyl (BINAP); 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TSTU); 4-dimethylaminopyridine (DMAP); 3-morpholinopropane-1-sulfonic acid (MOPS); (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (xantphos); acetic acid (AcOH); acetic anhydride (Ac2O); acetonitrile (CH3CN); ammonium hydroxide (NH4OH); aqueous (aq.); atmosphere (atm.); back pressure regulator (BPR); broad (br); bromo-tris-25 pyrrolidino-phosphonium hexafluorophosphate (PyBroP); benzotriazole-1-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate (BOP); cesium carbonate (Cs2CO3); doublet (d); 1,2-dichloroethane (DCE); dichloromethane (DCM); dicyclohexyl(2’,6’-dimethoxy[1,1’- biphenyl]-2-yl)phosphane (SPhos); dicyclohexyl[2 ,4 ,6 -tris(propan-2-yl)[1,1 -biphenyl]-2-yl]phosphane (XPhos); diethyl ether (Et2O); diisopropyl azodicarboxylate (DIAD); dimethyl 30 sulfoxide (DMSO); diphenylphosphoryl azide (DPPA); di-tert-butyl dicarbonate (Boc2O); equivalent(s) (equiv.); ethanol (EtOH); ethyl acetate (EtOAc); ethyl iodide (EtI); ethyl (E)-2-(((((9H- fluoren-9-yl)methoxy)carbonyl)oxy)imino)-2-cyanoacetate (Fmoc-Oxyma); fetal bovine serum (FBS); Förster resonance energy transfer (FRET); gram(s) (g); high performance liquid chromatography (HPLC); high-resolution mass spectrum (HRMS); homogeneous time-resolved 35 FRET (HTRF); hour(s) (hr); hydrochloric acid (HCl); inner diameter (I.D.); isopropanol (iPrOH); isopropylamine (iPr2NH); liquid chromatography coupled with mass spectrometry (LCMS); liter(s) (L); lithium aluminium hydride (LAH); lithium bis(trimethylsilyl)amide (LHMDS); lithium diisopropylamide (LDA); lithium bromide (LiBr); lithium hydroxide (LiOH); luminescence (LUM); magnesium sulfate (MgSO4); mass spectrum (MS); mass-to-charge ratio (m / z or M / Z); meta- 40 chloroperoxybenzoic acid (mCPBA); metabolism (MT); methanol (MeOH); methyl iodide (MeI); methyl magnesium bromide (MeMgBr); methyl tert-butyl ether (MTBE); 2-methyl tetrahydrofuran PAT059646-WO-PCT 5 (2-MeTHF); microwave (MW); microliter(s) (μL); micrometer(s) (μm); micromole(s) (μmol); milliliter(s) (mL); millimeter(s) (mm); millimole(s) (mmol); minute(s) (min); mole(s) (mol); multiplet (m); N-(3-dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDC); n-butyllithium (n-BuLi); N-chlorosuccinimide (NCS); N-hydroxy succinimide (NHS); N,N-diisopropylethylamine (DIPEA); N,N-dimethylformamide (DMF); N-methylpyrrolidone (NMP); isopropanol (iPrOH); 10 pentet (p); potassium hydroxide (KOH); potassium tert-butoxide (KOtBu); palladium(II) acetate (Pd(OAc)2); palladium on carbon (Pd / C); palladium hydroxide (Pd(OH)2); para-toluene sulfonic acid (PTSA); para-toluenesulfonyl chloride (TsCl); phosphate buffered saline (PBS); quartet (q); retention time (Rt); Roswell Park Memorial Institute medium (RPMI); room temperature (RT); saturated (sat.); singlet (s); second (sec.); sodium bicarbonate (NaHCO3); sodium borohydride 15 (NaBH4); sodium carbonate (Na2CO3); sodium hydride (NaH); sodium hydroxide (NaOH); sodium potassium-2,3-dihydroxybutane-1,4-dioate (Rochelle’s salt); sodium sulfate (Na2SO4); sodium thiosulfate (Na2S2O3); supercritical fluid chromatography (SFC); tert-butoxycarbonyl (Boc); tert- butyldimethylsilyl chloride (TBSCl); tetrabutylammonium fluoride (TBAF); tetrahydrofuran (THF); tetramethylammonium fluoride (TMAF); toluenesulfonylmethyl isocyanide (TosMIC); 20 triethylamine (NEt3); triethylsilane (Et3SiH); trifluoroacetic acid (TFA); triisopropylsilyl chloride (TIPS-Cl); trimethylaluminum (AlMe3); trimethylsilyl trifluoromethanesulfonate (TMSOTf); triplet (t); tris(2-carboxyethyl)phosphine (TCEP); tris(dibenzylidene)dipalladium(0) (Pd2dba3); tri-tert- butylphosphonium tetrafluoroborate (TTBP-HBF4); thionyl chloride (SOCl2); trimethylsilyl chloride (TMSCl); weight (wt.); silica gel, silica (SiO2), silver(I) oxide (Ag2O); silver(I)25 trifluoromethanesulfonate (AgOTf); para-toluenesulfonyl 1,2-diphenyl-1,2-ethylenediamine (Ts- DPEN). LCMS CONDITIONS RNXMON-basic (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 30mm; eluent A: H2O 30 + 5 mM ammonium hydroxide; eluent B: CH3CN + 5 mM ammonium hydroxide; eluent: 2 to 98% B in 2.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) RXNMON-Acidic (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.1% formic acid; eluent B: CH3CN + 0.1% formic acid; eluent: 2 to 98% B in 2.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) 35 RXNMON-TFA (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.05% trifluoroacetic acid; eluent B: CH3CN + 0.05% trifluoroacetic acid; eluent: 2 to 98% B in 2.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) 1 PAT059646-WO-PCT 5 FinalAnalysis-Basic (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 30mm; eluent A: H2O + 5 mM ammonium hydroxide; eluent B: CH3CN + 5 mM ammonium hydroxide; eluent: 2 to 98% B in 5.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) FinalAnalysis-Acidic (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.1% formic acid; eluent B: CH3CN + 0.1% formic acid; eluent: 2 to 98% B in 5.00 min; flow 10 rate: 1.0 mL / min; column temperature: 50°C.) FinalAnalysis-TFA (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.05% trifluoroacetic acid; eluent B: CH3CN + 0.05% trifluoroacetic acid; eluent: 2 to 98% B in 5.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) FinalAnalysis-Acidic-NonPolar (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; 15 eluent A: H2O + 0.1% formic acid; eluent B: CH3CN + 0.1% formic acid; eluent: 40 to 98% B in 2.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) FinalAnalysis-Basic-NonPolar (Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 30mm; eluent A: H2O + 5 mM ammonium hydroxide; eluent B: CH3CN + 5 mM ammonium hydroxide; eluent: 40 to 98% B in 2.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.) 20 Peptide Method (Acquity CSH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.05% trifluoroacetic acid; eluent B: CH3CN + 0.05% trifluoroacetic acid; eluent: 2 to 98% B in 5.00 min; flow rate: 1.0 mL / min; column temperature: 50°C.); Unless otherwise noted, HRMS was measured by Peptide Method with a MS detector. HPLC-quant.: (Zorbax Eclipse XDB-C18; particle size: 1.8 m; column size: 4.6 mm x 50 mm; 25 eluent A: H2O + 0.05% trifluoroacetic acid; eluent B: CH3CN + 0.05% trifluoroacetic acid; eluent: 5 to 100% B in 6.00 min; flow rate: 1.0 mL / min; column temperature: 35°C; detection at 215 nm) Final_Analysis_2min (Aquity CORTECS C18; particle size: 2.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.05% formic acid + 3.75 mM ammonium acetate; eluent B: 2-PrOH + 0.05% formic acid; eluent: 5 to 50% B in 1.40 min, 50 to 98% B in 0.3 min; flow rate: 1.0 mL / min; column 30 temperature: 80°C) HRMS_2min (Acquity CSH C18; particle size: 1.7 μm; column size: 2.1 x 50mm; eluent A: H2O + 0.05% trifluoroacetic acid; eluent B: CH3CN + 0.05% trifluoroacetic acid; eluent: 2 to 98% B in 2.00 min; flow rate: 1.0 mL / min; column temperature: 50°C) Prep_SFC1 (Column: Chiralcel OX-H 21x250mm 5um, Flow Rate: 100 g per minute, Cosolvent: 35 15% 4:1 heptane:isopropanol in CO2, detection: 211nm, back pressure regulator: 125 bar, Injection Size: 24.0mg (30.0 mg / mL in 4:1 Hp / IPA)) PAT059646-WO-PCT 5 Prep_SFC2 (2 x CHIRALPAK IG; particle size: 5 μm; column size: 30 x 250mm; modifier: 14% EtOH + 0.05% NH3; flow rate: 95.0 mL / min; duration: 2.2 min; preheater temperature: 40°C; back pressure regulator: 100 bar; detection wavelength: 214 nm) Prep_SFC3 (ChiralPak IG; particle size: 5 μm; flow rate: 80 mL / min; column size: 21 x 250 mm; modifier: 20% MeOH in CO2; detection wavelength: 215 nm; back pressure regulator: 125 bar) 10 Prep_SFC4 (Chiralcel OJ-H; particle size: 5 μm; flow rate: 85 mL / min; column size: 30 x 150 mm; modifier: 15% CH3OH in CO2; pre-heater temperature: 35 °C; detection wavelength: 220 nm; back pressure regulator: 100 bar) Prep_SFC5 (ChiralPak AD-H; particle size: 5 μm; flow rate: 45 mL / min; column size: 20 x 250 mm; modifier: 15% CH3OH in CO2; pre-heater temperature: 35 °C; detection wavelength: 220 nm; 15 back pressure regulator: 100 bar) Prep_SFC6 (ChiralPak IC; particle size: 5 μm; flow rate: 80 mL / min; column size: 21 x 250 mm; modifier: 15% MeOH in CO2; detection wavelength: 220 nm; back pressure regulator: 125 bar) Prep_SFC7 (ChiralPak IG; particle size: 4 μm; flow rate: 150 g / min; column size: 30 x 250 mm; modifier: 12% MeOH in CO2; detection wavelength: 215 nm; back pressure regulator: 125 bar) 20 Prep_SFC8 (Waters diol; particle size: 5 μm; flow rate: 120 g / min; column size: 30 x 250 mm; modifier: 30% MeOH containing 10 mM NH3in CO2; detection wavelength: 261 nm; back pressure regulator: 125 bar) Chiral_SFC1 (CHIRALPAK IG; particle size: 5 μm; column size: 4.6 x 100mm; modifier: 8% EtOH + NH3; flow rate: 3.0 mL / min; column temperature: 40°C; backpressure: 1800 psi) 25 Chiral_UPLC1 (OJ-RH; particle size: 5 μm; column size: 4.6 x 150mm; eluent 60% MeOH + 0.05% FA; flow rate: 0.5 mL / min; detection wavelength: 210 nm) Intermediate 1 3,4-di-tert-butyl 2-methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2,3,4-tricarboxylate 30 PAT059646-WO-PCT 5 Procedure Step a: To a stirred solution of di-tert-butyl (E)-diazene-1,2-dicarboxylate (8.00 g) in toluene (10 mL) was added methyl (E)-penta-2,4-dienoate (4.68 g). The resulting mixture was stirred at 80°C for 36 hr. The reaction mixture was purified directly by column chromatography (SiO2, 0 to 100% 10 EtOAc in heptane) to afford 1,2-di-tert-butyl 3-methyl 3,6-dihydropyridazine-1,2,3-tricarboxylate (7.70 g) as a white solid. LC / MS (RXNMON-Acidic method): M / Z = 343 [M+H]+.1H NMR (400 MHz, CDCl3) 5.93 (d, J = 2.9 Hz, 2H), 5.32 (s, 1H), 4.49 - 4.27 (m, 1H), 3.74 (s, 3H), 3.72 - 3.56 (m, 1H), 1.48 (s, 18H). 15 Step b: To a stirred solution of 1,2-di-tert-butyl 3-methyl 3,6-dihydropyridazine-1,2,3-tricarboxylate (7.50 g) in THF (20 mL) under a nitrogen atmosphere was added lithium borohydride (2 M in THF, 32.9 mL) dropwise. The resulting mixture was stirred at 0°C for 2 hr then warmed to RT and stirred for 1 hr. The reaction mixture was quenched by addition of sat. NaHCO3solution (20 mL), then diluted with EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (3 x 20 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 0 to 100% EtOAc in heptane) to afford di-tert-butyl 3-(hydroxymethyl)-3,6- 114 PAT059646-WO-PCT 5 dihydropyridazine-1,2-dicarboxylate (5.30 g) as a colorless oil. LC / MS (RXNMON-Acidic method): M / Z = 315 [M+H]+.1H NMR (400 MHz, CDCl3) 5.87 – 5.67 (m, 2H), 4.69 (s, 1H), 4.40 – 4.18 (m, 1H), 3.97 – 3.26 (m, 3H), 2.68 (s, 1H), 1.53 – 1.45 (m, 18H). Step c: To a stirred solution of di-tert-butyl 3-(hydroxymethyl)-3,6-dihydropyridazine-1,2- 10 dicarboxylate (5.30 g), DMAP (206 mg), and triethylamine (1.88 g) in DCM (30 mL) was added tert-butylchlorodiphenylsilane (4.63 g). The resulting mixture was stirred at 0°C for 4 hr. The reaction mixture was concentrated, and the resulting residue was taken up in minimal acetonitrile. The crude mixture was purified by column chromatography (C18, 40 to 100% acetonitrile in water + 0.1% formic acid), followed by lyophilization, to afford di-tert-butyl 3-(((tert- 15 butyldiphenylsilyl)oxy)methyl)-3,6-dihydropyridazine-1,2-dicarboxylate (7.10 g) as a colorless oil. LC / MS (RXNMON-Acidic-NonPolar method): M / Z = 575 [M+Na]+.1H NMR (400 MHz, CDCl3) 7.69 - 7.62 (m, 4H), 7.45 - 7.32 (m, 6H), 6.08 - 5.72 (m, 2H), 4.67 (d, J = 84.8 Hz, 1H), 4.42 - 4.14 (m, 1H), 4.03 - 3.50 (m, 3H), 1.45 (s, 9H), 1.27 (d, J = 5.5 Hz, 9H), 1.06 (s, 9H). 20 Step d: To a vigorously stirred solution of di-tert-butyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)-3,6- dihydropyridazine-1,2-dicarboxylate (150 mg) and benzyltriethylammonium chloride (2.2 mg) in DCM (0.50 mL) under a nitrogen atmosphere was added potassium hydroxide (8.0 M solution in water, 850 μL). The resulting mixture was cooled to 0°C, and bromoform (stabilized with ethanol, 1.71 g) was added dropwise over 30 min. using a syringe pump. The reaction mixture was stirred 25 at 0°C for 2 hr, then allowed to warm to RT and stirred for 16 hr. The reaction was quenched by addition of water (2 mL) and DCM (10 mL), then passed through a phase separator, washing with DCM. The resulting organic layer was concentrated under reduced pressure and the crude mixture was purified by column chromatography (SiO2, 0 to 50% EtOAc in heptane) to afford di- tert-butyl 7,7-dibromo-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4-diazabicyclo[4.1.0]heptane-3,4- 30 dicarboxylate (130mg) as a colorless oil. LC / MS (RXNMON-Acidic-NonPolar method): M / Z = 747 [M+Na]+.1H NMR (400 MHz, CDCl3) 7.69 - 7.62 (m, 4H), 7.45 - 7.36 (m, 6H), 4.65 - 4.49 (m, 1H), 4.47 - 4.21 (m, 1H), 4.06 - 3.80 (m, 1H), 3.57 - 3.40 (m, 1H), 3.06 - 2.88 (m, 1H), 2.31 - 2.10 (m, 2H), 1.37 (s, 9H), 1.18 (s, 9H), 1.10 (s, 9H). 35 Step e: To a stirred solution of di-tert-butyl 7,7-dibromo-2-(((tert-butyldiphenylsilyl)oxy)methyl)- 3,4-diazabicyclo[4.1.0]heptane-3,4-dicarboxylate (2.80 g) in toluene (20 mL) was added tributyltin hydride (5.62 g) and AIBN (317 mg). The resulting solution was purged with nitrogen gas and then stirred at 80°C for 2 hr. The reaction mixture was cooled to 0°C and diluted with EtOAc (20 mL), then quenched with 10% aq. potassium fluoride solution (10 mL), resulting in a fine white 40 precipitate. The resulting mixture was filtered over Celite®, and the layers of the filtrate were separated. The aq. layer was extracted with EtOAc (3 x 20 mL), and the combined organic layers PAT059646-WO-PCT 5 were washed with brine (20 mL), dried over Na2SO4, and concentrated to afford a yellow oil, which crystallized under high vacuum. The crystals were washed with deionized water and ice-cold methanol, then dried under reduced pressure to afford di-tert-butyl 2-(((tert- butyldiphenylsilyl)oxy)methyl)-3,4-diazabicyclo[4.1.0]heptane-3,4-dicarboxylate (2.10 g) as colorless crystals. LC / MS (RXNMON-Acidic-NonPolar method): M / Z = 589 [M+Na]+.1H NMR (400 10 MHz, CDCl3) 7.71 – 7.63 (m, 4H), 7.46 – 7.33 (m, 6H), 4.62 – 4.33 (m, 1H), 4.26 – 3.99 (m, 1H), 3.94 – 3.87 (m, 1H), 3.69 – 3.53 (m, 1H), 3.19 – 3.01 (m, 1H), 1.42 (s, 9H), 1.35 – 1.32 (m, 2H), 1.23 – 1.17 (m, 9H), 1.08 (s, 9H), 0.87 – 0.81 (m, 1H), 0.19 – 0.08 (m, 1H). Step f: To a stirred solution of di-tert-butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,4- 15 diazabicyclo[4.1.0]heptane-3,4-dicarboxylate (2.10 g) in THF (10 mL) at 0°C was added TBAF (1.0 M in THF, 5.6 mL) and the resulting solution was stirred at 0°C for 1 hr. The reaction solution was then allowed to warm to RT and stir for 5 hr. The reaction was concentrated under reduced pressure and the crude material was purified by column chromatography (SiO2, 0 to 100% EtOAc in heptane) to afford di-tert-butyl 2-(hydroxymethyl)-3,4-diazabicyclo[4.1.0]heptane-3,4- 20 dicarboxylate (1.05 g) as a colorless oil. LC / MS (RXNMON-Acidic method): M / Z = 329 [M+H]+.1H NMR (400 MHz, CDCl3) 4.67 – 4.39 (m, 1H), 4.27 – 4.07 (m, 1H), 3.76 – 3.45 (m, 2H), 3.42 – 3.09 (m, 1H), 2.79 – 2.53 (m, 1H), 1.54 – 1.42 (m, 18H), 1.24 – 1.11 (m, 1H), 0.85 – 0.76 (m, 1H), 0.69 – 0.59 (m, 1H), 0.28 – 0.09 (m, 1H). 25 Step g: To a stirred solution of di-tert-butyl 2-(hydroxymethyl)-3,4-diazabicyclo[4.1.0]heptane-3,4- dicarboxylate (1.05 g) in acetonitrile (10 mL) at RT under a nitrogen atmosphere was added TEMPO (30.0 mg), sodium chlorite (578 mg), and pH 7 phosphate buffer (10 mL). Vigorous stirring produced a pale-yellow emulsion, to which was added sodium hypochlorite (0.74 M aq. solution, 260 L) dropwise. The resulting deep-red mixture was stirred at RT for 4 hr, then cooled 30 to 0°C, and quenched with sat. aq. sodium thiosulfate solution (10 mL), then acidified by addition of sat. citric acid solution (10 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (20 mL) under a nitrogen atmosphere, and to this solution was added cesium carbonate (1.26 g) and 35 iodomethane (684 mg). The resulting mixture was stirred at RT for 24 hr, then diluted with water (30 mL) and EtOAc (20 mL). The layers were separated, and the aq. layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (C18, 0 to 100% acetonitrile in water + 0.1% formic acid) to afford 3,4-di-tert- 40 butyl 2-methyl 3,4-diazabicyclo[4.1.0]heptane-2,3,4-tricarboxylate (870 mg) as a yellow oil. LC / MS (RXNMON-Acidic method): M / Z = 379 [M+Na]+.1H NMR (400 MHz, CDCl3) 5.11 (s, 1H), PAT059646-WO-PCT 5 4.32 - 4.21 (m, 1H), 3.76 (s, 3H), 3.25 - 3.08 (m, 1H), 1.45 (s, 18H), 1.39 - 1.33 (m, 2H), 0.89 - 0.83 (m, 1H), 0.14 - 0.06 (m, 1H). Step h: Racemic 3,4-di-tert-butyl 2-methyl 3,4-diazabicyclo[4.1.0]heptane-2,3,4-tricarboxylate (670 mg) was purified by chiral SFC (Prep_SFC1 method) to give 3,4-di-tert-butyl 2-methyl 10 (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2,3,4-tricarboxylate (260 mg) as the first eluting isomer. Intermediate 2 Note: axial chirality of compounds is shown in below scheme. 15 benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate

[0010] PAT059646-WO-PCT 5 Procedure Step a: To a mixture of 3-bromo-5-fluoropicolinonitrile (910 g) in toluene (9.1 L) was added MeMgBr (3 M in 2-MeTHF, 1.96 L) dropwise at 5°C. The mixture was stirred at 5°C for 1 hr. The 10 reaction mixture was poured into 10% aq. HCl solution (4.55 L) and stirred for 30 min. at 10°C. The reaction mixture was partitioned between water and toluene and the aq. phase was extracted with toluene (4.55 L). The combined organic layers were washed with brine (4.55 L) and concentrated under reduced pressure at 60°C to yield the desired product as an oil (890 g), which was used in the next step without further purification. 15 PAT059646-WO-PCT 5 Step b: To a mixture of 1-(3-bromo-5-fluoropyridin-2-yl)ethan-1-one (855 g) in DMF (8.55 L) was added benzyl piperazine-1-carboxylate (867 g) and K2CO3(742 g). The reaction was stirred at 50°C for 16 hr. The reaction mixture was poured into ice / water (17 L) and stirred at RT for 3 hr. The mixture was filtered and rinsed with water. The filter cake was treated with MTBE at RT for 16 hr, filtered, and rinsed with MTBE (428 mL) to yield the desired product as a light-yellow solid 10 (1387 g).1H NMR (300 MHz, DMSO-d6) 8.37 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.45 – 7.29 (m, 5H), 5.12 (s, 2H), 3.61 – 3.41 (m, 8H), 2.54 (s, 3H). Step c: To a mixture of benzyl 4-(6-acetyl-5-bromopyridin-3-yl)piperazine-1-carboxylate (533 g) in DCM (5.0 L) was added DIEA (463 g) and formic acid (275 g). The headspace of the flask was 15 evacuated and backfilled with nitrogen and then RuCl (p-cymene) [(S,S)-Ts-DPEN] (37.7 g) was added. The reaction was stirred at 35°C for 16 hr. The reaction mixture was cooled down to 5°C and water (2.5 L) was added. The resulting mixture was stirred for 30 min. at 25°C. The reaction mixture was partitioned between water and DCM; the organic layer was washed with 5% NaCl (2.5 L) and concentrated under reduced pressure at 40°C. The residue was purified by column 20 chromatography (SiO2, 33% EtOAc in heptane) to afford the desired product as a brown solid (484 g).1H NMR (300 MHz, DMSO-d6) 8.30 (d, J = 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.43 – 7.28 (m, 5H), 5.10 (d, J = 6.4 Hz, 2H), 5.05 – 4.89 (m, 2H), 3.54 (s, 4H), 3.30 – 3.17 (m, 4H), 1.34 (d, J = 6.2 Hz, 3H). 25 Step d: To a mixture of benzyl (S)-4-(5-bromo-6-(1-hydroxyethyl)pyridin-3-yl)piperazine-1- carboxylate (400.0 g) in DMF (3.6 L) was added t-BuOLi (105.0 g) at 25°C. Next, MeI (248 g) was dropwise to the mixture. The resulting reaction mixture was stirred at 25°C for 16. To the reaction mixture was added water (1.8 L) and stirred 25°C for 2 hr, which was filtered and rinsed with water (360 mL). The filter cake was treated with MTBE (1.5 L) and heptane (735 mL) at 25°C for 16 hr. 30 Filtration gave the desired product as a brown solid (253 g).1H NMR (400 MHz, DMSO-d6) 8.33 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 2.5 Hz, 1H), 7.44 – 7.29 (m, 5H), 5.11 (s, 2H), 4.73 (q, J = 6.4 Hz, 1H), 3.57 (d, J = 25.5 Hz, 4H), 3.30 – 3.22 (m, 4H), 3.11 (d, J = 9.7 Hz, 3H), 1.36 (d, J = 6.4 Hz, 3H). 35 Step e: A mixture of benzyl (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate (132 g), bis(pinacolato)diboron (108 g), Pd(dppf)Cl2(22.2 g), KOAc (74.5 g) in toluene (1.2 L) was degassed and purged with nitrogen (3x) and stirred at 100°C for 10 hr. The reaction mixture was concentrated then redissolved in EtOAc (600 mL). Sulfhydryl silica gel (150 g) was added, and the mixture was stirred at 25°C for 30 min. The reaction mixture was filtered, washed40 by EtOAc (3 x 300 mL), and concentrated to yield crude benzyl (S)-4-(6-(1-methoxyethyl)-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylate (227 g) as a PAT059646-WO-PCT 5 black brown oil. LC / MS (FinalAnalysis-Basic method): M / Z = 400 [M-C6H10+H]+. The product was used in the next step without further purification. Step f: To a solution of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H- indole (141 g)) and benzyl (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 10 yl)pyridin-3-yl)piperazine-1-carboxylate (157 g) in dioxane (600 mL), water (200 mL) and toluene (200 mL) was added K3PO4(115 g) and Pd(dppf)Cl2(15.9 g). The mixture was sparged with nitrogen and stirred at 80°C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated and purified by column chromatography (SiO2, 0 to 10% methanol in DCM). The residue was triturated with MTBE at RT for 12 hr. The desired product (66.3 g) was obtained as15 an off-white solid. for 12 hr. The mixture was filtered, concentrated and dried to yield (S)-4-(5-(5- bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (66.3 g) as an off-white solid.1H NMR (400 MHz, DMSO-d6) = 11.30 (s, 1H), 8.50 - 8.38 (m, 1H), 7.85 - 7.66 (m, 1H), 7.52 (br d, J = 6.4 Hz, 4H), 7.43 - 7.39 (m, 4H), 7.38 - 7.36 (m, 6H), 7.30 (br d, J = 8.4 Hz, 2H), 7.25 - 7.23 (m, 1H), 7.20 20 (dd, J = 1.6, 8.6 Hz, 1H), 5.12 - 5.10 (m, 2H), 4.12 - 4.05 (m, 1H), 3.51 (br s, 4H), 3.32 - 3.20 (m, 3H), 3.20 - 3.14 (m, 4H), 2.86 (br s, 2H), 1.33 - 1.29 (m, 3H), 1.12 - 1.00 (m, 2H), 0.98 - 0.93 (m, 9H), 0.70 - 0.59 (m, 6H) Step g: To a solution of benzyl (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- 25 dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (73.0 g) in DMF (730 mL) was added Cs2CO3(81.6 g) and EtI (26.0 g) at 0°C. The reaction mixture stirred at 25°C for 12 hr. The reaction was stirred at 30°C for 4 hr. The resulting mixture was diluted with EtOAc (800 mL) and washed with brine (3 x 800 mL). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to yield benzyl (S)-4-(5-(5-bromo-3-(3-((tert-30 butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3- yl)piperazine-1-carboxylate (83.9 g) as a brown oil. Step h: A mixture of benzyl (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate 35 (83.9 g) and CsF (42.3 g) in DMF (800 mL) was evacuated and backfilled with nitrogen (3x). The reaction was stirred at 66°C for 24 hr. The reaction was cooled to 25°C and to it was added CsF (42.3 g) and it was stirred at 66°C for 12 hr. The resulting mixture was diluted with EtOAc (1 L) and washed with brine (3 x 1.0 L). Then the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0 to 100% EtOAc in40 petroleum ether) twice to yield benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2- PAT059646-WO-PCT 5 dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (axial chirality as shown in structure) (20.2 g) as an off-white solid. m / z = 665 [M+3H]+Intermediate 3 and Intermediate 3a Note: axial chirality of compounds is as shown in below scheme. 10 (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoic acid Procedure 15 Step a: A suspension of Intermediate 2 (369 mg) and methyl (S)-2-((tert-butoxycarbonyl)amino)- 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (482 mg) was prepared under a nitrogen atmosphere in 5 wt% aq. Tween80:lecithin (8:2 w:w ratio, 11 mL) and isopropanol (5.5 mL) was added. The resulting solution was degassed for 5 min. via sparging with nitrogen.1,1'-Bis (di-t-butylphosphino)ferrocene palladium dichloride (18.1 20 mg) and triethylamine (282 mg) were sequentially charged to the degassed mixture and the solution was stirred at 0°C for 1 hr. Additional methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (161 mg) was charged to the mixture after 1 hr and stirring at 80°C continued for an additional 30 min. The reaction mixture was extracted with EtOAc (3 x 15.0 mL), and the organic extracts were 25 passed through an phase separator. The filtrate was concentrated and the remaining residue was purified by column chromatography (SiO2, 0 to 100% (3:1 EtOAc / ethanol) in heptane) to afford benzyl 4-(5-(5-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-5- ((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (570 mg) as a tan foam. LC / MS 30 (FinalAnalysis-Basic method): M / Z = 1035 [M+H]+. PAT059646-WO-PCT 5 Step b: To a stirred solution of benzyl 4-(5-(5-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy- 3-oxopropyl)-5-((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol- 2-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (621 mg) in methanol (8.0 mL) under nitrogen was added Pd(OH)2 on carbon (82.8 mg, 10% wt.). The reaction vessel was 10 evacuated and backfilled with hydrogen. The reaction stirred at RT for 3 h. The reaction mixture was filtered under nitrogen by washing with MeOH, and then concentrated to afford methyl (S)-2- ((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoate (475 mg) as an orange foam. LC / MS (FinalAnalysis- 15 Basic method): M / Z = 901 [M+H]+. Step c: To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3- hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5- yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (475 mg) in isopropanol (5.0 mL) under nitrogen 20 was charged aq. formaldehyde (393 μL, 37 wt%). Sodium triacetoxyborohydride (335 mg) was added and the resulting suspension stirred at RT for 2 hr. The reaction mixture was concentrated to 1 / 3 of initial volume, diluted with DCM (10 mL), quenched with sat. NaHCO3(5 mL), filtered through a phase separator, and concentrated. The crude material was purified by column chromatography (C18, 20 to 70% acetonitrile in water + 0.1% formic acid), followed by25 lyophilization to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)propanoate (393 mg) as a white solid. LC / MS (Peptide method): M / Z = 915 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8.46 – 8.40 (m, 3H), 7.83 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.5, 1.7 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 2.9 30 Hz, 1H), 7.14 (s, 1H), 6.98 (d, J = 1.9 Hz, 1H), 6.73 (t, J = 1.8 Hz, 1H), 4.43 (s, 1H), 4.28 – 4.19 (m, 1H), 4.04 (m, 2H), 3.86 (m, 1H), 3.63 (s, 3H), 3.25 (d, J = 4.4 Hz, 3H), 3.10 – 2.95 (m, 3H), 2.93 – 2.88 (m, 1H), 2.85 (s, 3H), 2.71 – 2.65 (m, 1H), 2.45 (t, J = 4.9 Hz, 3H), 2.21 (s, 3H), 1.35 (d, J = 6.2 Hz, 3H), 1.32 (s, 9H), 1.27 (dd, J = 8.9, 5.9 Hz, 4H), 1.15 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 7.4 Hz, 18H), 0.68 (s, 3H), 0.61 (s, 3H). 35 Step d: To a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)propanoate (393 mg) in DCE (10 mL) was added trimethyltin hydroxide (389 mg) under a nitrogen atmosphere. The resulting suspension was stirred at 70°C 40 for 4 hr. The reaction mixture was cooled to RT, diluted with DCM (10 mL), and quenched with aq. sodium hydrogen sulfate (0.05M, 4.6 mL). The organic layer was then passed through a phase PAT059646-WO-PCT 5 separator and concentrated to afford (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3- hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)- 1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid (axial chirality as shown in structure)(462 mg) as a tan solid. LC / MS (Peptide method): M / Z = 903 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8.45 (d, J = 2.8 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 8.5 10 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.08 (d, J = 11.7 Hz, 1H), 6.95 (s, 1H), 6.66 (s, 1H), 6.35 (d, J = 8.1 Hz, 1H), 4.42 (t, J = 5.3 Hz, 1H), 4.03 (m, 3H), 3.88 (dd, J = 14.5, 7.1 Hz, 1H), 3.25 (q, J = 4.3 Hz, 3H), 3.07 (dd, J = 10.3, 5.5 Hz, 1H), 3.03 – 2.96 (m, 2H), 2.86 (s, 3H), 2.68 (d, J = 6.7 Hz, 1H), 2.46 (t, J = 5.0 Hz, 3H), 2.22 (s, 3H), 1.36 (d, J = 6.3 Hz, 3H), 1.32 (s, 8H), 1.30 – 1.27 (m, 4H), 1.15 (t, J = 7.2 Hz, 4H), 1.10 (d, J = 7.4 Hz, 18H), 0.86 (t, J = 6.7 Hz, 4H), 0.69 (s, 3H), 0.62 15 (s, 3H). Intermediate 4 Note: axial chirality of compounds is as shown in below scheme. (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- 20 methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoic acid PAT059646-WO-PCT 5 Procedure Step a: To a solution of Intermediate 2 (28.2 g) in toluene (200 mL) was added Pin2B2(16.1 g) and KOAc (10.3 g). To this mixture was added Pd(dppf)Cl2(3.11 g). The reaction was stirred at 100°C for 12 hr. The reaction was concentrated under reduced pressure to yield the crude residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl10 acetate = 1:0 to 0:1) to yield benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate (18.7 g) as a yellow solid. LC / MS: M / Z = 711.6 [M+H]+. Step b: A mixture of benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5-15 tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate (270 mg), methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate (153 mg), PdCl2(dtbpf) (24.8 mg) and potassium carbonate (105 mg) in 1,4-dioxane (2.0 mL) and water (0.4 mL) was stirred at 85°C for 3 hr under nitrogen. The reaction mixture was diluted with DCM and water and the layers were separated. The aq. 20 layer was extracted with DCM (3x), and the combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (C18, 0 to 100% acetonitrile in water + 0.1% formic acid) to give benzyl 4-(5-(5- (2-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)thiazol-4-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate 25 (250 mg) as a beige powder after lyophilization.1H NMR (400 MHz, DMSO-d6) 8.46 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.80 (s, 1H), 7.75 (dd, J = 8.6, 1.6 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.39 - 7.31 (m, 6H), 5.11 (s, 2H), 4.51 (td, J = 8.8, 4.9 Hz, 1H), 4.43 (t, J = 5.3 Hz, 1H), 4.10 - 4.00 (m, 2H), 3.93 - 3.82 (m, 1H), 3.68 (s, 3H), 3.56 (s, 4H), 3.51 - 3.37 (m, 2H), 3.28 (q, J = 4.8 Hz, 4H), 3.12 - 2.97 (m, 2H), 2.84 (s, 3H), 2.71 - 2.65 (m, 1H), 2.22 (d, J 30 = 14.0 Hz, 1H), 1.37 (t, J = 2.4 Hz, 12H), 1.15 (t, J = 7.1 Hz, 3H), 0.67 (s, 3H), 0.61 (s, 3H). Step c: A flask containing benzyl 4-(5-(5-(2-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3- oxopropyl)thiazol-4-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (250 mg) and Pd(OH)2on carbon (212 mg, 35 20% wt.) in MeOH (2.0 mL) under nitrogen atmosphere was evacuated and backfilled with hydrogen (2x). The reaction was stirred at RT for 2 hr. The reaction diluted with methanol, filtered. The filtrate was dried under reduced pressure to yield methyl (S)-2-((tert-butoxycarbonyl)amino)- 3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1- yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoate (155 mg). LC / MS (RXNMON-Acidic 40 method): M / Z = 735 [M+H]+. PAT059646-WO-PCT 5 Step d: A solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2- yl)propanoate (155 mg) and aq. formaldehyde solution (47.1 L, 37% wt.) in MeOH (2.0 mL) was stirred at RT for 20 min. before addition of sodium triacetoxyborohydride (89 mg). The reaction stirred at RT for 2 h. Additional formaldehyde solution (24 L) and sodium triacetoxyborohydride 10 (45 mg) were added and the reaction stirred at RT for 1 hr. The reaction was quenched directly with a volumetric equivalent of sat. NaHCO3Solution. and DMSO and stirred vigorously. The mixture was then partially dried under reduced pressure to remove MeOH. The resulting slurry was purified by column chromatography (C18, 0 to 100% acetonitrile in water + 0.1% TFA) to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-15 ((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2- yl)propanoate (150 mg) as a yellow solid. LC / MS (RXNMON-Acidic method): M / Z = 750 [M+H]+. Step e: A solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5- 20 yl)thiazol-2-yl)propanoate (150 mg) and trimethyltin hydroxide (181 mg) in DCE (2.0 mL) was stirred at 60°C for 16 hr under nitrogen. Additional trimethyltin hydroxide (90 mg) was added and the reaction was stirred at 60°C for 6 hr. The reaction mixture was concentrated and purified by column chromatography (C18, 0 to 100% acetonitrile in water + 0.1% TFA) to give (S)-2-((tert- butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- 25 methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoic acid (axial chirality as shown in structure)(140 mg) as a yellow solid. LC / MS (Peptide method): M / Z = 735 [M+H]+. Intermediate 5 30 Note: axial chirality of compounds is as shown in below scheme. tert-butyl ((61R,65S,66S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)- indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate

[0011] PAT059646-WO-PCT 5 Procedure Step a, part 1: To a stirred solution of Intermediate 1 (20.0 mg) in DCM (0.5 mL) was added trifluoroacetic acid (215 μL). The resulting solution was stirred at RT for 1 hr. The reaction mixture 10 was concentrated under reduced pressure. The resulting residue was taken up in DCM and then concentrated under reduced pressure (3x) to afford methyl (1S,2S,6R)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylate bis-trifluoroacetate salt (14.2 mg) LC / MS (RXNMON- Acidic method): M / Z = 156 [M+H]+. 15 Step a, part 2: To a stirred solution of Intermediate 3 (trifluoroacetic acid salt; 25.0 mg) and methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate bis-trifluoroacetate salt (14.2 mg) in DMF (0.50 mL) was added DIPEA (52 μL) and HATU (18.7 mg). The resulting solution was stirred at RT for 30 min. The reaction mixture was diluted with DMSO (1 mL) and purified by column chromatography (C18, 0 to 100% acetonitrile in water + 0.1% TFA) followed by lyophlization to20 afford methyl (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate (27.0 mg) as a yellow solid. LC / MS (RXNMON-Acidic method): M / Z = 1039 [M+H]+. PAT059646-WO-PCT 5 Step b: To a stirred solution of methyl (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1- ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylate (22.0 mg) in DCE (1.0 mL) was added trimethyltin hydroxide (38.3 mg). The solution was stirred at 75°C for 24 hr. The reaction was cooled to RT 10 and quenched with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylic acid (17.0 15 mg). LC / MS (Peptide method): M / Z = 1025 [M+H]+. Step c: To a stirred solution of (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)- 1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2- 20 carboxylic acid (14.5 mg) in DCM (1.0 mL) was added EDC (13.6 mg) and HOAt (9.6 mg). The solution stirred at RT for 20 hr under nitrogen. The reaction mixture was concentrated and purified by column chromatography (C18, 0 to 100% acetonitrile in water + 0.1% TFA) followed by lyophilization to afford tert-butyl ((61R,65S,66S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-25 63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4- yl)carbamate (axial chirality as shown in structure)(14.0 mg) as a white solid. LC / MS (Peptide method): M / Z = 1007 [M+H]+. Intermediate 6 30 Note: axial chirality of compounds is as shown in below scheme. tert-butyl ((61R,65S,66S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11H-8-oxa-63,64-diaza-2(4,2)-thiazola-1(5,3)-indola- 6(3,5)-bicyclo[4.1.0]heptanacycloundecaphane-4-yl)carbamate

[0012] PAT059646-WO-PCT 5 Procedure Step a, part 1: A solution of Intermediate 1 (111 mg) in DCM (3.5 mL) and TFA (1.2 mL) was stirred at RT for 1 hr under nitrogen. The reaction mixture was concentrated and dried under10 reduced pressure to yield methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate bis- trifluoroacetate salt (120 mg) as a yellow oil. LC / MS (RXMON-Acidic method): M / Z = 157 [M+H]+. Step a, part 2: To a solution of Intermediate 4 (47.8 mg) in NMP (0.10 mL) was added methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate bis-trifluoroacetate salt (27.5 mg), 15 followed by DIPEA (0.11 mL) and HATU (49.5 mg) under nitrogen. The solution was stirred at RT for 30 min. The reaction mixture was diluted with minimal DMSO and purified by column chromatography (C18, 10 to 40% acetonitrile in water + 0.1% TFA) to yield a yellow solid after lyophilization. This solid was reconstituted in EtOAc and neutralized via vigorous stirring in the presence of sat. NaHCO3solution. The resulting organic layer was then passed through a phase20 separator, concentrated, and dried to yield methyl (1S,2S,6R)-4-((2S)-2-((tert- butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylate (22.1 mg) as a pale yellow foam. LC / MS (Peptide method): M / Z = 895 [M+Na]+. 25 PAT059646-WO-PCT 5 Step b: To a solution of methyl (1S,2S,6R)-4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl- 3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3- yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate (22.1 mg) in DCE (0.5 mL) under nitrogen was added trimethyltin hydroxide (22.9 mg). The resulting suspension was stirred at 70°C for 1.5 hr. The reaction mixture was cooled to RT, diluted with 10 DCM (5.0 mL), and quenched with aq. NaHSO4 (0.05 M, 2.5 mL). The organic layer was then passed through a phase separator and concentrated to afford crude (1S,2S,6R)-4-((S)-2-((tert- butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylic acid (21.7 mg) as an off-white foam. This material was 15 used in the next step without further purification. LC / MS (Peptide method): M / Z = 860 [M+H]+. Step c: To a solution of crude (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)- 1H-indol-5-yl)thiazol-2-yl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylic acid (21.7 mg) 20 and HOAt (17.2 mg) in DCM (2.50 mL) under a nitrogen atmosphere was added a solution of EDC (24.3 mg) in DCM (0.5 mL) dropwise over the course of 20 min. The resulting suspension was stirred at RT for 16 hr. The reaction mixture was concentrated and purified by column chromatography (C18, 10 to 50% acetonitrile in water + 0.1% TFA) to yield tert-butyl ((61R,65S,66S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-25 10,10-dimethyl-5,7-dioxo-11H-8-oxa-63,64-diaza-2(4,2)-thiazola-1(5,3)-indola-6(3,5)- bicyclo[4.1.0]heptanacycloundecaphane-4-yl)carbamate trifluoroacetate salt (axial chirality as shown in structure) (8.3 mg) as a pale yellow solid after lyophilization. Intermediate 7 30 N-methyl-N-(morpholine-4-carbonyl)-L-valine Procedure Step a: To a solution of N-methyl-L-valine benzyl ester 4-toluenesulfonate (464 mg) in DCM (6.2 35 mL) at 0°C was added DIPEA (1.23 mL). The solution was stirred at 0°C for 10 min. Triphosgene (174.9 mg) was added and the reaction was stirred at 0°C for 10 min, then allowed to warm to RT and stirred for 30 min. Morpholine (103 mg) was added to the reaction at 0°C. The reaction mixture was warmed to RT and stirred for 1 hr. The reaction mixture was quenched with sat. NaHCO3 PAT059646-WO-PCT 5 solution and stirred vigorously. The quenched mixture was passed through a phase separator and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 0 to 80% EtOAc in heptane) to yield benzyl N-methyl-N-(morpholine-4- carbonyl)-L-valinate (230 mg) as a clear oil. LC / MS (FinalAnalysis-acidic method): M / Z = 335 [M+H]+. 10 Step b: A flask containing benzyl N-methyl-N-(morpholine-4-carbonyl)-L-valinate (231 mg) and Pd on carbon (732 mg, 10 wt%) in MeOH (8.1 mL) at RT was evacuated and backfilled with nitrogen. Triethylsilane (240 mg) was added over the course of 5 min. The reaction was stirred at RT for 30 min. The reaction mixture was filtered over a pad of Celite®, rinsed with methanol, and 15 then concentrated to yield N-methyl-N-(morpholine-4-carbonyl)-L-valine (171 mg) as a colorless oil that solidifies over time. LC / MS (RXNMON-Acidic method): M / Z = 245 [M+H]+. Intermediate 8 1-(6-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methylpiperazine 20 Procedure Step a: A mixture of 3-bromo-2-chloro-5-iodopyridine (25.0 g) and cesium carbonate (64.0 g) in isopropanol (250 mL) was stirred at 80°C for 17 hr. Additional cesium carbonate (12.8 g) was 25 added and the reaction mixture was stirred at 80°C for 5 hr. The reaction mixture was concentrated, diluted in EtOAc, filtered over a pad of Florisil®, concentrated, and dried under reduced pressure which yielded 3-bromo-5-iodo-2-isopropoxypyridine (26.0 g) as a dark orange oil.1H NMR (400 MHz, CDCl3) 8.22 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.1 Hz, 1H), 5.27 (hept, J = 6.2 Hz, 1H), 1.37 (d, J = 6.2 Hz, 6H). 30 Step b: To a solution of 3-bromo-5-iodo-2-isopropoxypyridine (1.04 g) and xantphos (176 mg) in toluene (6.1 mL) was added 1-methyl piperazine (320 mg), bis(dibenzylideneacetone)dipalladium (137 mg), and sodium tert-butoxide (2M in THF, 3.80 mL). The solution was sparged with nitrogen for 5 min. then stirred at 60°C for 20 min. The reaction was cooled to RT and poured into brine. 35 The aq. layer was extracted with EtOAc (3x), and the combined organic layers were washed with PAT059646-WO-PCT 5 brine, dried over Na2SO4, filtered, and concentrated. The material was purified by column chromatography (C18, 10 to 60% acetonitrile in water + 0.1% formic acid) which yielded 1-(5- bromo-6-isopropoxypyridin-3-yl)-4-methylpiperazine (580 mg) as an orange oil. LC / MS (FinalAnalysis-acidic method): M / Z = 316 [M+H]+.1H NMR (400 MHz, CDCl3) 7.73 (d, J = 2.7 Hz, 1H), 7.49 (d, J = 2.7 Hz, 1H), 5.21 (hept, J = 6.2 Hz, 1H), 3.14 (s, 4H), 2.63 (s, 2H), 2.40 (s, 10 2H), 1.36 (d, J = 6.2 Hz, 6H). Step c: A vial containing 1-(5-bromo-6-isopropoxypyridin-3-yl)-4-methylpiperazine (209 mg), bis(pinacolato)diborane (338 mg), potassium acetate (196 mg), and PdCl2(dtbpf) (43.4 mg) was evacuated and backfilled with nitrogen. Toluene (6.7 mL) was added, and the reaction mixture 15 was sparged with nitrogen for 5 min. then stirred at 90°C for 18 hr. The reaction mixture was filtered over pad of Florisil® and Celite®, rinsed with EtOAc and MeOH, then concentrated. The crude residue was dissolved in EtOAc, filtered through phase separator, concentrated, dissolved in heptane, filtered through a phase separator, concentrated, dissolved in DCM, filtered, and concentrated to yield crude 1-(6-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 20 yl)pyridin-3-yl)-4-methylpiperazine (300 mg) as a brown oil. The material was used in the next step without further purification. LC / MS (FinalAnalysis-Acidic): M / Z = 280 [M-C6H10+H]+(mass of boronic acid; BPin ester hydrolyzes under LCMS conditions). Intermediate 9 and Intermediate 9a 25 tert-butyl ((61R,65S,66S,4S)-11-ethyl-12-(2-isopropoxy-5-(4-methylpiperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)- bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate

[0013] PAT059646-WO-PCT 5 Procedure Step a: To a solution of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (46.0 g), methyl (S)- 2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoate (62.5 g) and K2CO3(48.0 g) in 1,4-dioxane (460 mL) and10 water (92.0 mL) that had been degassed and purged with nitrogen (3x) was added bis(di-tert- butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (4.94 g). The reaction mixture was stirred at 85 C for 4 hr. The resulting mixture was combined with other two batches (5.0 g and 9.3 g of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate were used in the same manner) for the subsequent workup. The reaction mixture was concentrated under reduced pressure to PAT059646-WO-PCT 5 remove dioxane and water. The residue was purified by column chromatography (SiO2, 0 to 17% EtOAc in petroleum ether) to afford methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5- yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (92.0 g) as a white solid.1H NMR (400 MHz, DMSO-d6) 10.98 (d, J = 1.6 Hz, 1H), 7.68 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 – 7.26 (m, 2H), 7.15 – 7.08 (m, 2H), 6.95 (s, 1H), 6.72 (s, 1H), 4.23 (td, J = 10.2, 4.9 10 Hz, 1H), 3.74 (s, 2H), 3.61 (s, 3H), 3.08 – 2.97 (m, 1H), 2.92 – 2.81 (m, 1H), 2.70 (s, 2H), 2.03 (s, 3H), 1.35 – 1.26 (m, 12H), 1.10 (d, J = 7.3 Hz, 18H), 0.93 (s, 6H). Step b: To a solution of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (65.0 g) and NaHCO315 (9.3 g) in THF (650 mL) was added AgOTf (22.7 g) in THF (100 mL) and I2(16.8 g) in THF (100 mL) at 0 C. The reaction mixture was stirred at 0 C for 2 hr. Another portion of AgOTf (3.79 g) in THF (15.0 mL) and I2(3.74 g) in THF (15.0 mL) were then added dropwise, and the reaction mixture was stirred at 0 C for 1 hr. The reaction was stirred for a total of 3 hr at 0 C. The resulting mixture was combined with two batches (5.0 g and 20.0 g of methyl (S)-3-(3-(3-(3-acetoxy-2,2-20 dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate were used in the same manner) for the subsequent workup. The combined crude products were diluted with aq. Na2S2O3(2.0 L) and extracted with EtOAc (3 x 3.0 L). The combined organic layers were washed with brine (2 x 1.5 L), dried over Na2SO4and filtered. The residue was purified by column chromatography (SiO2, 1 to 17% EtOAc in petroleum25 ether) to afford methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (50.5 g) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) 11.63 (d, J = 17.3 Hz, 1H), 7.65 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.11 (s, 1H), 6.94 (s, 1H), 6.73 (s, 1H), 4.23 (dd, J = 13.0, 9.7 Hz, 1H), 3.84 (s, 2H), 3.63 (s, 3H), 3.03 (dd, J = 13.7, 4.5 Hz, 1H), 2.95 – 2.81 (m, 1H), 2.67 (s, 2H), 2.04 (s, 30 3H), 1.34 – 1.22 (m, 12H), 1.09 (d, J = 7.2 Hz, 18H), 0.99 (s, 6H). Step c: To a solution of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenylycarbo)-2-((tert-butoxnyl)amino)propanoate (750 mg) in DCE (5.0 mL) was added trimethyltin hydroxide (496 mg). The reaction was stirred at 80°C for 24 hr. 35 Additional trimethyltin hydroxide (248 mg) was added and the reaction mixture stirred at 80°C for 24 hr. The reaction was cooled to RT, diluted with water (5 mL), and stirred vigorously for 5 min. The milky mixture was diluted with DCM, passed through a phase separator, and rinsed with DCM. The pale, yellow solution was concentrated under reduced pressure to yield (S)-2-((tert- butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5- 40 ((triisopropylsilyl)oxy)phenyl)propanoic acid (765 mg) as an off-white solid. This material was used in the next step without further purification. LC / MS (RXNMON-basic method): M / Z = 765 [M+H]+. PAT059646-WO-PCT 5 Step d: To a solution of Intermediate 1 (391 mg) in DCM (9.0 mL) was added TFA (3.0 mL). The reaction was stirred at RT for 3 hr then concentrated under reduced pressure. To a solution of the resultant yellow liquid and (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2- dimethylpropyl)-2-iodo-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid (780 mg) in 10 DMF (4.00 mL) was added DIPEA (1.07 mL) and HATU (427 mg). The reaction mixture stirred at RT for 20 min. and then purified by column chromatography (SiO2, 0 to 100% (3:1 EtOAc / EtOH) in heptane) which yielded methyl (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3- hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylate (705 mg) as a white solid. LC / MS (RXNMON-acidic 15 method): M / Z = 904 [M+H]+.1H NMR (400 MHz, DMSO-d6) 11.52 (s, 1H), 7.70 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.30 – 7.19 (m, 1H), 7.06 (s, 1H), 6.95 – 6.88 (m, 1H), 6.68 (s, 1H), 6.36 (d, J = 8.7 Hz, 1H), 5.23 (d, J = 6.9 Hz, 1H), 5.10 (td, J = 8.7, 3.9 Hz, 1H), 4.61 (t, J = 5.2 Hz, 1H), 3.90 – 3.59 (m, 7H), 3.41 (d, J = 13.2 Hz, 1H), 3.32 (s, 5H), 3.24 (d, J = 5.3 Hz, 3H), 2.95 – 2.82 (m, 2H), 1.34 – 1.15 (m, 20H), 0.89 (s, 9H), 0.75 (td, J = 8.5, 4.6 Hz, 1H), 0.47 (d, J = 5.3 Hz, 1H). 20 Step e: To a solution of methyl (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3- hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylate (705 mg) in DCE (4.0 mL) was added trimethyltin hydroxide (424 mg). The reaction was stirred at 70°C for 4 hr. The reaction was cooled to RT, 25 diluted with water, stirred vigorously for 5 min, diluted with DCM, passed through a phase separator, rinsed with DCM, and concentrated under reduced pressure. The crude material was purified by column chromatography (C18, 20 to 100% acetonitrile in water + 0.1% NH4OH). Fractions containing the product were concentrated and sat. NaHCO3solution (15 mL) was added. The mixture was extracted with DCM (3 x 15 mL) and the combined organic layers were passed30 through a phase separator and concentrated under reduced pressure to yield (1S,2S,6R)-4-((S)- 2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylic acid (415 mg) as a white solid. LC / MS (Peptide Method): M / Z = 911 [M+H]+. 35 Step f: To a solution of (1S,2S,6R)-4-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2- dimethylpropyl)-2-iodo-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylic acid (415 mg) in DCM (20 mL) was added 1H- benzo[d][1,2,3]triazol-1-ol hydrate (249 mg, 86% wt.) and EDC (179 mg). The reaction mixture was stirred at RT for 14 hr. The reaction was diluted with water (15 mL) and stirred vigorously for 40 5 min. The resulting biphasic mixture was passed through a phase separator and the organic layer was concentrated. The crude material was purified by column chromatography (SiO2, 0 to 100% PAT059646-WO-PCT 5 3:1 EtOAc / EtOH in heptane) to yield tert-butyl ((61R,65S,66S,4S)-12-iodo-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana- 2(1,3)-benzenacycloundecaphane-4-yl)carbamate (338 mg) as a white sold. LC / MS (Peptide Method): M / Z = 893 [M+H]+. 10 Step g: To a solution of tert-butyl ((61R,65S,66S,4S)-12-iodo-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (338 mg) in DMF (3.0 mL) was added DIPEA (206 L), cesium carbonate (506 mg), and iodoethane (62.1 L). The reaction was stirred at 35°C for 2.5 hr. The reaction was diluted with water (10 mL) and stirred vigorously. The aq. layer was 15 extracted with EtOAc (3x), and the combined organic extracts were concentrated. The crude material was purified by column chromatography (SiO2, 0 to 60% 3:1 EtOAc / EtOH in heptane) to yield tert-butyl ((61R,65S,66S,4S)-11-ethyl-12-iodo-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (328 mg) as a white solid. LC / MS (FinalAnalysis- 20 Basic method): M / Z = 900 [M+H]+.1H NMR (400 MHz, DMSO-d6) 7.92 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.46 (dd, J = 8.8, 1.7 Hz, 1H), 7.26 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (t, J = 1.9 Hz, 1H), 6.81 (s, 1H), 4.91 (t, J = 9.1 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.38 – 4.22 (m, 3H), 4.16 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 11.0 Hz, 1H), 3.51 (d, J = 11.0 Hz, 1H), 3.27 (d, J = 13.2 Hz, 1H), 3.14 (d, J = 14.4 Hz, 1H), 2.76 (dd, J = 14.0, 9.9 Hz, 1H), 2.59 (d, J = 13.8 Hz, 1H), 1.38 25 – 1.19 (m, 21H), 1.09 (dd, J = 7.4, 1.7 Hz, 18H), 1.02 – 0.91 (m, 4H), 0.40 (d, J = 5.5 Hz, 1H). Step h: To a solution of tert-butyl ((61R,65S,66S,4S)-11-ethyl-12-iodo-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (328 mg), Intermediate 8 (crude, 198 mg), aq. K3PO430 solution (155 mg, 730 L, 1.0 molar), and mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2 -amino-1,1 -biphenyl)]palladium(II) (26.6 mg) were dissolved in 1,4-dioxane (3.7 mL) and spargedwith nitrogen for 5 min. before heating at 85°C for 1.5 hr. The reaction mixture was poured into separatory funnel and diluted with sat. NaHCO3 solution. The aq. layer was extracted with EtOAc (3x), and the combined organic layers were washed with brine and concentrated. The crude 35 material was purified by column chromatography (C18, 50 to 100% acetonitrile in water + 0.1% TFA) to yield tert-butyl ((61R,65S,66S,4S)-11-ethyl-12-(2-isopropoxy-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)- indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (200 mg) as a brownish orange solid. LC / MS (FinalAnalysis-Acidic method): M / Z = 1007 [M+H]+.1H NMR 40 (400 MHz, DMSO-d6) 7.99 – 7.84 (m, 2H), 7.59 – 7.52 (m, 1H), 7.51 – 7.45 (m, 1H), 7.40 – 7.31 (m, 1H), 7.27 (s, 0H), 7.23 – 7.16 (m, 1H), 7.15 – 7.08 (m, 1H), 7.05 – 6.98 (m, 1H), 6.83 – 6.77 PAT059646-WO-PCT 5 (m, 1H), 6.64 (s, 0H), 5.36 – 5.22 (m, 1H), 5.01 – 4.87 (m, 1H), 4.82 – 4.72 (m, 1H), 4.39 – 4.28 (m, 1H), 4.25 – 4.08 (m, 2H), 3.98 – 3.83 (m, 1H), 3.81 – 3.65 (m, 1H), 3.61 – 3.40 (m, 1H), 3.28 – 3.20 (m, 1H), 3.14 – 3.06 (m, 4H), 2.78 – 2.66 (m, 1H), 2.65 – 2.57 (m, 1H), 2.27 – 2.18 (m, 3H), 2.17 – 2.01 (m, 1H), 1.97 – 1.86 (m, 4H), 1.78 – 1.62 (m, 4H), 1.52 (s, 1H), 1.35 – 1.32 (m, 9H), 1.32 – 1.28 (m, 4H), 1.28 – 1.18 (m, 6H), 1.14 (s, 1H), 1.11 – 1.08 (m, 18H), 1.04 – 1.00 (m, 10 1H), 0.96 (s, 2H), 0.93 – 0.87 (m, 2H), 0.55 – 0.44 (m, 1H), 0.39 (s, 3H). Intermediate 10 (2R,3S)-3-phenyloxetane-2-carboxylic acid 15 Procedure Step a: A solution of styrene (26.0 g) and 2-oxoacetic acid (74.0 g, 50% in water) in CH3CN (1 L) was purged with nitrogen for 10 min. while the entire vessel was sonicated. The reaction mixture was transferred to a photoreactor consisting of a closed borosilicate cylinder equipped with a cold 20 finger, which was set to 5°C. The cylinder was irradiated with total 801W high power LEDs (365 nm) for 24 hr, and then the reaction mixture was concentrated at 40°C to yield 68.2 g of a viscous pale-brown oil that was dissolved in 250 mL MTBE and washed twice with 100 mL water followed by 216 mL 1 N NaOH solution. The basic aqueous solution was washed with 150 mL MTBE then acidified by slow addition of 12.8 g conc. H2SO4to a pH of <3 and extracted with MTBE. The 25 combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield a crude cis / trans mixture of 3-phenyloxetane-2-carboxylic acid (35.5 g) as a viscous pale brown oil. HPLC (HPLC-quant. method): Rt = 3.01 min. (cis acid); 3.42 min. (trans acid). MS (ES–): m / z 177 [M–H]–. 30 Step b: To a solution of a crude cis / trans mixture of 3-phenyloxetane-2-carboxylic acid (25.9 g) in 150 mL absolute EtOH was added AmberChromTM, 50WX4 (5.9 g) and the suspension heated at 60°C for 2 hr, then at 70°C for another 4.5 hr. The reaction mixture was cooled to RT, filtered, and concentrated to yield 28.0 g of orange oil. The crude material was purified by column PAT059646-WO-PCT 5 chromatography (5 to 30% EtOAc / heptane) to afford racemic ethyl cis-3-phenyloxetane-2- carboxylate (1.76 g) as pale-yellow oil as the second eluting isomer. LC / MS (Final_Analysis_2min method): Rt = 0.71 min, m / z 207 [M+H]+.1H NMR (400 MHz, DMSO-d6) 7.33 (d, J = 3.5 Hz, 4H), 7.29 – 7.23 (m, 1H), 5.47 (d, J = 9.2 Hz, 1H), 4.91 (dd, J = 8.2, 6.0 Hz, 1H), 4.80 (t, J = 6.4 Hz, 1H), 4.57 (m, 1H), 3.70 (q, J = 7.1 Hz, 2H), 0.69 (t, J = 7.1 Hz, 3H). 10 Step c: Ethyl cis-3-phenyloxetane-2-carboxylate (1.15 g) was dissolved in EtOH + 0.05 NH3(18 mL) and then purified by chiral SFC (Prep_SFC2 method) to give ethyl (2R,3S)-3-phenyloxetane- 2-carboxylate as the first eluting isomer as colorless oil (514 mg; 98% ee). Chiral SFC (Chiral_SFC1 method): Rt = 1.15 min. LC / MS (Final_Analysis_2min method): m / z 207 [M+H]+.1H 15 NMR (400 MHz, DMSO-d6) 7.30 – 7.36 (m, 5 H), 5.47 (d, J = 9.2 Hz, 1 H), 4.91 (dd, J = 8.1, 6.0 Hz, 1 H), 4.80 (t, J = 6.3 Hz, 1 H), 4.54 – 4.60 (m, 2 H), 3.70 (q, J = 7.1 Hz, 3 H), 0.69 (t, J = 7.1 Hz, 3 H). Step d: A mixture of (2R,3S)-3-phenyloxetane-2-carboxylate (496 mg) in THF (2.5 mL) and MeOH 20 (2.5 mL) was cooled in an ice bath. LiOH monohydrate (151 mg) was added, and the resulting mixture stirred at 0°C for 3 h. The reaction mixture was diluted with DCM (10 mL) and the biphasic mixture was acidified to be a pH of 3.5 with citric acid (4 mL, 10% aqueous solution), followed by the addition of solid citric acid (0.2 g). The phases were separated, and the aqueous layer extracted 6 times with DCM. The combined organic phases were dried over sodium sulfate, 25 filtered, and concentrated to yield (2R,3S)-3-phenyloxetane-2-carboxylic acid (399 mg; >99% ee) as a white powder. Chiral UPLC (Chiral_UPLC1 method): Rt = 5.71 min. LC / MS (Final_Analysis_2min): m / z 177 [M–H]–.1H NMR (400 MHz, DMSO-d6) 12.45 (s, 1H), 7.39 – 7.30 (m, 4H), 7.29 – 7.23 (m, 1H), 5.39 (d, J = 9.1 Hz, 1H), 4.90 (dd, J = 8.1, 5.9 Hz, 1H), 4.70 (t, J = 6.3 Hz, 1H), 4.50 (td, J = 8.6, 6.6 Hz, 1H). 30 Intermediate 11 (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)morpholine 35 PAT059646-WO-PCT 5 Step a: To a mixture of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (3.05 g), Pd(OAc)2 (100 mg), rac-BINAP (278 mg) and Cs2CO3(5.812 g) in toluene (30 mL) at RT was added morpholine (855 mg, 846 L) under nitrogen. The reaction mixture was allowed to stir at 90°C for 16 hr, cooled to RT, filtered, and concentrated. The residue was purified by flash column chromatography on (SiO2, 0 to 30% 3:1 EtOAc / EtOH in heptane) to afford (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin- 10 3-yl)morpholine (2.35 g) as an orange oil. LC / MS (RXNMON-Acidic): M / Z = 301.0 [M+H]+.1H NMR (400 MHz, CDCl3) 8.30 (d, J = 2.6 Hz, 1H), 7.30 (s, 1H), 4.86 (q, J = 6.4 Hz, 1H), 3.91 – 3.82 (m, 4H), 3.29 (s, 3H), 3.24 – 3.15 (m, 4H), 1.47 (d, J = 6.4 Hz, 3H). Step b: To a solution of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)morpholine (1.88 g) in15 DMSO (25 mL), 4,4,5,5-tetraethyl-2-(4,4,5,5,-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (5.71 g), Pd(dppf)Cl2-DCM adduct (127 mg) and potassium phenoxide (1.90 g) were added. The mixture was allowed to stir at 60°C for 1 hr under nitrogen, after which time it was cooled to RT and diluted with water and EtOAc. The layers were separated. The aq. layer was extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried 20 over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 0 to 60% 3:1 EtOAc / EtOH in heptane) to afford (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5- tetraethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)morpholine (1.35 g) along with a small amount of impurities as orange oil. LC / MS (RXNMON-Basic): M / Z = 405.0 [M+H]+.1H NMR (400 MHz, CDCl3) 8.35 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 3.1 Hz, 1H), 4.95 (q, J = 6.4 Hz, 1H), 3.93 – 3.82 25 (m, 4H), 3.24 (s, 3H), 3.22 – 3.16 (m, 4H), 1.92 – 1.70 (m, 8H), 1.46 (d, J = 6.4 Hz, 3H), 1.02 – 0.95 (m, 12H). The following intermediates of Table 1 were synthesized using the above procedure or modifications of the above procedure using the corresponding amine coupling partner. 30 Table 1: 4,4,5,5-tetraethyl-1,3,2-dioxaborolane intermediates PAT059646-WO-PCT 5 Intermediate 13 (S)-8-(6-((S)-1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl)octahydropyrazino[2,1-c][1,4]oxazine 10 Procedure Step a: To a solution of (S)-octahydropyrazino[2,1-c][1,4]oxazine (328 mg) and (S)-3-bromo-5- iodo-2-(1-methoxyethyl)pyridine (745 mg) in toluene (11.2 mL) was added xantphos (126 mg), KOtBu (489 mg), and Pd2dba3(39.9 mg). The reaction was purged with nitrogen (3x) and stirred at 100°C under nitrogen for 2 hr. The reaction was diluted with EtOAc, filtered through Celite®, 15 and concentrated. The residue was purified by column chromatography (SiO2, 0 to 100% 3:1 EtOAc / EtOH in heptane) to afford (S)-8-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3- yl)octahydropyrazino[2,1-c][1,4]oxazine (281.1 mg). LC / MS (RXNMON-Acidic method): M / Z = 356.4 [M+H]+. 20 Step b: To a solution of (S)-8-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)octahydropyrazino[2,1- c][1,4]oxazine (281 mg) and bis(pinacolato)diboron (301 mg) in 2-MeTHF (7.7 mL) was added potassium 2-ethylhexanoate (316 mg) and Pd(dppf)Cl2(86.6 mg). The reaction was purged with nitrogen (3x) and heated at 80°C for 2 hr. The reaction was partitioned with 2% wt. aq. NaHCO3. The aq. layer was extracted with EtOAc. The organic extract was dried with Na2SO4and 25 concentrated. The residue was purified by column chromatography (propylamine SiO2, 0 to 11% EtOH in heptane) to afford (S)-8-(6-((S)-1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine (271 mg). LC / MS (RXNMON-Acidic method): M / Z = 322.4 [M-C6H10]+.1H NMR (400 MHz, CDCl3) 8.30 (d, J = 3.0 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 4.81 (q, J = 6.5 Hz, 1H), 3.89 (m, 1H), 3.84 – 3.71 (m, 2H), 3.59 30 (m, 1H), 3.37 (m, 2H), 3.29 – 3.19 (m, 3H), 3.02 (m, 1H), 2.91 (d, J = 11.1 Hz, 1H), 2.75 (d, J = 11.6 Hz, 1H), 2.56 – 2.39 (m, 4H), 1.45 (m, 3H), 1.36 (d, J = 1.3 Hz, 12H). PAT059646-WO-PCT 5 Intermediate 14 and Intermediate 14a (3S,4S)-1-(methoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid Procedure Step a: To a suspension of racemic cis-methyl 4-phenylpyrrolidine-3-carboxylate hydrochloride 10 (2 g) and NaHCO3(2.09 g) in DCM (30 mL) and water (3 mL) was added methyl carbonochloridate (1.28 mL). The reaction was stirred at RT for 30 min. The reaction mixture was diluted with water, extracted with DCM (2x), passed through a phase separator, and concentrated. The residue was purified by column chromatography (SiO2, 0 to 55% EtOAc in heptane) to afford racemic cis- dimethyl 4-phenylpyrrolidine-1,3-dicarboxylate (1.68 g) as an orange oil. LC / MS (FinalAnalysis- 15 Basic) M / Z = 264.3 [M+H]+. Step b: Racemic cis-dimethyl 4-phenylpyrrolidine-1,3-dicarboxylate (1.68 g) was purified by chiral SFC (Prep_SFC3 method) to yield dimethyl (3S,4S)-4-phenylpyrrolidine-1,3-dicarboxylate (0.766 g) as the first eluting isomer, a pale orange solid.1H NMR (400 MHz, CDCl3) 7.33 – 7.22 (m, 20 3H), 7.18 – 7.13 (m, 2H), 3.94 – 3.80 (m, 3H), 3.76 (s, 3H), 3.72 (q, J = 6.9 Hz, 2H), 3.41 (s, 4H). LC / MS (FinalAnalysis-Basic) M / Z = 264.3 [M+H]+. Step c: A mixture of dimethyl (3S,4S)-4-phenylpyrrolidine-1,3-dicarboxylate (150 mg) and trimethyltin hydroxide (155 mg) in DCE (5.6 mL) was stirred at 85°C. After stirring for 24 hr, 25 additional trimethyltin hydroxide (52 mg) was added. After stirring for 6 hr, additional trimethyltin hydroxide (103 mg) was added. The reaction stirred for a total of 4 days. The reaction mixture was concentrated, suspended in EtOAc and 1N aq. HCl, and the phases were separated. The aq. layer was extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and concentrated. The residue was purified by column chromatography [SiO2, 030 to 60% 3:1 EtOAc / EtOH (containing 1% AcOH) in heptane] to yield (3S,4S)-1-(methoxycarbonyl)- 4-phenylpyrrolidine-3-carboxylic acid (130 mg) as a white solid.1H NMR (400 MHz, DMSO) 12.25 (d, J = 2.4 Hz, 1H), 7.30 (td, J = 7.4, 2.2 Hz, 2H), 7.26 – 7.21 (m, 1H), 7.20 (s, 2H), 3.72 (dq, J = 11.6, 6.0 Hz, 2H), 3.67 – 3.61 (m, 4H), 3.59 (d, J = 7.0 Hz, 2H), 3.43 (dd, J = 14.5, 6.9 Hz, 1H). LC / MS (FinalAnalysis-Basic) M / Z = 250.3 [M+H]+. 35 PAT059646-WO-PCT 5 The following intermediates of Table 2 were synthesized using the above procedure or modifications of the above procedure. Table 2: Phenylpyrrolidine intermediates 10 Intermediate 16 dimethyl (3S,4S)-4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)pyrrolidine-1,3-dicarboxylate Procedure Step a: To a mixture of dimethyl (3S,4S)-4-phenylpyrrolidine-1,3-dicarboxylate (400 mg) and 15 AgOTf (781 mg) in DCM (13 mL) was added AcOH (46 mg, 4 L) and I2(771 mg) at 0 °C. After 1.5 hr, the mixture was allowed to warm to RT and stir for 2 hr. After this time, the mixture was poured into dilute, aq. NH4OH (50 mL) and sat. aq. sodium thiosulfate (10 mL). The mixture was filtered, and the filtrate was extracted with DCM (3x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column20 chromatography (SiO2; 10 to 50% EtOAc in heptane) to afford dimethyl (3S,4S)-4-(4- PAT059646-WO-PCT 5 iodophenyl)pyrrolidine-1,3-dicarboxylate (465 mg) as a colorless syrup.1H NMR (400 MHz, CDCl3) 7.65 – 7.59 (m, 2H), 6.94 – 6.87 (m, 2H), 3.90 – 3.77 (m, 3H), 3.75 (s, 4H), 3.65 (q, J = 7.0 Hz, 1H), 3.45 (s, 3H), 3.43 – 3.35 (m, 1H). Step b: Dimethyl (3S,4S)-4-(4-iodophenyl)pyrrolidine-1,3-dicarboxylate (105 mg), tert-butyl 10 piperazine-1-carboxylate (53 mg), Cs2CO3(219 mg), Pd2(dba)3(7.4 mg), and XPhos (7.7 mg) were dissolved in toluene (2.7 mL) and sparged with nitrogen for 5 min. The mixture was then stirred at 110°C for 20 h, after which time it was filtered and concentrated. The residue was purified by column chromatography (SiO2; 30 to 60% EtOAc in heptane) to afford dimethyl (3S,4S)-4-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)pyrrolidine-1,3-dicarboxylate (74 mg) 15 as a yellow foam. LC / MS (FinalAnalysis-Basic): M / Z = 448.5 [M+H]+.1H NMR (400 MHz, CDCl3) 7.07 (d, J = 8.4 Hz, 2H), 6.93 – 6.78 (m, 2H), 3.86 – 3.80 (m, 1H), 3.79 – 3.71 (m, 5H), 3.70 – 3.62 (m, 2H), 3.58 (s, 4H), 3.45 – 3.40 (m, 3H), 3.40 – 3.32 (m, 1H), 3.15 – 3.05 (m, 4H), 1.48 (s, 9H). 20 Intermediate 17 (3S,4S)-1-(methoxycarbonyl)-4-(4-(4-methylpiperazin-1-yl)phenyl)pyrrolidine-3-carboxylic acid Procedure 25 Step a: A solution of dimethyl (3S,4S)-4-(4-(4-(tert-butoxycarbonyl)piperazin-1- yl)phenyl)pyrrolidine-1,3-dicarboxylate (74 mg) and trimethyltin hydroxide (60 mg) in DCE (1.1 mL) was stirred at 85 °C for 5 hr. After this time, additional trimethyltin hydroxide (30 mg) was added and stirring continued for 17 hr. After this time, additional trimethyltin hydroxide (15 mg) was added and the reaction stirred for an additional 8 hr, for a total of 30 hr at 85 °C. The mixture 30 was then concentrated and diluted with 1N aq. HCl and EtOAc. The aq. layer was extracted with EtOAc (3x), and the combined organic extracts were washed with brine, passed through a phase separator and concentrated. The residue was purified by column chromatography (SiO2; 0 to 75% 3:1 EtOAc / EtOH in heptane) to afford (3S,4S)-4-(4-(4-(tert-butoxycarbonyl)piperazin-1- yl)phenyl)-1-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (53 mg) as a white solid. LC / MS 35 (FinalAnalysis-Basic): M / Z = 434.4 [M+H]+.1H NMR (400 MHz, DMSO) 12.20 (s, 1H), 7.03 (d, PAT059646-WO-PCT 5 J = 8.4 Hz, 2H), 6.91 – 6.82 (m, 2H), 3.73 – 3.50 (m, 9H), 3.43 (t, J = 5.1 Hz, 4H), 3.05 (t, J = 5.3 Hz, 4H), 1.41 (s, 9H). Intermediate 18 (3S,4S)-4-(4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)-1-(methoxycarbonyl)pyrrolidine-3- 10 carboxylic acid Procedure Step a: To a solution of Intermediate 17 (76 mg) in DCM (1.3 mL) was added TFA (0.4 mL) and the solution was allowed to react at RT for 2 hr. The reaction mixture was concentrated, and the 15 resulting residue was redissolved in DCM and concentrated to dryness; this process was repeated (3x). The resulting material was treated with sat. aq. NaHCO3and extracted with DCM (3x). The combined organic extracts were passed through a phase separator and concentrated to afford dimethyl (3S,4S)-4-(4-(piperazin-1-yl)phenyl)pyrrolidine-1,3-dicarboxylate (68 mg) as a yellow residue. LC / MS (RXNMON-Basic) M / Z = 348.5 [M+H]+. 20 Step b: To solution of dimethyl (3S,4S)-4-(4-(piperazin-1-yl)phenyl)pyrrolidine-1,3-dicarboxylate (30 mg), 2-hydroxyacetic acid (6.8 mg), and DIPEA (32.9 mg, 44.4 L) in acetonitrile (800 μL) was added HATU (35.5 mg). The reaction stirred at RT for 45 min., after which time the reaction was diluted with sat. aq. NaHCO3 and EtOAc. The aq. layer was extracted with EtOAc (3x) and 25 the combined organic extracts were washed with brine, passed through a phase separator and concentrated to afford crude dimethyl (3S,4S)-4-(4-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)pyrrolidine-1,3-dicarboxylate (37 mg) as a pale yellow solid, which was taken as-is to the next step. LC / MS (RXNMON-Basic) M / Z = 406.5 [M+H]+. 30 Step c: To a solution of crude dimethyl (3S,4S)-4-(4-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)pyrrolidine-1,3-dicarboxylate (37 mg) was added trimethyltin hydroxide (61 mg) in DCE (800 μL). The reaction was stirred at 85°C for 3 days, after which time the reaction mixture was concentrated and the residue treated with aq.1N HCl and EtOAc. The aq. layer was extracted PAT059646-WO-PCT 5 with EtOAc, and the combined organic extracts were washed with brine, passed through a phase separator, and concentrated. The residue was purified by preparatory HPLC (C18, 10 to 30% acetonitrile in water (+ 0.1% formic acid)) to afford (3S,4S)-4-(4-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)-1-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (12 mg) as a white solid. LC / MS (FinalAnalysis-Basic) M / Z = 392.5 [M+H]+.1H NMR (400 MHz, DMSO) 7.14 (s, 4H), 4.15 – 4.13 10 (m, 3H), 3.72 – 3.65 (m, 4H), 3.62 (d, J = 3.9 Hz, 4H), 3.58 – 3.54 (m, 4H), 3.45 – 3.33 (m, 2H), 3.22 (m, 2H), 2.07 (s, 2H). Intermediate 19 (2R,3R)-3-(4-(4-methylpiperazin-1-yl)phenyl)tetrahydrofuran-2-carboxylic acid 15 Procedure Step a: To a solution of (2R,3R)-3-phenyltetrahydrofuran-2-carboxylic acid (10 g) in EtOH (260 mL) was added conc. H2SO4(226 mg, 416 L). The reaction was heated at 90°C for 5 hr. The reaction mixture was concentrated and diluted in EtOAc and sat. NaHCO3. The aq. layer was 20 extracted with EtOAc (2x), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford ethyl (2R,3R)-3-phenyltetrahydrofuran-2-carboxylate (11.2 g) as a clear, yellow oil.1H NMR (400 MHz, CDCl3) 7.31 – 7.19 (m, 5H), 4.65 (d, J = 8.1 Hz, 1H), 4.43 (ddd, J = 8.5, 7.4, 5.0 Hz, 1H), 4.03 (q, J = 8.0 Hz, 1H), 3.86 – 3.64 (m, 3H), 2.45 – 2.33 (m, 2H), 0.82 (t, J = 7.1 Hz, 3H). LC / MS (FinalAnalysis-Basic) M / Z = 221.1 [M+H]+. 25 Step b: To a solution of ethyl (2R,3R)-3-phenyltetrahydrofuran-2-carboxylate (989 mg) and Ag(OTf) (2.31 g) in DCM (40 mL) and AcOH (135 mg, 129 L) at 0 °C was added I2(2.28 g). The reaction mixture was allowed to warm to RT and stir for 1.5 hr, after which time it was poured into PAT059646-WO-PCT 5 dilute aq. NH4OH and sat. aq. sodium thiosulfate. The resulting precipitate was filtered, and the filtrate was extracted with DCM (3x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2; 0-15% EtOAc in heptane) to afford ethyl (2R,3R)-3-(4- iodophenyl)tetrahydrofuran-2-carboxylate (909 mg) as a clear oil.1H NMR (400 MHz, CDCl3) 10 7.63 – 7.58 (m, 2H), 7.00 – 6.95 (m, 2H), 4.62 (d, J = 7.8 Hz, 1H), 4.40 (td, J = 8.4, 4.2 Hz, 1H), 4.05 – 3.98 (m, 1H), 3.86 (dq, J = 10.8, 7.2 Hz, 1H), 3.75 (dq, J = 10.8, 7.1 Hz, 1H), 3.67 (q, J = 7.9 Hz, 1H), 2.43 – 2.23 (m, 2H), 0.90 (s, 3H). LC / MS (RXNMON-basic) M / Z = 347.1 [M+H]+. Step c: A mixture of (2R,3R)-3-(4-iodophenyl)tetrahydrofuran-2-carboxylate (300 mg), tert-butyl 15 piperazine-1-carboxylate (254 mg), Cs2CO3(1.11 g), Pd2dba3(31.2 mg), and XPhos (32.5 mg) in toluene (12 mL) was sparged with nitrogen for 5 min. and heated at 110°C for 20 hr. The reaction mixture was filtered over a pad of Celite® and concentrated. The residue was purified by column chromatography (SiO2; 25-45% EtOAc in hepane) to afford tert-butyl 4-(4-((2R,3R)-2- (ethoxycarbonyl)tetrahydrofuran-3-yl)phenyl)piperazine-1-carboxylate (109 mg) as an off-white 20 solid.1H NMR (400 MHz, MeOD) 7.15 – 7.10 (m, 2H), 6.94 – 6.89 (m, 2H), 4.60 (d, J = 8.1 Hz, 1H), 4.32 (td, J = 7.9, 4.6 Hz, 1H), 3.98 (td, J = 8.2, 7.4 Hz, 1H), 3.84 – 3.64 (m, 3H), 3.55 (t, J = 5.2 Hz, 4H), 3.08 (dd, J = 6.3, 4.1 Hz, 4H), 2.37 – 2.24 (m, 2H), 1.48 (s, 9H), 0.83 (t, J = 7.1 Hz, 3H). LC / MS (FinalAnalysis-Basic) M / Z = 405.5 [M+H]+. 25 Step d: To a solution of tert-butyl 4-(4-((2R,3R)-2-(ethoxycarbonyl)tetrahydrofuran-3- yl)phenyl)piperazine-1-carboxylate (109 mg) in DCM (2 mL) was added TFA (500 μL). The reaction was stirred at RT for 30 min. The reaction mixture was then concentrated, diluted in DCM, and concentrated again; this process was repeated (3x). The remaining residue was dissolved in DCM and washed with sat. NaHCO3. The aq. layer was extracted with DCM (3x), and 30 the combined organic extracts were passed through a phase separator, and concentrated to afford ethyl (2R,3R)-3-(4-(piperazin-1-yl)phenyl)tetrahydrofuran-2-carboxylate (93 mg). LC / MS (RXMON-Basic) M / Z = 305.4 [M+H]+. Step e: To a solution of ethyl (2R,3R)-3-(4-(piperazin-1-yl)phenyl)tetrahydrofuran-2-carboxylate 35 (93 mg) in MeOH (2.5 mL) was added aq. formaldehyde (65.4 mg, 60 L, 37% wt). The reaction was stirred for 30 min. and then sodium triacetoxyhydroborate (114 mg) was added. The reaction was stirred at RT for 30 min. and was then diluted with brine and sat. NaHCO3and the aq. layer was extracted with DCM (3x). The combined organic layers were passed through a phase separator and concentrated to afford ethyl (2R,3R)-3-(4-(4-methylpiperazin-1- 40 yl)phenyl)tetrahydrofuran-2-carboxylate (87 mg). PAT059646-WO-PCT 5 Step f: To a solution ethyl (2R,3R)-3-(4-(4-methylpiperazin-1-yl)phenyl)tetrahydrofuran-2- carboxylate (87 mg) in THF (800 μL), MeOH (800 μL), and water (800 μL) was added aq. 1N LiOH (23 mg, 1 mL). The reaction stirred at RT for 24 hr, after which time additional aq.1N LiOH (5.7 mg, 240 μL) was added, and the reaction stirred overnight for 16 hr. The reaction stirred for a total of 40 hr. The volatiles were removed and the mixture was purified by column10 chromatography (C18; 0 to 15% acetonitrile in water (+0.1% NH4OH)) to afford (2R,3R)-3-(4-(4- methylpiperazin-1-yl)phenyl)tetrahydrofuran-2-carboxylic acid (72 mg) as a white solid after lyophilization.1H NMR (400 MHz, DMSO) 7.12 – 7.06 (m, 2H), 6.76 – 6.69 (m, 2H), 4.17 – 4.11 (m, 1H), 4.11 – 4.00 (m, 1H), 3.79 – 3.69 (m, 1H), 3.36 – 3.32 (m, 3H), 3.08 – 2.99 (m, 4H), 2.43 (t, J = 5.0 Hz, 4H), 2.20 (s, 3H), 1.99 – 1.87 (m, 1H). LC / MS (RXNMON-basic) M / Z = 291.5 [M+H]+. 15 Intermediate 20 (2R,3S)-1-(tert-butoxycarbonyl)-3-phenylazetidine-2-carboxylic acid Procedure 20 Step a: (2RS,3SR)-1-(tert-butoxycarbonyl)-3-phenylazetidine-2-carboxylic acid (820 mg) was purified by chiral SFC (Prep_SFC6 method) to yield (2R,3S)-1-(tert-butoxycarbonyl)-3- phenylazetidine-2-carboxylic acid as the second eluting isomer. LC / MS (RXNMON-Acidic): M / Z = 276.3 [M–H]–25 Intermediate 21 (1R,2S)-2-phenylcyclopropane-1-carboxylic acid Procedure Step a: Racemic cis 2-phenylcyclopropane-1-carboxylic acid (243 mg) was purified by SFC 30 (Prep_SFC4 method) to yield (1R,2S)-2-phenylcyclopropane-1-carboxylic acid (111 mg) as the first eluting isomer, a white solid. LC / MS (FinalAnalysis-Basic) M / Z = 163.0 [M+H]+.1H NMR (400 PAT059646-WO-PCT 5 MHz, CDCl3) 7.29 – 7.18 (m, 5H), 2.69 – 2.59 (m, 1H), 2.06 (ddd, J = 9.2, 7.7, 5.6 Hz, 1H), 1.68 (ddd, J = 7.7, 5.6, 5.1 Hz, 1H), 1.38 (ddd, J = 8.7, 7.7, 5.1 Hz, 1H). Intermediate 22 (1R,2S)-2-phenylcyclobutane-1-carboxylic acid 10 Procedure Step a: Racemic cis 2-phenylcyclobutane-1-carboxylic acid (250 mg) was purified by SFC (Prep_SFC5 method) to yield (1R,2S)-2-phenylcyclobutane-1-carboxylic acid (124 mg) as the second eluting isomer, a yellow oil. LC / MS (FinalAnalysis-Basic) M / Z = 175.1 [M+H]+.1H NMR 15 (400 MHz, CDCl3) 7.31 – 7.13 (m, 5H), 4.03 – 3.88 (m, 1H), 3.58 – 3.41 (m, 1H), 2.71 – 2.53 (m, 1H), 2.32 (m, 2H), 2.26 – 2.13 (m, 1H). Intermediate 23 onyl)(methyl)amino)-3-methylpent-4-enoic acid 20 Procedure Step a: A solution of (2S,3R)-2-(((S)tert-butylsulfinyl)amino)-3-methylpent-4-enoic acid (250 mg) in DCM (3.6 mL) was cooled to 0 °C and 4N HCl in dioxane (195 mg, 1.34 mL) was added. The solution was stirred at RT for 50 min. The mixture was then concentrated to afford (2S,3R)-2- 25 amino-3-methylpent-4-enoic acid hydrochloride (165.0 mg) as a white solid.1H NMR (400 MHz, DMSO) 13.81 (s, 1H), 8.35 (s, 2H), 5.81 (ddd, J = 17.4, 10.4, 7.2 Hz, 1H), 5.32 – 5.02 (m, 2H), 3.87 (d, J = 4.5 Hz, 1H), 2.89 – 2.72 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H). PAT059646-WO-PCT 5 Step b: A solution of (2S,3R)-2-amino-3-methylpent-4-enoic acid hydrochloride (158 mg) in 1,4- dioxane (1.91 mL) was cooled to 0 °C and 1N aq. NaOH (95 mg, 2.4 mL) was added. A solution of Boc2O (245 mg, 263 L) was added to the reaction at 0 °C and the reaction was allowed to warm to RT and stir for 42 hr. The reaction pH was then adjusted to 10 with aq.1N NaOH. The resulting basic aq. mixture was washed with Et2O. The remaining aq. layer was acidified to pH 2 10 with aqueous 1N HCl and extracted with 15 mL portions of EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford (2S,3R)-2-((tert- butoxycarbonyl)amino)-3-methylpent-4-enoic acid (210 mg) as a colorless oil.1H NMR (400 MHz, DMSO) 12.50 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 5.75 (ddd, J = 17.5, 10.4, 7.3 Hz, 1H), 5.08 – 4.96 (m, 2H), 3.93 (dd, J = 8.7, 6.3 Hz, 1H), 2.59 (p, J = 6.9 Hz, 1H), 1.38 (s, 9H), 0.96 (d, 15 J = 6.9 Hz, 3H). Step c: A solution of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-methylpent-4-enoic acid (210 mg) in THF (5.9 mL) was cooled to 0 °C. NaH (110 mg, 60% wt.) was added in portions. Following complete addition, MeI (1.04 g) was added and the reaction was allowed to warm to RT and stir 20 for 22 hr. Additional NaH (44 mg, 60% wt.) and MeI (520 mg, 229 L) were added and stirring at RT was continued for 16 hr. Et2O was added and the reaction was quenched with water (15 mL). The resulting organic phase was washed with additional water (15 mL). The combined aq. extracts were acidified to a pH of 3 with aq. citric acid and extracted with 15 mL portions of EtOAc (3x). Combined organic extracts were washed with aq. sodium thiosulfate solution, dried over25 Na2SO4, filtered, and concentrated to afford (2S,3R)-2-((tert-butoxycarbonyl)(methyl)amino)-3- methylpent-4-enoic acid (150 mg) as an oil.1H NMR (400 MHz, DMSO) 12.60 (s, 1H), 5.80 (m, 1H), 5.17 – 4.96 (m, 2H), 4.26 (dd, J = 97.9, 10.1 Hz, 1H), 2.76 (s, 3H), 2.74 – 2.63 (m, 1H), 1.40 (d, J = 8.7 Hz, 9H), 0.91 (dd, J = 13.2, 6.8 Hz, 3H). 30 Intermediate 24 N-(tert-butoxycarbonyl)-N-methyl-L-alloisoleucine PAT059646-WO-PCT 5 Procedure Step a: To a solution of (2S,3R)-2-(((S)-tert-butylsulfinyl)amino)-3-methylpent-4-enoic acid (250 mg) in MeOH (5 mL) was charged Pd(OH)2on carbon (151 mg, 20% wt.). The reaction vessel was evacuated and backfilled with H2. The reaction was stirred under an atmosphere of H2at RT for 22 hr. The reaction was filtered and concentrated to afford ((S)-tert-butylsulfinyl)-L- 10 alloisoleucine (252 mg) as a reddish-brown oil. LC / MS (RXMON-Acidic method): M / Z = 236.0 [M+H]+. Step b: To a solution of ((S)-tert-butylsulfinyl)-L-alloisoleucine (85.6 mg) in DCM (1.2 mL). The solution was cooled to 0 °C and 4N HCl in 1,4-dioxane (455 L) was added. The reaction was 15 stirred at RT for 30 min., after which time the solution was concentrated to afford L-alloisoleucine hydrochloride (67 mg) as a white solid.1H NMR (400 MHz, DMSO) 13.79 (s, 1H), 8.25 (s, 2H), 3.83 (s, 1H), 1.94 (ddd, J = 13.0, 9.2, 5.6 Hz, 1H), 1.52 (dq, J = 13.8, 6.8 Hz, 1H), 1.25 – 1.08 (m, 1H), 0.97 – 0.85 (m, 6H). 20 Step c: To a vial charged with L-alloisoleucine hydrochloride (67 mg) was added 1,4-dioxane (759 L). The reaction solution was cooled to 0 °C and aq.1N NaOH (949 L) was added. Following this, Boc2O (99 mg) was added, and the reaction was allowed to warm to RT. Additional aq.1N NaOH (949 L) and Boc2O (99 mg) were added. The reaction stirred for total of 29 hr, after which time the pH was adjusted to 10 with aq.1N NaOH. The mixture was washed with Et2O and the 25 aq. layer was then acidified to pH 2 with aq.1N HCl and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford (tert- butoxycarbonyl)-L-alloisoleucine (85.6 mg) as a white solid.1H NMR (400 MHz, DMSO) 12.45 (s, 1H), 6.85 (d, J = 8.9 Hz, 1H), 4.00 (dd, J = 8.9, 5.0 Hz, 1H), 1.86 – 1.76 (m, 1H), 1.39 (s, 9H), 1.36 – 1.29 (m, 1H), 1.14 (dt, J = 14.2, 7.3 Hz, 1H), 0.88 – 0.82 (m, 6H). 30 Step d: To a solution of (tert-butoxycarbonyl)-L-alloisoleucine (70 mg) in THF (2.0 mL) at 0 °C was sequentially added MeI (344 mg, 151 L) and NaH (73 mg, 60% wt.). The reaction was allowed to warm to RT and stir for 28 hr. The reaction was then diluted with Et2O and washed with water (15 mL, 2x). Combined aq. extracts were acidified with citric acid (pH 3) and extracted 35 with EtOAc. Combined organic extracts were dried over Na2SO4, filtered, and concentrated. This residue was purified by column chromatography (C18; 10 to 100% acetonitrile in water + 0.1% formic acid) to afford N-(tert-butoxycarbonyl)-N-methyl-L-alloisoleucine (40 mg) as a colorless oil after lyophilization.1H NMR (400 MHz, DMSO) 12.64 (s, 1H), 4.20 (dd, J = 100.9, 10.0 Hz, 1H), 2.73 (d, J = 2.2 Hz, 3H), 2.01 – 1.83 (m, 1H), 1.44 (d, J = 7.7 Hz, 1H), 1.39 (d, J = 9.2 Hz, 9H), 40 1.09 (dq, J = 14.9, 7.6 Hz, 1H), 0.88 (t, J = 7.4 Hz, 3H), 0.78 (dd, J = 9.6, 6.7 Hz, 3H). PAT059646-WO-PCT 5 Intermediate 25 N-(tert-butoxycarbonyl)-N,O-dimethyl-L-threonine Procedure Step a: To a solution of methyl (tert-butoxycarbonyl)-L-threoninate (3 g) in acetonitrile (130 mL) 10 at 0 °C under nitrogen was added Ag2O (13.4 g) and MeI (14.1 g, 6.19 mL). The reaction allowed to warm to RT and stir for 4 days. After this time, the reaction was filtered, rinsed with acetonitrile, and concentrated. The residue was purified by column chromatography (SiO2; 5 to 30% EtOAc in heptane) to afford methyl N-(tert-butoxycarbonyl)-O-methyl-L-threoninate (2.39 g) as a colorless oil.1H NMR (400 MHz, CDCl3) 5.21 (d, J = 9.5 Hz, 1H), 4.27 (dd, J = 9.5, 2.4 Hz, 1H), 3.90 (qd, 15 J = 6.3, 2.4 Hz, 1H), 3.76 (s, 3H), 3.28 (s, 3H), 1.45 (s, 9H), 1.20 (d, J = 6.3 Hz, 3H). Step b: To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-threoninate (2.39 g) in THF (16 mL) and MeOH (16 mL) at 0 °C was added aq.1.0N LiOH (810 mg, 34 mL). The reaction was allowed to warm to RT and stir for 2.5 hr. After this time, the mixture was cooled to 0 °C, 1N aq. HCl (21 20 mL) was added, and the mixture was concentrated. The remaining aq. mixture was extracted with EtOAc (3x), the organic layers were passed through a phase separator. Filtrate was concentrated to afford N-(tert-butoxycarbonyl)-O-methyl-L-threonine (2.18 g) as a white solid.1H NMR (400 MHz, CDCl3) 5.36 – 5.25 (m, 1H), 4.41 – 4.31 (m, 1H), 4.02 – 3.91 (m, 1H), 3.46 – 3.37 (m, 3H), 1.46 (s, 9H), 1.21 (d, J = 6.4 Hz, 3H). 25 Step c: To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (500 mg) in THF (20 mL) at 0 °C under a nitrogen atmosphere was added NaH (176 mg, 60% wt.) in one portion. After 30 min., MeI (1.53 g, 670 L) and DMF (332 L) were added. The solution stirred at 0 °C for 2 hr then was allowed to warm to RT and stir for 20 hr. The reaction mixture was quenched with water, 30 diluted with aq. HCl and brine. The aq. layer was extracted with EtOAc (3x). The combined organic extracts were passed through a phase separator and concentrated. The residue was purified by column chromatography (SiO2; 5 to 35% 3:1 EtOAc / EtOH (containing 1% AcOH) in heptanes) to afford N-(tert-butoxycarbonyl)-N,O-dimethyl-L-threonine (278 mg) as white solid.1H NMR (400 MHz, CDCl3) 4.80 – 4.73 (m, 0.7H), 4.71 – 4.63 (m, 0.3H), 4.08 – 4.02 (m, 0.7H), 4.02 – 3.93 PAT059646-WO-PCT 5 (m, 0.3H), 3.33 (dm, J = 1.1 Hz, 3H), 2.96 (dm, J = 4.5 Hz, 3H), 1.51 – 1.42 (m, 9H), 1.23 – 1.15 (m, 3H). Intermediate 26 benzyl 4-(5-((61R,65S,66S,4S)-4-((tert-butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo-10 25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana- 2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate 15 Procedure Step a: To a solution of Intermediate 3a (11.83 g) in acetonitrile (45.8 mL) under nitrogen atmosphere was added water (900 mg, 900 μL), Et3N (2.9 g, 4 mL), and LiBr (5 g). The resulting 20 mixture was stirred at RT for 16 hr, upon which time additional LiBr (1 g) was added, and the PAT059646-WO-PCT 5 mixture was then heated to 50 °C for 4 hr. After this time, the reaction was cooled to RT and stirred for 48 hr, during which time a precipitate formed. The first crop of solids was collected via vacuum filtration and rinsed with cold acetonitrile. The filtrate was concentrated to half of its volume and cooled to 5 °C to precipitate additional product. This second crop was isolated via vacuum filtration and combined with the first crop to afford (2S)-3-(3-(2-(5-(4-10 ((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (10.5 g) as a white solid after drying. LC / MS (RXMON acidic_nonpolar): M / Z = 1020.6 [M+H]+. 15 Step b, part 1: To Intermediate 1 (220 mg) in DCM (35 mL) was added TFA (35 mL) and the solution was stirred at RT for 2 hr, after which time, the reaction mixture was concentrated and the residue was azeotropically dried with heptane and left to dry in vacuo for 16 hr to afford methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate, trifluoroacetate salt (3.35 g) which was advanced directly to subsequent amide coupling. 20 Step b, part 2: Crude methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate, trifluoroacetate salt was reconstituted in DMF (30 mL) and (2S)-3-(3-(2-(5-(4- ((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- 25 butoxycarbonyl)amino)propanoic acid (10.5 g) was added. The reaction apparatus was purged with nitrogen (3x) and the solution was cooled to 0 °C. DIPEA (4.25 g, 5.73 mL) was added, and the mixture was stirred for 5 min., after which time HATU (3.93 g) was added, and the solution was allowed to stir for 5 min. at °C and then warm to RT. After stirring at RT for 1 hr, ice (75 mL) was added to triturate the product. After melting, the reaction suspension was filtered and the30 retained solids were washed with water (75 mL) to afford methyl (1S,2S,6R)-4-((2S)-3-(3-(2-(5- (4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate (11.36 g) as an off-white solid after drying. LC / MS (FinalAnalysis-Acidic): M / Z = 1159.9 [M+H]+. 35 Step c: To a solution of methyl (1S,2S,6R)-4-((2S)-3-(3-(2-(5-(4-((benzyloxy)carbonyl)piperazin- 1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)-3,4- diazabicyclo[4.1.0]heptane-2-carboxylate (10.82 g) in acetonitrile (200 mL) under nitrogen 40 atmosphere was added water (3 g, 3 mL), Et3N (2.363 g, 3.25 mL), and LiBr (4.055 g). The solution was then stirred at 50 °C for 16 hr, after which time additional LiBr (2 g) and water (1 g, PAT059646-WO-PCT 5 1 mL) were added, and the mixture was allowed to cool to RT and stir for 56 hr. After 72 hr, the reaction was concentrated to half of its original volume and EtOAc (300 mL) was added. The resulting mixture was washed with aq.0.5N HCl and the organic phase was dried over Na2SO4and filtered. The filtrate was concentrated to afford (1S,2S,6R)-4-((2S)-3-(3-(2-(5-(4- ((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-10 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylic acid (11.5 g) as a yellow solid, containing some impurities, which was carried forward to the next step as-is. LC / MS (FinalAnalysis-Basic-NonPolar): M / Z = 1144.7 [M+H]+. 15 Step d: To a solution of EDC (2.60 g), HOAt (1.85 g) and DMAP (664 mg) in DCM (500 mL) was added, via mechanical syringe driver, a solution of (1S,2S,6R)-4-((2S)-3-(3-(2-(5-(4- ((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylic acid (7.5 g) in 20 DMF (20 mL) at a rate of 3 mL / hr. Following complete addition, the reaction was washed with sat. aq. NaHCO3solution (100 mL), water (100 mL, 3x) and the resulting organic phase was dried over Na2SO4. Filtration and concentration afforded a crude semi-solid which was purified by column chromatography (SiO2;0 to 15% EtOAc / EtOH 3:1 in DCM) to afford benzyl 4-(5- ((61R,65S,66S,4S)-4-((tert-butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-25 ((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (4.33 g) as a white solid.1H NMR (400 MHz, DMSO) 8.47 (d, J = 2.9 Hz, 1H), 7.95 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.56 – 7.49 (m, 1H), 7.40 – 7.34 (m, 4H), 7.35 – 7.31 (m, 1H), 7.31 (s, 1H), 7.28 – 7.24 (m, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.06 – 7.01 (m, 1H), 6.79 (s, 1H), 5.11 (s, 2H), 5.00 30 – 4.91 (m, 1H), 4.91 – 4.84 (m, 1H), 4.28 – 4.08 (m, 4H), 3.75 (d, J = 10.9 Hz, 1H), 3.65 (d, J = 10.8 Hz, 1H), 3.57 (s, 4H), 3.31 – 3.21 (m, 5H), 3.14 (s, 3H), 2.93 – 2.81 (m, 1H), 2.77 – 2.68 (m, 1H), 2.67 – 2.56 (m, 2H), 1.38 – 1.34 (m, 3H), 1.33 (s, 9H), 1.29 – 1.27 (m, 2H), 1.26 – 1.18 (m, 5H), 1.13 – 1.06 (m, 18H), 0.97 – 0.91 (m, 3H), 0.88 – 0.83 (m, 4H), 0.44 (s, 2H), 0.36 – 0.28 (m, 1H). LC / MS (Peptide method): M / Z = 1126.6500 [M+H]+. 35 The following intermediates of Table 3 were synthesized using the above procedure or modifications of the above procedure using the corresponding hydropyridazine building block and Intermediate 3. Note: Axial chirality of compounds is as shown in structures in Table 3. 40 Table 3: Macrocycle intermediates PAT059646-WO-PCT 5 Intermediate 27 benzyl 4-(5-((61R,65S,66S,4S)-11-ethyl-10,10-dimethyl-4-((S)-3-methyl-2-((2R,3R)-N-methyl-3- phenyltetrahydrofuran-2-carboxamido)butanamido)-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-10 oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-12- yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate

[0014] PAT059646-WO-PCT 5 Step a: To a solution of benzyl 4-(5-((61R,65S,66S,4S)-4-((tert-butoxycarbonyl)amino)-11-ethyl- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)- bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3- 10 yl)piperazine-1-carboxylate (248 mg) in DCM (1.6 mL) was added TFA (627 mg, 421 μL). The solution was stirred at RT for 1 hr. The reaction mixture was concentrated and the residue was triturated with Et2O to afford benzyl 4-(5-((61R,65S,66S,4S)-4-amino-11-ethyl-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana- 2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- 15 carboxylate trifluoroacetate salt (370 mg) as a yellow foam. LC / MS (RXNMON-Acidic): M / Z = 1027.6 [M+H]+. Step b: To a solution of benzyl 4-(5-((61R,65S,66S,4S)-4-amino-11-ethyl-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-20 2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate trifluoroacetate salt (370 mg) in DMF (2 mL) a 0 °C under nitrogen, was added Boc- N-Me-L-valine (101 mg), DIPEA (285 mg, 384 μL) and COMU (189 mg). The reaction mixture was allowed to warm to RT and stir for 15 min. After this time, the reaction mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with sat. aq. NaHCO3, brine, 25 dried over Na2SO4, filtered, and concentrated. The residue was purified by column PAT059646-WO-PCT 5 chromatography (SiO2; 0 to 100% EtOAc in heptane) to afford benzyl 4-(5-((61R,65S,66S,4S)-4- ((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-11-ethyl-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana- 2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate (280 mg) as a foamy solid. LC / MS (RXNMON-Acidic): M / Z = 1240.4 [M+H]+. 10 Step c: To a solution of benzyl 4-(5-((61R,65S,66S,4S)-4-((S)-2-((tert- butoxycarbonyl)(methyl)amino)-3-methylbutanamido)-11-ethyl-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)- benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate 15 (280 mg) in DCM (2 mL) was added TFA (411 μL). The reaction solution was stirred at RT for 1 hr, after which time it was concentrated to dryness. The residue was re-dissolved in DCE, concentrated, and the remaining residue was triturated with Et2O to afford benzyl 4-(5- ((61R,65S,66S,4S)-11-ethyl-10,10-dimethyl-4-((S)-3-methyl-2-(methylamino)butanamido)-5,7- dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana-20 2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate trifluoroacetate salt (300 mg) as a yellow solid. LC / MS (RXNMON-Acidic): M / Z = 1140.6 [M+H]+. Step d: To a solution of benzyl 4-(5-((61R,65S,66S,4S)-11-ethyl-10,10-dimethyl-4-((S)-3-methyl-2-25 (methylamino)butanamido)-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)- indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate trifluoroacetate salt (270 mg) in DMF (1.5 mL) under nitrogen was added (2R,3R)-3-phenyltetrahydrofuran-2-carboxylic acid (62 mg) followed by DIPEA (276 mg, 372 μL) and HATU (162 mg). After stirring at RT for 1 hr, the reaction mixture 30 was diluted with MeOH and purified by column chromatography (C18; 10 to 100% acetonitrile in water + 0.1% formic acid) to afford benzyl 4-(5-((61R,65S,66S,4S)-11-ethyl-10,10-dimethyl-4-((S)- 3-methyl-2-((2R,3R)-N-methyl-3-phenyltetrahydrofuran-2-carboxamido)butanamido)-5,7-dioxo- 25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)-bicyclo[4.1.0]heptana- 2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1- 35 carboxylate (231 mg). HRMS: M / Z = 1314.7500 [M+H]+. The following intermediates of Table 4 were synthesized using the above procedure or modifications of the above procedure. 40 Table 4: Cbz-protected macrocycle intermediates PAT059646-WO-PCT 5 Intermediate 29 (2R,3R)-N-((2S)-1-(((61R,65S,66S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(piperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)- indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1- 10 oxobutan-2-yl)-N-methyl-3-phenyltetrahydrofuran-2-carboxamide Step a: To a solution of Intermediate 27 (130 mg) in THF (8 mL) and EtOH (3 mL) was added 15 Pd(OH)2on carbon (69 mg, 10% wt.). The reaction mixture was purged with H2and stirred under an H2atmosphere at RT for 30 min., after which time Celite® and water were added. The mixture was filtered, and the filter cake was washed with methanol (10 mL). The combined filtrate was concentrated, and the residue was purified by column chromatography (C18; 10 to 100% acetonitrile in water + 0.1% TFA). The product fraction was concentrated, naturalized with sat. PAT059646-WO-PCT 5 aq. NaHCO3 and extracted with EtOAc. The EtOAc extract was concentrated to afford (2R,3R)- N-((2S)-1-(((61R,65S,66S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)-indola-6(3,5)- bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)- N-methyl-3-phenyltetrahydrofuran-2-carboxamide (110 mg) as a white foam. LC / MS 10 (FinalAnalysis-Acidic): M / Z = 1180.4 [M+H]+. The following intermediates of Table 5 were synthesized using the above procedure or modifications of the above procedure. 15 Table 5: Cbz-protected macrocycle intermediates Intermediate 31 (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoate 20 PAT059646-WO-PCT 5 Step a: To a suspension of zinc dust (1.21 g) in DMF (20 mL) under nitrogen atmosphere was added I2(141 mg). The mixture was stirred for 15 min., after which time methyl (R)-2-((tert- butoxycarbonyl)amino)-3-iodopropanoate (1.83 g) and I2(141 mg) were sequentially added. The mixture was allowed to stir at RT for 1 hr. After this time, a solution of 4-(benzyloxy)-1-fluoro-2- iodobenzene (1.22 g) in DMF (5 mL), Pd2(dba)3(85 mg), and SPhos (153 mg) were sequentially 10 added. The mixture was allowed to stir at RT for 15 min. and then 50 °C for 1 hr. The reaction was diluted with water (150 mL) and EtOAc (50 mL) and the suspension was filtered. The EtOAc extract was washed with water (15 mL, 3x), brine, passed through a phase separator, and concentrated. The resulting residue was purified by column chromatography (SiO2; 0 to 20% EtOAc in heptane) to afford methyl (S)-3-(5-(benzyloxy)-2-fluorophenyl)-2-((tert- 15 butoxycarbonyl)amino)propanoate (1.23 g) as a yellow oil. LC / MS (FinalAnalysis-Acidic): M / Z = 304.1 [M-Boc+H]+. Step b: To a solution of methyl (S)-3-(5-(benzyloxy)-2-fluorophenyl)-2-((tert- butoxycarbonyl)amino)propanoate (1.23 g) in MeOH (15 mL) under nitrogen atmosphere was 20 charged Pd(OH)2on carbon (2.14 g, 10% wt.). The mixture was purged with H2and allowed to stir under a H2atmosphere for 2 hr, after which time the mixture was filtered and concentrated to afford crude methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5-hydroxyphenyl)propanoate (1.014 g) which was used without further purification. LC / MS (RXMON-Acidic): M / Z = 214.2 [M- Boc+H]+. 25 Step c: To a solution of crude methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5- hydroxyphenyl)propanoate (1.01 g) in 2-MeTHF (10 mL) under nitrogen atmosphere was sequentially charged imidazole (621 mg) and TIPS-Cl (880 mg, 976 μL). The reaction mixture was left to stir at RT for 16 hr. After this time, the mixture was concentrated and the resulting 30 residue purified by column chromatography (SiO2; 0 to 20% EtOAc in heptane) to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoate (1.745 g), with some impurities, as a colorless oil.1H-NMR (400 MHz, CDCl3) 6.86 (t, J = 9.1 Hz, 1H), 6.75 – 6.68 (m, 1H), 6.64 (dd, J = 6.2, 3.0 Hz, 1H), 5.01 (d, J = 8.3 Hz, 1H), 4.56 (q, J = 6.6 Hz, 1H), 3.72 (s, 3H), 3.10 – 3.00 (m, 2H), 1.41 (s, 9H), 1.25 – 1.18 (m, 3H), 1.08 (d, J = 7.4 Hz, 18H). 35 Step d: 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (1.179 g) and 4,4’-di-tert-butyl- 2,2’-dipyridine (299.2 mg) were suspended in heptane (12 mL) and placed under nitrogen atmosphere. (1,5-cylooctadiene)(methoxy)iridium(I) dimer (370 mg) was added and the mixture was stirred at RT for 5 min., after which time a solution of methyl (S)-2-((tert- 40 butoxycarbonyl)amino)-3-(2-fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoate (1.75 g) in heptane (12 mL) was added. The reaction mixture was stirred at 75 °C for 1 hr and then concentrated. The PAT059646-WO-PCT 5 resulting residue was purified by column chromatography (SiO2, 0 to 20% EtOAc in heptane) to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (1.071 g) as a colorless syrup.1H NMR (400 MHz, CDCl3) 7.07 (t, J = 3.7 Hz, 1H), 6.73 (dd, J = 6.1, 3.2 Hz, 1H), 4.98 (d, J = 8.3 Hz, 1H), 4.52 (q, J = 6.9 Hz, 1H), 3.71 (s, 3H), 3.12 – 2.94 (m, 2H), 1.41 (s, 9H), 1.34 (s, 11H), 10 1.25 – 1.18 (m, 3H), 1.08 (s, 7H), 1.10 (s, 10H).19F NMR (376 MHz, CDCl3) -117.93. Intermediate 32 tert-butyl ((61R,65S,66S,4S)-11-ethyl-22-fluoro-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-63,64-diaza-1(5,3)- 15 indola-6(3,5)-bicyclo[4.1.0]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate Procedure Step a: Intermediate 2 (552 mg), Intermediate 31 (450 mg), Pd(dtbpf)Cl2(49 mg) and K2CO3(209 mg) in 1,4-dioxane (4 mL) and water (800 L), was flushed with nitrogen and stirred at 70°C for 20 1 hr. The reaction was diluted with water and EtOAc. The layers were separated. The aq. layer was extracted with EtOAc (3x), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated onto Celite® (15 g). The adsorbed material was purified by column chromatography (SiO2; 0 to 100 EtOAc / EtOH 3:1 in heptane) to afford benzyl 4-(5-(5- PAT059646-WO-PCT 5 (3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2-fluoro-5- ((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1- methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (760 mg) as a colorless oil. LC / MS (FinalAnalysis-Acidic): M / Z = 1053.0 [M+H]+. 10 Step b: A solution of benzyl 4-(5-(5-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3- oxopropyl)-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H- indol-2-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (760 mg) in MeOH (10 mL) was purged with nitrogen, then Pd(OH)2on carbon (532 mg, 20% wt.) was added. The mixture was purged again with nitrogen, then H2via balloon. The reaction was stirred at RT for 2 15 hr under H2. After this time, the reaction was flushed with nitrogen prior to workup, then diluted with excess MeOH. The slurry was filtered under nitrogen protection and the filtrate concentrated to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-2-fluoro- 5-((triisopropylsilyl)oxy)phenyl)propanoate, which was carried forward to the next step without 20 further purification. LC / MS (RXMON-Acidic): M / Z = 919.0 [M+H]+. Step c: To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(piperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-2- fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoate (80 mg) in MeOH (3 mL) was added aq. 25 formaldehyde (21 mg, 20 L, 37% wt.) and the solution was allowed to stir at RT for 30 min., after which time sodium triacetoxyhydroborate (37 mg) was added and the mixture stirred for 2 hr. The reaction was partially concentrated and purified by column chromatography (SiO2; 0 to 50% MeOH in DCM) to afford methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5- 30 yl)-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoate (70 mg) as a colorless oil. LC / MS (RXMON-Basic): M / Z = 933.2 [M+H]+. Step d: To a solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5- 35 yl)-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoate (350 mg) in DCE (3 mL) was added trimethyltin hydroxide (339 mg) and the mixture was purged with nitrogen and stirred at 75°C for 4 hr. After this time, the reaction was cooled to RT and diluted with 10 volumetric equivalents of DCM. The mixture was quenched with aq.0.05N sodium bisulfite (37.54 mL) with vigorous stirring for 5 min. The layers were separated. The aq. layer was extracted with DCM (3x), and the 40 combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2- PAT059646-WO-PCT 5 ((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)-2-fluoro-5- ((triisopropylsilyl)oxy)phenyl)propanoic acid (340 mg). LC / MS (Peptide method): M / Z = 919.0 [M+H]+. Step e, part 1: To Intermediate 1 (220 mg) in DCM (2.5 mL) was added TFA (2.4 mL) and the 10 solution was stirred at RT for 1 hr, after which time, the reaction mixture was concentrated. Additional DCM was added and concentrated and this process was repeated 3x to afford methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate, trifluoroacetate salt (157 mg) which was carried forward without further purification. 15 Step e, part 2: To methyl (1S,2S,6R)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate (157 mg) at RT, a solution of (2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 2-fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoic acid (340 mg), DIPEA (574 mg, 774 L), and HATU (282 mg) in DMF (3 mL) was added. The reaction was stirred at RT for 3 hr. Purification 20 by column chromatography (C18; 10 to 100% acetonitrile in water (+0.1% NH4OH)) afforded methyl (1S,2S,6R)-4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)- 2-fluoro-5-((triisopropylsilyl)oxy)phenyl)propanoyl)-3,4-diazabicyclo[4.1.0]heptane-2-carboxylate (260 mg) as a white solid after lyophilization. LC / MS (Peptide method): M / Z = 1057.0 [M+H]+. 25 Step f: To a solution of methyl (1S,2S,6R)-4-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiper...

Claims

PAT059646-WO-PCT 5 CLAIMS 1. A compound of formula (I) or formula (XX),10 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 15 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 20 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6R2is optionally substituted 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, 25 and S;PAT059646-WO-PCT 5 R3; is selected from the group consisting of H, halo, OH, CN, C1-10 alkyl, C1-6 heteroalkyl, C1-6 haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-310 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; 15 L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; 20 R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; each Rxis independently selected from H, C1-6alkyl, C3-6cycloalkyl, and C1-6haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; 25 m is 0 or 1; and n is 0, 1, 2, or 3, wherein at least one of the following is true: a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; 30 wherein R7is optionally further substituted.

2. A compound of formula (I),PAT059646-WO-PCT 5 wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- 10 membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and 15 ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10 alkyl, C1-6 heteroalkyl, C1-6 20 haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or 25 two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; 30 R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl, aryl, or 5-6 membered heteroaryl with 1-3 ring atoms selected from N, O, and S; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6 alkyl, C3-6 cycloalkyl, or C1-6 haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms 35 independently selected from the group consisting of N, O and S, and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3, wherein at least one of the following is true: 40 a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; orPAT059646-WO-PCT 5 b) R7is C2-6 alkenyl, C2-6 alkynyl, C4-6 cycloalkenyl, or C1-6 alkyl substituted by C4-6 cycloalkenyl; wherein R7is optionally further substituted.

3. A compound of formula (I) 10wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; 15 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 20 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6 alkyl, C1-6 heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; 25 R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-330 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2;PAT059646-WO-PCT 5 L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W, or L is absent; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted; R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; W is -COR9, wherein R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms 10 independently selected from the group consisting of N, O and S; and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3; wherein at least one of the following is true: 15 a) R9is 2-oxetanyl or 2-azetidinyl, each optionally substituted; or b) R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted.

4. A compound of formula (Iw) or formula (XXw) 20wherein ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted;PAT059646-WO-PCT 5 ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; 15 R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3 alkyl, C1-3 20 heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; 25 R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; m is 0 or 1; and n is 0, 1, 2, or 3. 30 5. A compound of formula (Iw)PAT059646-WO-PCT 5 ring A is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring A is optionally substituted; ring B is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of 10 N, O, and S, and ring B is optionally substituted; ring C is 6-membered aryl, 6-membered heteroaryl with 1-3 ring atoms which are N, or 5- membered heteroaryl with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and ring C is optionally substituted; and ring B is edge-fused to ring C to form a BC ring system; 15 each R1is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6; R2is substituted pyridine or substituted phenyl; R3is selected from the group consisting of H, halo, OH, CN, C1-10alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6, or R3is absent; 20 each R4is independently selected from the group consisting of H, halo, C1-6alkyl, and C1-6haloalkyl; each R5is independently selected from the group consisting of H, halo, OH, CN, C1-3alkyl, C1-3heteroalkyl, C1-3haloalkyl, and C3-6cycloalkyl; or two R5groups are taken together with the carbon atom to which they are connected to form a 25 C3-6cycloalkyl; each R6is independently selected from the group consisting of H, OH, C1-6alkyl, C1-6haloalkyl, C1-6heteroalkyl, and NH2; R9is C3-7cycloalkyl or 3-7 membered heterocyclyl having 1-3 ring atoms independently selected from the group consisting of N, O and S; and R9is optionally substituted; 30 m is 0 and n is 0; or m is 0 and n is 1.

6. The compound of any one of claims 1-5, wherein ring A is phenyl, pyridine, thiazole, triazole, oxazole, or oxadiazole, and ring A is substituted with 0-3 R10; 35 wherein R10is selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6.

7. The compound of claim 6, wherein ring A isPAT059646-WO-PCT 58. The compound of claim 7, wherein ring A is10 9. The compound of any one of claims 1-8, wherein the BC ring system is indole, benzothiophene, benzoxazole, or indolizine, each of which optionally has 1-3 additional N ring atoms in its 6-membered ring, wherein each BC ring system is optionally substituted, for example wherein the BC ring system is optionally substituted with 1-3 R11, wherein each R11is independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-615 heteroalkyl, C1-6haloalkyl, NH2, and COR6.

10. The compound of any one of claims 1-9, wherein the BC ring system is 20for example wherein either 0 or 1 of X2are N, and the remaining X2are CR11, for example wherein the BC ring system is, wherein each R11is independently selected from the group consisting of H, halo, OH, CN, C1-625 alkyl, C1-6heteroalkyl, C1-6haloalkyl, NH2, and COR6.

11. The compound of any one of claims 1-10, whereinPAT059646-WO-PCT 5 each R1is independently selected from the group consisting of H, halo, C1-6 alkyl, or C1-6 haloalkyl; for example wherein each R1is H.

12. The compound of any one of claims 1-11, wherein R2is substituted pyridine. 10 13. The compound of any one of claims 1-12, wherein R2is, wherein R2ais C1-10alkyl, C3-6cycloalkyl, or C1-10heteroalkyl, and R2ais optionally substituted by 1-3 15 substituents independently selected from the group consisting of halo, OH, CN, C1-6 alkyl, C1-6 heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, NRxCOR6, and COR6; for example, wherein R2ais C1-10optionally substituted heteroalkyl; R2bis 4-10-membered heterocycloalkyl, with 1-4 ring atoms selected from the group consisting of N, O, P(O)xx, and S(O)xx, wherein xx is 0, 1, or 2, and R2bis optionally substituted, for 20 example with 1-3 R2ba, wherein each R2bais independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, , C1-6haloalkyl, NH2, COR6, and -(CH2)0-2- heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, P(O)xx, and S(O)xx, wherein xx is 0, 1, or 2, and wherein each 25 phenyl, heterocycloalkyl, and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl; each R2cis independently selected from the group consisting of H, halo, OH, CN, C1-6alkyl, and C1-6heteroalkyl; for example, wherein each R2cis H; and 30 each Rxis independently selected from H, C1-6alkyl, C3-6cycloalkyl, and C1-6haloalkyl.

14. The compound of claim 13, wherein R2bis35 wherein X3is C, CRx, N, or P(O); is a single or double bond; andPAT059646-WO-PCT 5 each Rxis independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl; for example, wherein R2bais H, C1-6alkyl, -(CH2)0-2phenyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, COR6, or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S. 10 15. The compound of claim 13 or 14 wherein R2ais, wherein X4is O or N, and X5is CH; or X5is O or N, and X4is CH; and 15 R2aais C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2aais absent or H; R2abis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2abis absent or H; and R2acis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo or one OH, or R2acis 20 absent or H.

16. The compound of any one of claims 1-12, wherein 25is a single or double bond R2aais C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo, or R2aais absent or 30 H; R2abis C1-3 alkyl or C3-6 cycloalkyl, each optionally substituted with 1-3 halo, or R2abis absent or H; R2acis C1-3alkyl or C3-6cycloalkyl, each optionally substituted with 1-3 halo or one OH; andPAT059646-WO-PCT 5 R2bais H, C1-6 alkyl, -(CH2)0-2 phenyl, C1-6 heteroalkyl, C1-6 haloalkyl, C3-6 cycloalkyl, COR6, or heterocycloalkyl wherein the heterocycloalkyl is 4-7 membered with 1-3 ring atoms selected from the group consisting of N, O, and S, and each phenyl, cycloalkyl, or heterocycloalkyl is optionally substituted. 10 17. The compound of any one of claims 1-16, wherein R3is selected from the group consisting of H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl, or R3is absent; for example, R3is C1-6alkyl; for example, R3is ethyl.

18. The compound of any one of claims 1-17, wherein 15 each R4is independently selected from the group consisting of H, C1-6alkyl, and C1-6haloalkyl; for example, wherein each R4is H.

19. The compound of any one of claims 1-18, wherein each R5is independently selected from the group consisting of H and C1-6 alkyl; or 20 two R5groups are taken together with the carbon atom to which they are connected to form a C3-6cycloalkyl; for example wherein both R5are CH3.

20. The compound of any one of claims 1-19, wherein 25 L is absent, or L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W; R7is C1-6alkyl, C2-6alkenyl, or C2-6alkynyl, each optionally substituted by C3-6cycloalkyl; or R7is C3-6cycloalkyl; wherein R7is optionally further substituted by 1-3 substituents selected from the group consisting of halo, OH, C1-3haloalkyl, C1-3heteroalkyl, and C1-3alkyl; and R8is H or C1-3alkyl. 30 21. The compound of any one of claims 1-20, wherein R7is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, or C1-6alkyl substituted by C3-6cycloalkyl, wherein R7is optionally further substituted by 1-3 substituents selected from the group consisting of halo and C1-3alkyl. 35 22. The compound of any one of claims 1-21, wherein R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted by 1-3 substituents selected from the group consisting of halo and C1-3alkyl. 40 23. The compound of any one of claims 1-22, whereinPAT059646-WO-PCT 5 R7is10 24. The compound of any one of claims 1-23, wherein R9is C3-7cycloalkyl or 4-6 membered heterocycloalkyl having 1-3 ring atoms independently selected from the group consisting of N, O and S, wherein each R9is optionally substituted by 1-3 R9a, and optionally substituted with 1 R9bon a ring nitrogen atom, if present; each R9ais independently selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-615 alkenyl, C1-6alkynyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, COR6, NRxCOR6, and -(CH2)0-2heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and C1-6heteroalkyl. 20 25. The compound of any one of claims 1-24, wherein R9is 2-oxetanyl optionally substituted with 1-3 R9a.

26. The compound of any one of claims 1-25, wherein W is 25PAT059646-WO-PCT5 ,wherein R9bis H, C1-6alkyl, C1-6heteroalkyl, -(CH2)0-2phenyl, -(CH2)0-2-C3-6cycloalkyl, C1-6haloalkyl, NH2, COR6, NRxCOR6, and -(CH2)0-2heterocyclyl of 4-7 ring atoms with 1-3 ring atoms independently selected from the group consisting of N, O, and S, and wherein each phenyl, heterocyclyl and cycloalkyl is optionally substituted, for example with 1-3 substituents selected from the group consisting of halo, OH, CN, C1-6alkyl, C1-6haloalkyl, and 10 C1-6heteroalkyl, for example wherein R9bis H, C1-3alkyl, or NRxCO-C1-3alkyl.

27. The compound of claim 26, wherein W is. 15 28. The compound of any one of claims 1-27 wherein the compound is a compound of formula (III), formula (XXIII), or formula (XXXIII) 20PAT059646-WO-PCT 5for example, wherein all R1are H, for example wherein n is 0 or 1;for example a compound of formula (IIIa) 1029. The compound of any one of claims 1-27, wherein the compound is a compound of formula (IV), formula (XXIV), or formula (XXXIV) 15PAT059646-WO-PCT 5wherein n is 0 or 1; for example, wherein all R1are H; for example, wherein there are no R1110 substituents; for example, wherein the compound is a compound of formula (IVa)for example, wherein all R1are H; for example, wherein there are no R11substituents. 15 30. The compound of any one of claims 1-27, wherein the compound is a compound of formula (V), formula (VI), formula (XXV), formula (XXVI), formula (XXXV), formula (XXXVI)PAT059646-WO-PCT 510 wherein n is 0 or 1; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (V), formula (XXV), or formula (XXXV) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; 15 for example, a compound of formula (VI), formula (XXVI), or formula (XXXVI) wherein R10is H.

31. The compound of any one of claims 1-27, wherein the compound is a compound of formula (Vw)PAT059646-WO-PCT 5for example, wherein m is 0, and n is 0 or 1; for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (Vw) wherein there is one R10selected from the group 10 consisting of OH, NH2, and halo, and the remaining R10are H.

32. The compound of any one of claims 1-27, wherein the compound is a compound of formula (Va) or formula (VIa)15 for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (IVa) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; 20 for example, a compound of formula (Va) wherein R10is H.

33. The compound of any one of claims 1-27, wherein the compound is a compound of formula (VII), formula (XXVII), or formula (XXXVII)PAT059646-WO-PCT 510 for example, wherein all R1are H.

34. The compound of any one of claims 1-27 wherein the compound is a compound of formula (Iy’) or formula (XXy)PAT059646-WO-PCT 5for example, wherein all R1are H, for example wherein m is 1 and n is 0 or 1; 10 35. The compound of any one of claims 1-27 wherein the compound is a compound of formula (IIIy’), formula (XXIIIy’), or formula (XXXIIIy’)PAT059646-WO-PCT 510 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H, for example wherein n is 0 or 1; for example a compound of formula (IIIya’)15 wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H.

36. The compound of any one of claims 1-27, wherein the compound is a compound of 20 formula (Ivy’), formula (XXIVy’), or formula (XXXIVy’)PAT059646-WO-PCT 510 wherein n is 0 or 1; wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents; for example, wherein the compound is a compound of formula (IVya’)PAT059646-WO-PCT 5wherein the variables are defined as in various embodiments of the disclosure; for example, wherein all R1are H; for example, wherein there are no R11substituents. 10 37. The compound of any one of claims 1-27, wherein the compound is a compound of formula (Vy’) or formula (VIy’), formula (XXVy’), formula (XXVIy’), formula (XXXVIy’) or formula (XXXVIy’)wherein n is 0 or 1 ; wherein the variables are defined as in various embodiments of the disclosure;PAT059646-WO-PCT 5 for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (Vy’), formula (XXVy’), or formula (XXXVy’) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; 10 for example, a compound of formula (VIy’), formula (XXVIy’), or formula (XXXVIy’) wherein R10is H.

38. The compound of any one of claims 1-27, wherein the compound is a compound of formula (Vya’) or formula (VIya’) 15wherein the variables are defined as in various embodiments of the disclosure; 20 for example, wherein all R1are H; for example, wherein all R5are CH3; for example, wherein there are no R11substituents; for example, a compound of formula (Vya’) wherein there is one R10selected from the group consisting of OH, NH2, and halo, and the remaining R10are H; for example, a compound of formula (VIya’) wherein R10is H. 25 39. The compound of any one of claims 1-27, wherein the compound is a compound of formula (VIIy), formula (VIIIy), formula (XXVIIy), formula (XXVIIIy), formula (XXXVIIy), or formula (XXXVIIIy)PAT059646-WO-PCT 5 10PAT059646-WO-PCT 5for example, wherein all R1are H. 10 40. A compound of any one of claims 1-39, wherein L is -COCHR7N(R8)-*, wherein * indicates the point of attachment to W; R7is C2-6alkenyl, C2-6alkynyl, C4-6cycloalkenyl, or C1-6alkyl substituted by C4-6cycloalkenyl; wherein R7is optionally further substituted; and R8is H, C1-6alkyl, C3-6cycloalkyl, or C1-6haloalkyl; 15 for example wherein R7is.

41. A compound selected from the compounds disclosed in the specification. 20 42. A pharmaceutical composition comprising the compound of any one of claims 1-41 and a pharmaceutically acceptable carrier.

43. A method of treating cancer in a subject in need thereof, the method comprising 25 administering to the subject a therapeutically effective amount of the compound of any one of claims 1-41, or the pharmaceutical composition of claim 42.PAT059646-WO-PCT 5 44. The method of claim 43, wherein the cancer is a tumor or a hematological cancer, optionally, the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic 10 lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or 15 head and neck cancer.

45. The method of claim 43, wherein the cancer is non-small cell lung cancer, pancreatic cancer, colorectal cancer, melanoma, head and neck cancer, acute myeloid leukemia, or bladder cancer. 20

Images