Synthesis of ras inhibitors

Abstract

The present invention relates to Ras inhibitors, intermediates in the synthesis thereto, and methods for preparing the Ras inhibitors and the intermediates.

Description

[0001] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0002] PATENT

[0003] ATTORNEY DOCKET NO.: 51432-059WO2

[0004] SYNTHESIS OF RAS INHIBITORS

[0005] BACKGROUND

[0006] The vast majority of small molecule drugs act by binding a functionally important pocket on a

[0007] 5 target protein, thereby modulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates. The fact that many such drug / target interacting pairs are known may have misled some into believing that a small molecule modulator could be discovered for most, if not all, proteins provided a reasonable amount of time, effort, and resources. This is far from the case. Current estimates are that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The other 90% are currently considered refractory or intractable to the above-mentioned small molecule drug discovery. Such targets are commonly referred to as “undruggable.” These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular

[0008] 15 modalities capable of modulating the function of such undruggable targets.

[0009] It has been well established in literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play an essential role in various human cancers 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

[0010] 20 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 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., G13C) and 61 (e.g., Q61 K) of Ras are also responsible for oncogenic activity in some cancers.

[0011] Despite extensive drug discovery efforts against Ras during the last several decades, only two agents targeting the K-Ras G12C mutant have been approved in the U.S. (sotorasib and adagrasib). Additional efforts are needed to uncover additional medicines for cancers driven by the various Ras

[0012] 30 mutations, and there remains a need for convenient, scalable synthetic methods thereto.

[0013] SUMMARY OF THE INVENTION

[0014] The invention features methods of preparing Ras inhibitors, intermediates useful in the synthesis of Ras inhibitors, and methods of preparing the intermediates. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0015] PATENT ATTORNEY DOCKET NO.: 51432-059WO2

[0016] In an aspect, the disclosure features methods of preparing compounds having the structure of Formula A:

[0017] Formula A or a salt thereof, wherein

[0018] A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6- membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10- membered heteroarylene;

[0019] L is a linker;

[0020] R8is optionally substituted 5- to 10-membered heteroaryl;

[0021] R9is optionally substituted Ci-Ce alkyl;

[0022] R10is optionally substituted Ci-Ce alkyl, optionally substituted C1-C3 heteroalkyl, or optionally substituted 3- to 6-membered cycloalkyl;

[0023] R11is hydrogen or optionally substituted Ci-Ce alkyl; each R12is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1- C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; t is O, 1 , 2, or 3; z is 0, 1 , or 2; and each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6is, independently, hydrogen, halogen, hydroxyl, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted Ci-Ce heteroalkyl; or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl.

[0024] In some embodiments, L has the structure of Formula L1 :

[0025] Formula L1

[0026] X1is O or CH2 and is attached to ring A; and

[0027] Z is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted Ci-Ce alkylene, or optionally substituted Ci-Ce heteroalkylene. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0028] PATENT

[0029] ATTORNEY DOCKET NO.: 51432-059WO2

[0030] In some embodiments, L has the structure of Formula L2:

[0031] Formula L2

[0032] B is an optionally substituted 3- to 6-membered heterocycloalkylene;

[0033] R6is hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted Ce-Cw aryl, R

[0034] R7and R8are each, independently, H or optionally substituted Ci-Ce alkyl;

[0035] R9is optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocyclyl;

[0036] R10is optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted Ce-Cw aryl; and

[0037] R11is hydrogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2- Ce alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C3-C10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkenyl, optionally substituted Ce-C aryl, or optionally substituted 5- to 10-membered heteroaryl.

[0038] In some embodiments, L has the structure of Formula L3:

[0039] Formula L3.

[0040] In another aspect, the disclosure provides a method of preparing a compound of Formula 1 :

[0041] Formula 1 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0042] PATENT

[0043] ATTORNEY DOCKET NO.: 51432-059WO2 the method including condensing a compound of Formula 1 a and a compound of Formula 1 b to form the compound of Formula 1 :

[0044] Formula 1a Formula 1b Formula 1 wherein n is 0 or 1 ;

[0045] R1is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, or optionally substituted C1-C4 heteroalkyl; and

[0046] R2is optionally substituted C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl.

[0047] In some embodiments, the compound of Formula 1 is Formula 1 c:

[0048] Formula 1c wherein q is 0 or 1 .

[0049] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0050] PATENT

[0051] ATTORNEY DOCKET NO.: 51432-059WO2

[0052] In some embodiments, the compound of Formula 1 is Compound 1 b, Compound 1 c, Compound

[0053] 1 d, Compound 1 e, Compound 1 f, or Compound 1 g:

[0054] 5

[0055] In another aspect, the disclosure provides a method of preparing a compound of Formula 2: wherein n is 0 or 1 ;

[0056] R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0057] R3is optionally substituted Ci-Ce alkyl; PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0058] PATENT

[0059] ATTORNEY DOCKET NO.: 51432-059WO2 the method including coupling a compound of Formula 2b with a compound of Formula 1 to form the compound of Formula 2:

[0060] In another aspect, the disclosure provides a sodium salt of Compound 3:

[0061] Compound 3 Na salt

[0062] In another aspect, the disclosure provides a method of preparing the sodium salt of Compound 3, the method including: a) protecting Compound 3a to form Compound 3b:

[0063] Compound 3a Compound 3b

[0064] 10 b) borylating Compound 3b to form Compound 3c: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0065] PATENT

[0066] ATTORNEY DOCKET NO.: 51432-059WO2 c) hydrolyzing Compound 3c to form Compound 3d: d) coupling Compound 3d with Compound 3e«2HCI to form Compound 3f:

[0067] 5 e) hydrolyzing Compound 3f form the sodium salt of Compound 3:

[0068] In some embodiments, the hydrolyzing and borylating of (b) further includes contacting Compound 3b with an iridium catalyst.

[0069] In another aspect, the disclosure provides a method of preparing a compound of Formula 4f as a 10 racemic mixture of cis and trans isomers:

[0070] Formula 4f (mixture of cis / trans isomers, racemic) wherein m is 1 or 2; the method including: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0071] PATENT

[0072] ATTORNEY DOCKET NO.: 51432-059WO2 a) N-alkylating Compound 4a with a compound of Formula 4b to form a compound of Formula 4c:

[0073] Compound 4a Formula 4b Formula 4c b) acetylating the compound of Formula 4c by i) deprotonating the compound of Formula 4c using a base to form a deprotonated compound of Formula 4c; and ii) coupling the deprotonated compound of

[0074] 5 Formula 4c with Compound 4d to form a compound of Formula 4e:

[0075] Compound 4d c) cyclizing and protecting the compound of Formula 4e to form a racemic mixture of a compound of Formula 4f:

[0076] Formula 4e Formula 4f

[0077] (cis only, racemic) .anc|

[0078] 10 d) isomerizing the compound of Formula 4f to form a mixture of cis and trans isomers of the compound of Formula 4f:

[0079] Formula 4f Formula 4f (cis only, racemic) (mixture of cis / trans isomers, racemic)

[0080] In some embodiments, the cyclizing of (c) further includes contacting the compound of Formula 4e with a palladium catalyst.

[0081] 15 In some embodiments, the isomerizing of (d) produces a mixture of cis and trans isomers of the compound of Formula 4f, wherein the mixture includes at least about 80% trans isomer. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0082] PATENT

[0083] ATTORNEY DOCKET NO.: 51432-059WO2

[0084] In another aspect, the disclosure provides a method of preparing a compound of Formula 4u:

[0085] Formula 4u wherein m is 1 or 2; and

[0086] 5 R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; and

[0087] 10 R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; the method including: a) hydrolyzing a mixture of cis and trans isomers of a compound of Formula 4f to form a compound of Formula 4g that is enantiomerically pure:

[0088] Formula 4f Formula 4g (mixture of cis / trans isomers, racemic) b) coupling the compound of Formula 4g with a compound of Formula 4h to form a compound of

[0089] Formula 4i:

[0090] Formula 4i

[0091] 20 c) deprotecting the compound of Formula 4i to form a compound of Formula 4j: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0092] PATENT

[0093] ATTORNEY DOCKET NO.: 51432-059WO2

[0094] Formula 4i Formula 4j .anc| d) coupling the compound of Formula 4j with a compound of Formula 4k to form the compound of Formula 4u:

[0095] 5 In some embodiments, the hydrolyzing of (a) further includes contacting the compound of Formula 4f with a serine endoprotease.

[0096] In another aspect, the disclosure provides method of preparing a compound of Formula 4-I:

[0097] Formula 4-1 wherein

[0098] 10 m is 1 or 2; and

[0099] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;

[0100] 15 R6is optionally substituted Ci-Ce alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0101] X1is halogen; the method including: a) deprotecting a compound of Formula 4I to form a compound of Formula 4m: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0102] PATENT

[0103] ATTORNEY DOCKET NO.: 51432-059WO2

[0104] Formula 41 Formula 4m b) halogenating the compound of Formula 4m to form a compound of Formula 4n:

[0105] Formula 4m Formula 4n .andc) deprotecting the compound of Formula 4n to form the compound of Formula 4-I:

[0106] Formula 4n Formula 4-I

[0107] In some embodiments, the deprotecting of (a) further includes contacting the compound of

[0108] Formula 4I with a palladium catalyst.

[0109] In another aspect, the disclosure provides a method of preparing a compound of Formula 4q:

[0110] Formula 4q

[0111] 10 wherein PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0112] PATENT

[0113] ATTORNEY DOCKET NO.: 51432-059WO2 m is 1 or 2; and

[0114] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken

[0115] 5 together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; the method including: a) hydrolyzing a mixture of cis and trans isomers of a compound of Formula 4f to form a compound of Formula 4o: (mixture of cis / trans isomers, racemic)

[0116] 10 b) deprotecting the compound of Formula 4o to form a compound of Formula 5:

[0117] Formula 4o Formula 5 c) isomerizing the compound of Formula 5 to form a compound of Formula 4p that is enantiomerically pure:

[0118] Formula 5 Formula 4p .and

[0119] 15 d) coupling the compound of Formula 4p with a compound of Formula 4h to form the compound of Formula 4q:

[0120] In some embodiments, the deprotecting of (b) further includes contacting the compound of Formula 4o with a palladium catalyst. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0121] PATENT

[0122] ATTORNEY DOCKET NO.: 51432-059WO2

[0123] In another aspect, the disclosure provides a method of preparing a compound of Formula 4-I I :

[0124] Formula 4-II wherein m is 1 or 2; and

[0125] 5 R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;

[0126] R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted

[0127] 10 Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and the method including: a) O-sulfonating a compound of Formula 4q to form a compound of Formula 4r:

[0128] 15 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0129] PATENT ATTORNEY DOCKET NO.: 51432-059WO2 b) deprotecting the compound of Formula 4r to form a compound of Formula 4s:

[0130] Formula 4r Formula 4s c) coupling the compound of Formula 4s with a compound of Formula 4k to form a compound of

[0131] Formula 4t:

[0132] 5 d) hydrolyzing the compound of Formula 4t to form the compound of Formula 4-I I :

[0133] Formula 4t Formula 4-11

[0134] In some embodiments, wherein R7is

[0135] In another aspect, the invention provides a method of preparing a compound of Formula 5:

[0136] HO Boe

[0137] 10 Compound 5 wherein m is 1 or 0; the method including: a) protecting Compound 5a to form Compound 5b: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0138] PATENT

[0139] ATTORNEY DOCKET NO.: 51432-059WO2

[0140] Compound 5a Compound 5b . b) alkylating Compound 5b with X2-CH2(CH2)m-X3to form a compound of Formula 5c:

[0141] Compound 5b Formula 5c wherein X2and X3are halogen;

[0142] 5 c) deprotecting a compound of Formula 5c to form a compound of Formula 5d:

[0143] Formula 5c Formula 5d d) protecting the compound of Formula 5d to form a compound of Formula 5e:

[0144] Compound 5d Compound 5e . e) trans-esterifying the compound of Formula 5e to form a compound of Formula 5f: Boc HO Boc

[0145] 10 Formula 5e Formula 5f f) isomerizing the compound of Formula 5f to form a trans isomer of a compound of Formula 5g:

[0146] HO Boc HO Boc

[0147] Formula 5f Formula 5g .an(-| g) hydrolyzing the compound of Formula 5g to form the compound of Formula 5:

[0148] HO Boc HO Boc

[0149] Formula 5g Formula 5

[0150] 15 In some embodiments, X2and X3are independently selected from bromine, chlorine, or iodine. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0151] PATENT

[0152] ATTORNEY DOCKET NO.: 51432-059WO2

[0153] In another aspect, the disclosure provides a method of preparing Compound 6d:

[0154] Compound 6d the method including: a) protecting Compound 6a to form Compound 6b:

[0155] Compound 6a Compound 6b b) alkylating Compound 6b with an allyl halide to form Compound 6c:

[0156] Compound 6b Compound 6c wherein X4is a halogen; and c) cyclizing Compound 6c to form Compound 6d:

[0157] 1 0Compound 6c Compound ed

[0158] In some embodiments, the cyclizing of (c) further includes contacting Compound 6c with an oxidizing agent. In some embodiments, the oxidizing agent is a periodate salt.

[0159] In some embodiments, the cyclizing of (c) further includes contacting Compound 6c with an osmate catalyst.

[0160] 15 In some embodiments, X4is bromine, chlorine, or iodine. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0161] PATENT

[0162] ATTORNEY DOCKET NO.: 51432-059WO2

[0163] In an aspect, the disclosure provides a method of preparing a compound of Formula 6:

[0164] Formula 6 wherein p is 1 or 2;

[0165] 5 R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; the method including:

[0166] 10 a) reducing a compound of Formula 6d to form a compound of Formula 6e: b) deprotecting the compound of Formula 6e to form a compound of Formula 6f:

[0167] Formula 6e Formula 6f c) reducing the compound of Formula 6f to form a compound of Formula 6g:

[0168] 15 Formula 6f Formula 6g .andd) coupling the compound of Formula 6g with a compound of Formula 6h to form the compound of Formula 6: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0169] PATENT

[0170] ATTORNEY DOCKET NO.: 51432-059WO2 oc

[0171] Formula 6g Formula 6

[0172] In some embodiments, the reducing of (a) further includes contacting the compound of Formula 6d with a silane reducing agent.

[0173] 5 In some embodiments, the deprotecting of (b) further includes contacting the compound of Formula 6e with a palladium catalyst.

[0174] In some embodiments, the deprotecting of (c) further includes contacting a compound of Formula 6f with a reducing agent.

[0175] In some embodiments, p is 1 .

[0176] 10 In another aspect, the disclosure provides a method of preparing a compound of Formula 7d: wherein n is 0 or 1 ;

[0177] R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0178] R3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl; the method including: a) coupling a compound of Formula 2 with a sodium salt of Compound 3 to form a compound of

[0179] 20 Formula 7a: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0180] PATENT

[0181] ATTORNEY DOCKET NO.: 51432-059WO2 b) cyclizing the compound of Formula 7a to form a compound of Formula 7b: c) deprotecting the compound of Formula 7b to form a compound of Formula 7c: d) deprotecting the compound of Formula 7c to form the compound of Formula 7d: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0182] PATENT

[0183] ATTORNEY DOCKET NO.: 51432-059WO2

[0184] In some embodiments, the coupling of (a) further includes contacting a compound of Formula 2 and the sodium salt of Compound 3 with a palladium catalyst.

[0185] In another aspect, the disclosure provides a method of preparing a compound of Formula 7e:

[0186] 5 wherein n is 0 or 1 ; m is 1 or 2;

[0187] R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted

[0188] Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0189] 10 R3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl;

[0190] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken

[0191] 15 together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;

[0192] R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0193] X1is halogen;

[0194] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0195] PATENT

[0196] ATTORNEY DOCKET NO.: 51432-059WO2 the method including coupling a compound of Formula 7d with a compound 4-I to form the compound of Formula 7e:

[0197] In another aspect, the disclosure provides a method of preparing a compound of Formula A:

[0198] 5 wherein n is 0 or 1 ; m is 1 or 2;

[0199] 10 R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0200] R3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl;

[0201] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0202] R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; and

[0203] R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted

[0204] 20 Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; the method including cyclizing a compound of Formula 7e to form the compound of Formula A: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0205] In some embodiments, n is 0. In some embodiments, n is 1 .

[0206] In some embodiments, m is 1 . In some embodiments, m is 2.

[0207] In some embodiments, R2is optionally substituted C1-C4 alkyl. In some embodiments, R2is

[0208] 5 optionally substituted Ci-Ce alkenyl. In some embodiments, R2is optionally substituted Ci-Ce alkynyl. In some embodiments, R2is optionally substituted C3-C6 cycloalkyl. In some embodiments, R2is optionally substituted C3-C7 heterocycloalkyl.

[0209] In some embodiments, R3is optionally substituted Ci-Ce alkyl. In some embodiments, R3is optionally substituted Ci-Ce alkenyl. In some embodiments, R3is optionally substituted Ci-Ce alkynyl.

[0210] In some embodiments, R4and R5are each optionally substituted Ci-Ce alkyl. In some embodiments, R4and R5are each optionally substituted Ci-Ce alkenyl. In some embodiments, R4and R5are each optionally substituted Ci-Ce alkynyl. In some embodiments, R4and R5are each optionally substituted C1-C3 heteroalkyl. In some embodiments, R4and R5are each optionally substituted Ci-Ce cycloalkyl. In some embodiments, R4and R5are each optionally substituted C1-C7 heterocycloalkyl. In

[0211] 15 some embodiments, R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl. In some embodiments, R4and R5are taken together to form optionally substituted C3-C7 heterocycloalkyl.

[0212] In some embodiments, R6is optionally substituted Ci-Ce alkyl. In some embodiments, R6is optionally substituted Ci-Ce alkenyl. In some embodiments, R6is optionally substituted Ci-Ce alkynyl. In some embodiments, R6is optionally substituted C1-C3 heteroalkyl.

[0213] 20 In some embodiments, R6is optionally substituted C3-C6 cycloalkyl. In some embodiments, R6is optionally substituted C4 cycloalkyl. In some embodiments, R6is optionally substituted C5 cycloalkyl. In some embodiments, R6is optionally substituted Ce cycloalkyl.

[0214] In some embodiments, R6is optionally substituted C3-C7 heterocycloalkyl. In some embodiments, R6is optionally substituted C4 heterocycloalkyl. In some embodiments, R6is optionally substituted C5 heterocycloalkyl. In some embodiments, R6is optionally substituted Ce heterocycloalkyl.

[0215] Definitions and Chemical Terms

[0216] In this application, unless otherwise clear from context, (i) the term “a” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the

[0217] 30 alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or”; (iii) the terms “comprising” and “including” are understood to encompass PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0218] PATENT

[0219] ATTORNEY DOCKET NO.: 51432-059WO2 itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included.

[0220] As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the

[0221] 5 term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).

[0222] As used herein, the term “adjacent” in the context of describing adjacent atoms refers to bivalent atoms that are directly connected by a covalent bond.

[0223] A “compound of the present invention” and similar terms as used herein, whether explicitly noted or not, refers to Ras inhibitors described herein (e.g., Compound A) and intermediates in the synthesis thereto, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.

[0224] 15 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 indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in

[0225] 20 combination.

[0226] 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. 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

[0227] 25 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 stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0228] 30 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 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 pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2 ,4-triazole , 1 H- and 2H- isoindole, and 1 H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in

[0229] 40 equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0230] PATENT

[0231] ATTORNEY DOCKET NO.: 51432-059WO2

[0232] 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 of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,

[0233] 518O,32P,33P,35S,18F,36CI,123l and125l. Isotopically labeled compounds (e.g., those labeled with3H and 14C) 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 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. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those

[0234] 15 disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0235] 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, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid

[0236] 20 form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.

[0237] 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 include each and every individual subcombination of the members of such groups and ranges. For

[0238] 25 example, the term “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl. 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 subcombination of members at each position.

[0239] 30 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 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 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

[0240] 40 substituted Ci-Ce alkyl-C2-C9 heteroaryl,” 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 term “stable”, as used PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0241] PATENT

[0242] ATTORNEY DOCKET NO.: 51432-059WO2 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.

[0243] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted”

[0244] 5 group may be, independently, deuterium; halogen; -(CH2)o-4R°; -(CH2)o-40R°; -0(CH2)o-4R°; -0-(CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-i Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)O-40(CH2)O-I -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)o-4N(R°)2; -(CH2)o-4N(R°)C(0)R°; -N(R°)C(S)R°; - (CH2)O-4N(R0)C(0)NR°2; -N(R°)C(S)NR°2; -(CH2)O-4N(R°)C(0)OR°; -N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(0)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)O-4C(0)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4-C(0)-N(R°)2; -(CH2)O-4-C(0)-N(R0)-S(0)2-R°; -C(NCN)NR°2; -(CH2)O-4C(0)SR°; -(CH2)o-4C(0)OsiR°3; -(CH2)O-40C(0)R°; -OC(0)(CH2)O-4SR°; -SC(S)SR°; -(CH2)O-4SC(0)R°;

[0245] 15 -(CH2)O-4C(0)NR°2; -C(S)NRO2; -C(S)SR°; -(CH2)O-40C(0)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)2OR°; -(CH2)O-40S(0)2R°; -S(0)2NRO2; -(CH2)O-4S(0)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NRO2; -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; -(C1-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched

[0246] 20 alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6 aliphatic, -CH2Ph, -0(CH2)o-i Ph, -CH2-(5-6 membered heteroaryl ring), or a 3-6-membered saturated, partially 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,

[0247] 25 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.

[0248] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), may be, independently, halogen, -(CH2)O-2R*, -(haloR*), -(CH2)o-2OH, -(CH2)o-2OR*, -(CH2)o-2CH(OR*)2; -O(haloR’), -CN, -N3,

[0249] 30 -(CH2)O-2C(0)R*, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OsiR*3, -C(O)SR* -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)o-i Ph, 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 =0 and =S.

[0250] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =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,

[0251] 40 C1-6 aliphatic 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 from nitrogen, oxygen, PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0252] PATENT

[0253] ATTORNEY DOCKET NO.: 51432-059WO2 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, C1-6 aliphatic 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 from nitrogen,

[0254] 5 oxygen, or sulfur.

[0255] 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 C1-4 aliphatic, -CH2Ph, -0(CH2)o-i Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0256] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NRt2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each Rt is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -Oph, or an unsubstituted 3-6-membered saturated, partially

[0257] 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 Rf, 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.

[0258] Suitable substituents on an aliphatic group of Rfare independently halogen, -R*, -(haloR*), -OH,

[0259] 20 -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 C1-4 aliphatic, -CH2Ph, -0(CH2)o-i Ph, 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 Rfinclude =0 and =S.

[0260] 25 The term “acetyl,” as used herein, refers to the group -C(O)CH3.

[0261] The term “alkoxy,” as used herein, refers to a -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the remainder of the compound through an oxygen atom.

[0262] 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

[0263] 30 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 / so-propyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0264] 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-Cyalkylene” 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 20 (e.g., Ci-Ce, 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.

[0265] 40 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 -propenyl, 2-propenyl, PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0266] PATENT

[0267] ATTORNEY DOCKET NO.: 51432-059WO2

[0268] 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.

[0269] 5 The term “alkynyl,” as used herein, represents monovalent straight or branched chain 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.

[0270] The term “amino,” as used herein, represents -N(Rt)2, e.g., -NH2 and -N(CH3)2.

[0271] The term “aminoalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0272] 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

[0273] 15 atoms can be optionally substituted unless otherwise specified.

[0274] The term “Co,” as used herein, represents a bond. For example, part of the term -N(C(0)-(Co-Cs alkylene-H)- includes -N(C(0)-(Co alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0275] The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to a monovalent, optionally substituted C3-C12 monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused or

[0276] 20 spirocyclic, in which all the rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1 ,2-dihydronaphthyl, 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

[0277] 25 unless otherwise specified.

[0278] The term “carbonyl,” as used herein, represents a C(O) group, which can also be represented as C=O.

[0279] The term “carboxyl,” as used herein, means -CO2H, (C=O)(OH), COOH, or C(O)OH or the unprotonated counterparts.

[0280] 30 The term “cyano,” as used herein, represents a -CN group.

[0281] The term “cycloalkyl,” as used herein, represents a monovalent saturated cyclic hydrocarbon group, which may be bridged, fused or spirocyclic having from three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0282] The term “cycloalkenyl,” as used herein, represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group, which may be bridged, fused or spirocyclic having from three to eight ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds.

[0283] The term “diastereomer,” as used herein, means stereoisomers that are not mirror images of one another and are non-superimposable on one another.

[0284] 40 The term “enantiomer,” as used herein, means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0285] PATENT

[0286] ATTORNEY DOCKET NO.: 51432-059WO2 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%.

[0287] The term “haloacetyl,” as used herein, refers to an acetyl group wherein at least one of the hydrogens has been replaced by a halogen.

[0288] 5 The term “haloalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same of different halogen moieties.

[0289] The term “halogen,” as used herein, represents a halogen selected from bromine, chlorine, iodine, or fluorine.

[0290] 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). The heteroatom may appear in the middle or at the end of the radical.

[0291] 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

[0292] 15 that aromatic ring. Exemplary unsubstituted heteroaryl 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” includes 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,

[0293] 20 quinolinyl, 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.

[0294] The term “heterocycloalkyl,” as used herein, represents a monovalent monocyclic, bicyclic, or

[0295] 25 polycyclic ring system, which may be bridged, fused or spirocyclic, wherein at least one ring is nonaromatic and wherein the non-aromatic ring contains one, two, three, or four 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,

[0296] 30 or 2 to 9) carbons. The term “heterocycloalkyl” also represents a heterocyclic compound having a bridged 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 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. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1 ,2,3,4-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.

[0297] 40 The term “hydroxy,” as used herein, represents a -OH group.

[0298] The term “hydroxyalkyl,” as used herein, represents an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0299] PATENT

[0300] ATTORNEY DOCKET NO.: 51432-059WO2

[0301] The term “isomer,” as used herein, means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or

[0302] 5 cis / trans isomers). According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, 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 mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of compounds of the invention 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 stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0303] 15 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 forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the

[0304] 20 scope of the present invention.

[0305] The term “sulfonyl,” as used herein, represents an -S(O)2- group.

[0306] The term “thiocarbonyl,” as used herein, refers to a -C(S)- group.

[0307] As used herein, the term “linker” refers to a divalent organic moiety connecting a first moiety (e.g., one portion of a macrocycle) to a second moiety (e.g., a second portion of the same macrocycle). In

[0308] 25 some embodiments, the linker results in a compound capable of achieving an IC50 of 2 pM or less in the Ras-RAF disruption assay protocol provided in the Examples below, and provided here:

[0309] The purpose of this biochemical assay is to measure the ability of test compounds to facilitate ternary complex formation between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFRBDconstruct, inhibiting Ras signaling through a RAF effector.

[0310] In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCI and 5 mM MgCl2, tagless cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variant), and GST-BRAFRBDare combined in a 384-well assay plate at final concentrations of 25 pM, 12.5 nM and 50 nM, respectively. Compound is present in plate wells as a 10-point 3-fold dilution series

[0311] 35 starting at a final concentration of 30 pM. After incubation at 25 °C for 3 hours, a mixture of Anti- His Eu-W1024 and anti-GST allophycocyanin is then added to assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction incubated for an additional 1 .5 hours. TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0312] PATENT

[0313] ATTORNEY DOCKET NO.: 51432-059WO2 that facilitate disruption of a Ras:RAF complex are identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells.

[0314] This assay may be used to assess selectivity as well. In some embodiments, a compound of the present invention is selective for one or more particular Ras mutants (e.g., K-Ras Q61 H) over other Ras mutants

[0315] 5 or wild-type compared to what is known in the art.

[0316] In some embodiments, the linker comprises 20 or fewer linear atoms. In some embodiments, the linker comprises 15 or fewer linear atoms. In some embodiments, the linker comprises 10 or fewer linear atoms. In some embodiments, the linker has a molecular weight of under 500 g / mol. In some embodiments, the linker has a molecular weight of under 400 g / mol. In some embodiments, the linker has a molecular weight of under 300 g / mol. In some embodiments, the linker has a molecular weight of under 200 g / mol. In some embodiments, the linker has a molecular weight of under 100 g / mol. In some embodiments, the linker has a molecular weight of under 50 g / mol.

[0317] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain compounds described herein may be provided or utilized in any of a variety of forms such as, for

[0318] 15 example, salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may relate to a specific form of that compound. In some embodiments, reference to a particular compound may relate to that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered to be a different form of the compound than a racemic

[0319] 20 mixture of the compound; a particular salt of a compound may be considered to be a different form from another salt form of the compound; a preparation containing one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form from one containing the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form.

[0320] 25

[0321] DETAILED DESCRIPTION

[0322] Provided herein are synthetic methods and intermediates for making inhibitors, for example, compounds of Formula A. The methods and intermediates can be useful for achieving a higher yield, a higher chemical purity, and / or a higher stereoisomeric purity, and a lower cost for the preparation . Further synthetic details are provided in the Examples.

[0323] The compounds described herein may be prepared using the methods described herein and / or using known organic, inorganic, or enzymatic processes. The synthetic methods may employ the use of commercially available starting materials or starting materials prepared by processes known to those skilled in the art of organic synthesis. These methods include but are not limited to those methods

[0324] 35 described in the Schemes below. The methods herein may be used to prepare, e.g., a compound of PCT / US2024 / 023208 or PCT / US2024 / 023272, each of which are incorporated by reference. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0325] PATENT

[0326] ATTORNEY DOCKET NO.: 51432-059WO2

[0327] Synthetic Methods

[0328] In an aspect, the disclosure provides a method of preparing a compound of Formula 1 :

[0329] Formula 1

[0330] 5 the method comprising condensing a compound of Formula 1 a and a compound of Formula 1 b to form the compound of Formula 1 :

[0331] Fo wherein n is 0 or 1 ;

[0332] R1is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, or optionally substituted C1-C4 heteroalkyl; and

[0333] R2is optionally substituted C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl.

[0334] In some embodiments, the compound of Formula 1 is Formula 1 c:

[0335] 15

[0336] Formula 1c wherein q is 0 or 1 .

[0337] In some embodiments, the condensing is carried out using a 1 :1 .1 stoichiometric ratio of Compound 1 a relative to the compound of Formula la. In some embodiments, the condensing is carried out in a polar protic solvent. In some embodiments, the polar protic solvent is an alcoholic solvent. In some embodiments, the alcoholic solvent is ethanol or methanol. In some embodiments, the condensing is carried out above room temperature (e.g., above 20 °C, above 30 °C, above 40 °C, above 50 °C, above 60 °C, or above 70 °C). In some embodiments, the condensing is carried out at a temperature of at least 40 °C (e.g., 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, or 65 °C). In some embodiments, the condensing is carried

[0338] 25 out at a temperature from 40 °C to 60 °C. In some embodiments, the condensing is carried out for at least 10 hours (e.g., 10 h, 1 1 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, or 24 h). In some embodiments, the condensing is carried out from 10 h to 12 h.

[0339] In some embodiments, the condensing is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0340] PATENT

[0341] ATTORNEY DOCKET NO.: 51432-059WO2

[0342] Fo

[0343] In some embodiments, the compound of Formula 1 is Compound 1 b, Compound 1c, Compound 1 d, Compound 1 e, Compound 1 f, or Compound 1 g:

[0344] Compound 1f Compound 1g

[0345] In some embodiments, the condensing is carried out according to the following scheme:

[0346] Com poun a

[0347] In some embodiments, the condensing is carried out according to the following scheme:

[0348] Com poun a

[0349] In some embodiments, the condensing is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0350] PATENT

[0351] ATTORNEY DOCKET NO.: 51432-059WO2

[0352] Compound 1a-2

[0353] In some embodiments, the condensing is carried out according to the following scheme:

[0354] Compound 1a-3

[0355] In some embodiments, the condensing is carried out according to the following scheme:

[0356] Compound 1a-2

[0357] In some embodiments, the condensing is carried out according to the following scheme:

[0358] Compound 1a-3

[0359] 10 In another aspect, the disclosure provides a method of preparing a compound of Formula 2:

[0360] Formula 2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0361] PATENT

[0362] ATTORNEY DOCKET NO.: 51432-059WO2 wherein n is 0 or 1 ;

[0363] R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and 5 R3is optionally substituted Ci-Ce alkyl; the method including: a) borylating a compound of Formula 10 to form a compound of Formula 2a:

[0364] Formula 10 Formula 2a b) hydrolyzing and borylating the compound of Formula 2a in one step to form a compound of

[0365] 10 Formula 2b: c) coupling a compound of Formula 2b with a compound of Formula 1 to form the compound of

[0366] Formula 2:

[0367] 15 In some embodiments, the method includes the preparation of Compound 2: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0368] PATENT

[0369] ATTORNEY DOCKET NO.: 51432-059WO2

[0370] Compound 2 the method including: a) borylating Compound 10 to form Compound 2a:

[0371] 5 b) hydrolyzing and borylating Compound 2a in one step to form Compound 2b:

[0372] In some embodiments, the borylating of (a) further includes contacting a compound of Formula 10 10 (e.g., Compound 10) with a borylating agent. In some embodiments, the borylating agent is pinacolborane

[0373] (HBpin). In some embodiments, the borylating of (a) is carried out at a temperature of at least 25 °C (e.g., 25 °C, 30 °C, or 35 °C). In some embodiments, the borylating of (a) is carried out at a temperature from 25 °C to 35 °C. In some embodiments, the borylating of (a) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0374] PATENT

[0375] ATTORNEY DOCKET NO.: 51432-059WO2

[0376] Formula 2a

[0377] In some embodiments, the borylating of (a) is carried out according to the following scheme:

[0378] HBpin n-heptane, THF

[0379] 25 to 35 °C 3 h

[0380] Compound 10

[0381] In some embodiments, the hydrolyzing and borylating of (b) further includes contacting a

[0382] 5 compound of Formula 2a (e.g., Compound 2a) with a borylating agent. In some embodiments, the borylating agent is bis(pinacolato)diboron (B2Pin2). In some embodiments, the hydrolyzing and borylating of (b) further includes contacting a compound of Formula 2a (e.g., Compound 2a) with 4,4'-di-tert-butyl- 2,2'-dipyridyl (dtbpy). In some embodiments, the hydrolyzing and borylating of (b) further includes contacting a compound of Formula 2a (e.g., Compound 2a) with an iridium catalyst. In some

[0383] 10 embodiments, the iridium catalyst is [lr(OMe)(COD)]2. In some embodiments, the hydrolyzing and borylating of (b) is carried out at a temperature of at least 30 °C (e.g., 30 °C, 35 °C, or 40 °C). In some embodiments, the hydrolyzing and borylating of (b) is carried out at a temperature from 30 °C to 35 °C. In some embodiments, the hydrolyzing and borylating of (b) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0384] PATENT

[0385] ATTORNEY DOCKET NO.: 51432-059WO2

[0386] Formula 2a

[0387] In some embodiments, the hydrolyzing and borylating of (b) is carried out according to the following scheme:

[0388] 5 In some embodiments, the coupling of (c) further includes contacting a compound of Formula 2b

[0389] (e.g., Compound 2b) and the compound of Formula 1 with a base. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base. In some embodiments, the carbonate base is selected from CS2CO3, Na2CO3, or K2CO3. In some embodiments, the coupling of (c) is carried out using a 1 :1 .5 stoichiometric ratio of a compound of Formula 2b (e.g., Compound 2b)

[0390] 10 relative to the compound of Formula I. In some embodiments, the coupling of (c) is carried out at a temperature of at least 95 °C (95 °C, 98 °C, 100 °C, 105 °C, or 1 10 °C). In some embodiments, the coupling of (c) is carried out at a temperature from 98 °C to 105 °C. In some embodiments, the coupling of (c) is carried out according to the following scheme:

[0391] 15 In some embodiments, the coupling of (c) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0392] PATENT

[0393] ATTORNEY DOCKET NO.: 51432-059WO2

[0394] In another aspect, the disclosure provides a method of preparing a sodium salt of Compound 3:

[0395] Compound 3 Na salt the method including: a) protecting Compound 3a to form Compound 3b:

[0396] Compound 3a Compound 3b

[0397] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0398] PATENT

[0399] ATTORNEY DOCKET NO.: 51432-059WO2 b) borylating Compound 3b to form Compound 3c: c) hydrolyzing Compound 3c to form Compound 3d:

[0400] 5 d) coupling Compound 3d with Compound 3e«2HCI to form Compound 3f: e) hydrolyzing Compound 3f to form the sodium salt of Compound 3:

[0401] In some embodiments, the protecting of (a) further includes protecting the phenol of Compound

[0402] 10 3a with a silicon-based protecting group. In some embodiments, the silicon-based protecting group is selected from triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), or trimethylsilyl (TMS). In some embodiments, the silicon-based protecting group is TIPS. In some embodiments, the protecting of (a) includes contacting Compound 3a with a reactive silicon-based protecting group. In some embodiments, the reactive silicon-based protecting group is triisopropylsilyl chloride (TIPSCI), tert-butyldiphenylsilyl chloride (TBDPSCI), tert-butyldimethylsilyl chloride (TBDMSCI), or trimethylsilyl chloride (TMSCI). In some embodiments, the reactive silicon-based protecting group is triisopropylsilyl chloride (TIPSCI). In some embodiments, the protecting of (a) is carried out using a 1 :1 .5 stoichiometric ratio of Compound 3a relative to TIPSCI. In some embodiments, the protecting of (a) includes contacting Compound 3a with an organic base. In some embodiments, the protecting of (a) is

[0403] 20 carried out using a 1 :2.5 stoichiometric ratio of Compound 3a relative to the organic base. In some PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0404] PATENT

[0405] ATTORNEY DOCKET NO.: 51432-059WO2 embodiments, the organic base is imidazole. In some embodiments, the protecting of (a) is carried out at a temperature of at least 20 °C (e.g., 20 °C, 25 °C, 30 °C, or 35 °C). In some embodiments, the protecting of (a) is carried out at room temperature (e.g., 25 °C). In some embodiments, the protecting of (a) is carried out according to the following scheme:

[0406] In some embodiments, the borylating of (b) further includes contacting Compound 3b with a borylating agent. In some embodiments, the borylating of (b) is carried out using a 1 :3 stoichiometric ratio of Compound 3a relative to the borylating agent. In some embodiments, the borylating agent is bis(pinacolato)diboron (B2Pin2). In some embodiments, the borylating of (b) further includes contacting Compound 3b with 4,4'-di-tert-butyl-2,2'-dipyridyl (dtbpy). In some embodiments, the borylating of (b) further includes contacting the Compound 3b with an iridium catalyst. In some embodiments, the iridium catalyst is [lr(OMe)(COD)]2. In some embodiments, the borylating of (b) is carried out using a catalytic amount of both dtbpy and iridium catalyst relative to Compound 3b. In some embodiments, the borylating of (b) is carried out at a temperature of at least 70 °C (e.g., 70 °C, 75 °C, 80 °C, 85 °C, or 90 °C). In some

[0407] 15 embodiments, the borylating of (b) is carried out at a temperature from 80 °C to 85 °C. In some embodiments, the borylating of (b) is carried out according to the following scheme:

[0408] In some embodiments, the hydrolyzing of (c) further includes contacting Compound 3c with a base. In some embodiments, the base is an alkali base. In some embodiments, the alkali base is selected from LiOH, NaOH, KOH, Mg(OH)2, or Ba(OH)2. In some embodiments, the hydrolyzing of (c) is carried out using a 3.5:1 stoichiometric ratio of alkali base relative to Compound 3c. In some embodiments, the hydrolyzing of (c) includes contacting Compound 3c with water. In some embodiments, the hydrolyzing of (c) is carried out in a polar protic solvent. In some embodiments, the polar protic solvent is an alcoholic solvent. In some embodiments, the alcoholic solvent is methanol. In some embodiments, the hydrolyzing

[0409] 25 of (c) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, 10 °C, or 15 °C). In some embodiments, the hydrolyzing of (c) is carried out at a temperature from 0 °C to 10 °C. In some embodiments, the hydrolyzing of (c) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0410] PATENT

[0411] ATTORNEY DOCKET NO.: 51432-059WO2

[0412] In some embodiments, the coupling of (d) further includes contacting Compound 3d with a carbodiimide coupling reagent, an anti-racemization agent, and a base. In some embodiments, the carbodiimide coupling reagent is EDCI, the anti-racemization agent is HOBt, and the base is N- methylmorpholine (NMM). In some embodiments, the coupling of (d) is carried out according to the

[0413] 5 following scheme:

[0414] In some embodiments, the hydrolyzing of (e) further includes contacting Compound 3f with a base. In some embodiments, the base is an alkali base. In some embodiments, the alkali base is selected from LiOH, NaOH, KOH, Mg(OH)2, or Ba(OH)2. In some embodiments, the hydrolyzing of (e) is carried out using a 2.5:1 stoichiometric ratio of base relative to Compound 3d. In some embodiments, the hydrolyzing of (e) includes contacting Compound 3f with water. In some embodiments, the hydrolyzing of (e) is carried out in a polar protic solvent. In some embodiments, the polar protic solvent is an alcoholic solvent. In some embodiments, the alcoholic solvent is methanol. In some embodiments, the hydrolyzing of (e) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, 10 °C, or 15 °C). In some

[0415] 15 embodiments, the hydrolyzing of (e) further includes a second step, wherein the sodium salt of Compound 3 is formed by contacting Compound 3 with a sodium source. In some embodiments, the sodium source is a sodium alkaline salt. In some embodiments, the sodium alkaline salt includes sodium bicarbonate and sodium carbonate.

[0416] In some embodiments, the hydrolyzing of (e) is carried out according to the following scheme: compound o S san

[0417] In another aspect, the disclosure provides a method of preparing a compound of Formula 4f as a racemic mixture of cis and trans isomers:

[0418] Formula 4f (mixture of cis / trans isomers, racemic) wherein

[0419] 25 m is 1 or 2; the method including: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0420] PATENT

[0421] ATTORNEY DOCKET NO.: 51432-059WO2 a) N-alkylating Compound 4a with a compound of Formula 4b to form a compound of Formula 4c:

[0422] Compound 4a Formula 4b Formula 4c b) acetylating the compound of Formula 4c by i) deprotonating the compound of Formula 4c using a base to form a deprotonated compound of Formula 4c; and ii) coupling the deprotonated compound of

[0423] 5 Formula 4c with Compound 4d to form a compound of Formula 4e:

[0424] Compound 4d c) cyclizing and protecting the compound of Formula 4e to form a racemic mixture of a compound of Formula 4f:

[0425] Formula 4e Formula 4f (cis only, racemic) .anc|

[0426] 10 d) isomerizing the compound of Formula 4f to form a mixture of cis and trans isomers of the compound of Formula 4f:

[0427] Formula 4f Formula 4f

[0428] (cis only, racemic) (mixture of cis / trans isomers, racemic)

[0429] In some embodiments, the method includes the preparation of Compound 4f as a racemic mixture of cis and trans isomers:

[0430] Compound 4f

[0431] 15 (mixture of cis / trans isomers, racemic) the method including: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0432] PATENT

[0433] ATTORNEY DOCKET NO.: 51432-059WO2 a) N-alkylating Compound 4a with Compound 4b to form Compound 4c:

[0434] Compound 4a Compound 4b Compound 4c b) acetylating Compound 4c by i) deprotonating Compound 4c using a base to form a

[0435] 5 deprotonated Compound 4c; and ii) coupling deprotonated Compound 4c with Compound 4d to form Compound 4e:

[0436] Compound 4c

[0437] Compound 4e

[0438] Compound 4d c) cyclizing and protecting Compound 4e to form a racemic mixture of Compound 4f:

[0439] Compound 4e Compound 4f

[0440] 10 (cis only, racemic) .anc| d) isomerizing Compound 4f to form a mixture of cis and trans isomers of Compound 4f:

[0441] Compound 4f Compound 4f (cis only, racemic) (mixture of cis / trans isomers, racemic)

[0442] In some embodiments, the N-alkylating of (a) is carried out using a 1 .15:1 stoichiometric ratio of a compound of Formula 4b (e.g., Compound 4b) relative to Compound 4a. In some embodiments, the N- alkylating of (a) further includes contacting the compound of Formula 4b and Compound 4a with a base. In some embodiments, the base is an organic base. In some embodiments, the organic base is a non- nucleophilic base. In some embodiments, the non-nucleophilic base is N,N-diisopropylethylamine (DIEA), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1 ,5-diazabicyclo(4.3.0)non-5-ene (DBN). In some embodiments, the N-alkylating of (a) is carried out using a 2:1 stoichiometric ratio of base relative to

[0443] 20 Compound 4a. In some embodiments, the N-alkylating of (a) is carried out at a temperature of at least 70 °C (e.g., 70 °C, 75 °C, 80 °C, 85 °C, or 90 °C). In some embodiments, the N-alkylating of (a) is carried out at a temperature from 75 °C to 85 °C. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0444] PATENT

[0445] ATTORNEY DOCKET NO.: 51432-059WO2

[0446] In some embodiments, the N-alkylating of (a) is carried out according to the following scheme:

[0447] 1.0 equiv 1.15 equiv

[0448] Compound 4a 75-85 C

[0449] Formula 4b Formula 4c 20 h

[0450] In some embodiments, the N-alkylating of (a) is carried out according to the following scheme:

[0451] 1.0 equiv 1.15 equiv

[0452] Compound 4a 75-85 °C

[0453] Compound 4b Compound 4c

[0454] 20 h

[0455] 5 In some embodiments, the acetylating of (b) is carried out using a 1 .2:1 stoichiometric ratio of the base relative to the compound of Formula 4c (e.g., Compound 4c). In some embodiments, the acetylating of (b) further includes contacting the compound of Formula 4c (e.g., Compound 4c) with a non- nucleophilic base. In some embodiments, the base is a lithium base. In some embodiments, the lithium base is lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), or lithium

[0456] 10 tetramethylpiperidide (LiTMP). In some embodiments, the lithium base is lithium diisopropylamide (LDA). In some embodiments, the acetylating of (b) is carried out using a 1 .1 :1 stoichiometric ratio of the compound of Formula 4d (e.g., Compound 4d) relative to the compound of Formula 4c (e.g., Compound 4c). In some embodiments, the acetylating of (b) is carried out at a temperature at or below -50 °C (e.g., - 50 °C, -55 °C, -60 °C, -65 °C, or -70 °C). In some embodiments, the acetylating of (b) is carried out at a temperature from -55 °C to -65 °C. In some embodiments, the acetylating of (b) is carried out according to the following scheme:

[0457] Compound 4d

[0458] In some embodiments, the acetylating of (b) is carried out according to the following scheme: ompoun e

[0459] -55 to -65 °C, 2 h

[0460] Compound 4d

[0461] 20 In some embodiments, Compound 4d is prepared by:

[0462] (i) oxidizing 2-(benzyloxy)acetic acid with oxalyl chloride; and

[0463] (ii) coupling the oxidized compound with N,O-dimethylhydroxylamine hydrochloride. In some embodiments, the oxidizing of (i) is carried out using a 1 .05:1 stoichiometric ratio of oxalyl chloride relative PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0464] PATENT

[0465] ATTORNEY DOCKET NO.: 51432-059WO2 to 2-(benzyloxy)acetic acid. In some embodiments, the oxidizing of (i) is carried out at a temperature of at least 5 °C (e.g., 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C). In some embodiments, the oxidizing of (i) is carried out at a temperature from 10 °C to 20 °C. In some embodiments, the coupling of (ii) is carried out using a 1 .4:1 stoichiometric ratio of oxalyl chloride relative to 2-(benzyloxy)acetic acid. In some embodiments, the

[0466] 5 coupling of (ii) further includes a base. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is K2CO3 or Na2COs. In some embodiments, the coupling of (ii) is carried out using a 2:1 stoichiometric ratio of base relative to 2-(benzyloxy)acetic acid. In some embodiments, the coupling of (ii) is carried out at a temperature of at least 15 °C (e.g., 15 °C, 20 °C, or 25 °C, 30 °C, or 35 °C). In some embodiments, the coupling of (ii) is carried out at a temperature from 20 °C to 30 °C. In some embodiments, the preparation of Compound 4d is carried out according to the following scheme: i) (COCI)2

[0467] DCM, DMF, 10-20 °C, 2 h O ii) MeNH(OMe)HCI BnO. ,CL N

[0468] 2-(benzyloxy)acetic acidK2C°3. MTBE, 20 30 C, 6 h I

[0469] Compound 4d

[0470] In some embodiments, the cyclizing and protecting of (c) further includes contacting the compound of Formula 4e (e.g., Compound 4e) with a palladium catalyst. In some embodiments, the

[0471] 15 palladium catalyst is palladium on carbon (Pd / C). In some embodiments, the cyclizing and protecting of (c) further includes contacting the compound of Formula 4e (e.g., Compound 4e) with hydrogen gas. In some embodiments, the cyclizing and protecting of (c) further includes contacting the compound of Formula 4e (e.g., Compound 4e) with Boc anhydride. In some embodiments, the cyclizing and protecting of (c) is carried out using a 1 .3:1 stoichiometric ratio of Boc anhydride relative to the compound of Formula 4e (e.g., Compound 4e). In some embodiments, the cyclizing and protecting of (c) is carried out at a temperature of at least 20 °C (e.g., 20 °C, or 25 °C, or 30 °C). In some embodiments, the cyclizing and protecting of (c) is carried out at room temperature (e.g., 25 °C). In some embodiments, the cyclizing and protecting of (c) exclusively produces the cis isomer of the compound of Formula 4f (e.g., Compound 4f).

[0472] 25 In some embodiments, the cyclizing and protecting of (c) is carried out according to the following scheme:

[0473] Pd / C (0.1 w / w) EtO^O H2(15 atm) BOC2O

[0474] BnO / ""

[0475] EtOH BocN-H)mr.t. 7 h Formula 4f (cis only, racemic)

[0476] In some embodiments, the cyclizing and protecting of (c) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0477] PATENT

[0478] ATTORNEY DOCKET NO.: 51432-059WO2

[0479] Pd / C (0.1 w / w)

[0480] Compound 4e 7 h Compound 4f (cis only, racemic)

[0481] In some embodiments, the isomerizing of (d) further includes contacting the compound of Formula 4f (e.g., Compound 4f) with a base. In some embodiments, the base is a non-nucleophilic base. In some embodiments, the non-nucleophilic base is 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1 ,5-

[0482] 5 diazabicyclo(4.3.0)non-5-ene (DBN). In some embodiments, the isomerizing of (d) is carried out using a 1 :1 stoichiometric ratio of base relative to the compound of Formula 4f (e.g., Compound 4f). In some embodiments, the isomerizing of (d) is carried out at a temperature of at least 70 °C (e.g., 70 °C, 75 °C, 80 °C, or 85 °C). In some embodiments, the isomerizing of (d) produces a mixture of at least about 80% trans isomer (e.g., 80% trans, 85% trans, 90% trans, 95%, or 99% trans).

[0483] 10 In some embodiments, the isomerizing of (d) is carried out according to the following scheme:

[0484] Formula 4f 20 h Formula 4f (cis only, racemic) (mixture of cis / trans isomers, racemic)

[0485] In some embodiments, the isomerizing of (d) is carried out according to the following scheme:

[0486] Compound 4f 20 h Compound 4f (cis only, racemic) (mixture of cis / trans isomers, racemic)

[0487] In another aspect, the disclosure provides a method of preparing a compound of Formula 4u:

[0488] 15 Formula 4u wherein m is 1 or 2; and

[0489] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0490] PATENT

[0491] ATTORNEY DOCKET NO.: 51432-059WO2 alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0492] R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; and

[0493] 5 R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; the method including: a) hydrolyzing a mixture of cis and trans isomers of a compound of Formula 4f to form a

[0494] 10 compound of Formula 4g that is enantiomerically pure:

[0495] Formula 4f Formula 4g

[0496] (mixture of cis / trans isomers, racemic) b) coupling the compound of Formula 4g with a compound of Formula 4h to form a compound of

[0497] Formula 4i:

[0498] Formula 4i

[0499] 15 c) deprotecting the compound of Formula 4i to form a compound of Formula 4j:

[0500] Formula 4i Formula 4j .anc| d) coupling the compound of Formula 4j with a compound of Formula 4k to form the compound of

[0501] Formula 4u: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0502] PATENT

[0503] ATTORNEY DOCKET NO.: 51432-059WO2

[0504] In some embodiments, the hydrolyzing of (a) further includes contacting the compound of Formula 4f (e.g., Compound 4f) with a serine endoprotease. In some embodiments, the hydrolyzing of (a) is carried out using a catalytic amount of the serine endoprotease. In some embodiments, the serine

[0505] 5 endoprotease is a Savinase® enzyme. In some embodiments, the Savinase® enzyme is Savinase® 12T. In some embodiments, the hydrolyzing of (a) is carried out in an aqueous buffer. In some embodiments, the aqueous buffer includes a water-miscible organic solvent. In some embodiments, the organic solvent is DMSO. In some embodiments, the aqueous buffer is a phosphate buffer. In some embodiments, the phosphate buffer is phosphate-buffered saline (PBS). In some embodiments, the hydrolyzing of (a) is

[0506] 10 carried out at a temperature of at least 30 °C (e.g., 30 °C, 35 °C, or 40 °C). In some embodiments, the hydrolyzing of (a) is carried out at a temperature from 30 °C to 35 °C. In some embodiments, the hydrolyzing of (a) is carried out according to the following scheme:

[0507] Savinase 12T

[0508] Formula 4f Formula 4g (mixture of cis / trans isomers, racemic)

[0509] In some embodiments, the hydrolyzing of (a) is carried out according to the following scheme:

[0510] Savinase 12T

[0511] Compound 4f Compound 4g

[0512] (mixture of cis / trans isomers, racemic)

[0513] In some embodiments, the coupling of (b) further includes contacting the compound of Formula 4g (e.g., Compound 4g) and the compound of Formula 4h (e.g., Compound 4h HCI) with a base. In some embodiments, the base is an organic base. In some embodiments, the organic base is triethylamine (TEA). In some embodiments, the coupling of (b) further includes contacting the compound of Formula 4g

[0514] 20 (e.g., Compound 4g) with an organophosphorus ester. In some embodiments, the organophosphorus ester is tributyl phosphate (TBP). In some embodiments, the coupling of (b) is carried out using a 1 .1 :1 stoichiometric ratio of the compound of Formula 4h (e.g., Compound 4h HCI) relative to the compound of PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0515] PATENT

[0516] ATTORNEY DOCKET NO.: 51432-059WO2

[0517] Formula 4g (e.g., Compound 4g). In some embodiments, the coupling of (b) is carried out using a 4:1 stoichiometric ratio of base relative to the compound of Formula 4g (e.g., Compound 4g). In some embodiments, the coupling of (b) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, or 10 °C) for 2 hours, then carried out a temperature of at least 20 °C (e.g., 20 °C, 25 °C, or 30 °C) for 3 hours.

[0518] 5 In some embodiments, the coupling of (b) is carried out at a temperature from 0 °C to 10 °C for 2 hours, then carried out a temperature from 20 °C to 30 °C for 3 hours. In some embodiments, the coupling of (b) is carried out according to the following scheme: ( . equ v)

[0519] Formula 4i

[0520] In some embodiments, the coupling of (b) is carried out according to the following scheme: (1.1 equiv)

[0521] 10 Compound 4i

[0522] In some embodiments, the deprotecting of (c) further includes contacting the compound of Formula 4i (e.g., Compound 4i) with an acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the inorganic acid is HCI. In some embodiments, the acid is an organic acid. In some embodiments, the organic acid is trifluoroacetic acid. In some embodiments, the deprotecting of (c) is

[0523] 15 carried out using a 6:1 stoichiometric ratio of the acid relative to the compound of Formula 4i (e.g., Compound 4i). In some embodiments, the deprotecting of (c) is carried out at a temperature of at least 20 °C (e.g., 20 °C, 25 °C, 30 °C, or 35 °C). In some embodiments, the deprotecting of (c) is carried out according to the following scheme:

[0524] Formula 4i Formula 4j PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0525] PATENT

[0526] ATTORNEY DOCKET NO.: 51432-059WO2

[0527] In some embodiments, the deprotecting of (c) is carried out according to the following scheme:

[0528] Compound 4i Compound 4j HCI

[0529] In some embodiments, the coupling of (d) further includes contacting the compound of Formula 4j (e.g., Compound 4j HCI) and the compound of Formula 4k (e.g., Compound 4k) with a base. In some

[0530] 5 embodiments, the base is an organic base. In some embodiments, the organic base is triethylamine (TEA). In some embodiments, the coupling of (d) further includes contacting the compound of Formula 4j (e.g., Compound 4j HCI) and the compound of Formula 4k (e.g., Compound 4k) with an organophosphorus ester. In some embodiments, the organophosphorus ester is tributyl phosphate (TBP). In some embodiments, the coupling of (d) is carried out using a 4:1 stoichiometric ratio of the base

[0531] 10 relative to the compound of Formula 4j (e.g., Compound 4j HCI). In some embodiments, the coupling of (d) is carried out using a 1 .3:1 stoichiometric ratio of the compound of Formula 4k (e.g., Compound 4k) relative to the compound of Formula 4j (e.g., Compound 4j HCI). In some embodiments, the coupling of (d) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, or 10 °C) for 2 hours, then carried out a temperature of at least 20 °C (e.g., 20 °C, 25 °C, or 30 °C) for 3 hours. In some embodiments, the

[0532] 15 coupling of (d) is carried out at a temperature from 0 °C to 10 °C for 2 hours, then carried out a temperature from 20 °C to 30 °C for 3 hours.

[0533] In some embodiments, the coupling of (d) is carried out according to the following scheme:

[0534] Formula 4k

[0535] Formula 4j Formula 4u PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0536] PATENT

[0537] ATTORNEY DOCKET NO.: 51432-059WO2

[0538] In another aspect, the disclosure provides a method of preparing a compound of Formula 4-I: Formula 4-1 wherein m is 1 or 2; and

[0539] 5 R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0540] R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;

[0541] 10 R6is optionally substituted Ci-Ce alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0542] X1is halogen; the method including: a) deprotecting a compound of Formula 4I to form a compound of Formula 4m:

[0543] 15 Formula 41 Formula 4m b) halogenating the compound of Formula 4m to form a compound of Formula 4n:

[0544] Formula 4m Formula 4n .andc) deprotecting the compound of Formula 4n to form the compound of Formula 4-1: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0545] PATENT

[0546] ATTORNEY DOCKET NO.: 51432-059WO2

[0547] Formula 4n Formula 4-I

[0548] In another aspect, the disclosure provides a method of preparing a compound of Formula 4q:

[0549] Formula 4q wherein

[0550] 5 m is 1 or 2; and

[0551] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0552] R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally

[0553] 10 substituted C3-C7 heterocycloalkyl; the method including: a) hydrolyzing a mixture of cis and trans isomers of a compound of Formula 4f to form a compound of Formula 4o:

[0554] Formula 4f Formula 4o (mixture of cis / trans isomers, racemic)

[0555] 15 b) deprotecting the compound of Formula 4o to form a compound of Formula 5:

[0556] Formula 4o Formula 5 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0557] PATENT

[0558] ATTORNEY DOCKET NO.: 51432-059WO2 c) isomerizing the compound of Formula 5 to form a compound of Formula 4p that is enantiomerically pure: m

[0559] Formula 5 Formula 4p .and

[0560] 5 d) coupling the compound of Formula 4p with a compound of Formula 4h to form the compound of Formula 4q:

[0561] In some embodiments, the method includes the preparation of Compound 4q:

[0562] Compound 4q

[0563] 10 the method including: a) hydrolyzing a mixture of cis and trans isomers of Compound 4f to form Compound 4o:

[0564] Compound 4f Compound 4o (mixture of cis / trans isomers, racemic) b) deprotecting Compound 4o to form Compound 5:

[0565] Compound 4o Compound 5 .

[0566] 15 c) isomerizing Compound 5 to form enantiomerically pure Compound 4p: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0567] PATENT

[0568] ATTORNEY DOCKET NO.: 51432-059WO2

[0569] Compound 5 Compound 4p .andd) coupling Compound 4p with Compound 4h HCI to form Compound 4q:

[0570] Compound 4p

[0571] Compound 4q

[0572] In some embodiments, the hydrolyzing of (a) further includes contacting the compound of

[0573] 5 Formula 4f (e.g., Compound 4f) with a base. In some embodiments, the base is an alkali base. In some embodiments, the alkali base is selected from LiOH, NaOH, KOH, Mg(OH)2, or Ba(OH)2. In some embodiments, the alkali base is LiOH. In some embodiments, the hydrolyzing of (a) is carried out using a 3:1 stoichiometric ratio of base relative to the compound of Formula 4f (e.g., Compound 4f). In some embodiments, the hydrolyzing of (a) includes contacting the compound of Formula 4f (e.g., Compound 4f)

[0574] 10 with water. In some embodiments, the hydrolyzing of (a) is carried out in a polar protic solvent. In some embodiments, the polar protic solvent is an alcoholic solvent. In some embodiments, the alcoholic solvent is methanol. In some embodiments, the hydrolyzing of (a) is carried out at a temperature of at least 10 °C (e.g., 10 °C, 15 °C, 20 °C, or 25 °C). In some embodiments, the hydrolyzing of (a) is carried out at a temperature from 15 °C to 20 °C. In some embodiments, the hydrolyzing of (a) is carried out according to the following scheme:

[0575] Formula 4f Formula 4o

[0576] In some embodiments, the hydrolyzing of (a) is carried out according to the following scheme:

[0577] Compound 4f Compound 4o

[0578] In some embodiments, the deprotecting of (b) further includes contacting the compound of

[0579] 20 Formula 4o (e.g., Compound 4o) with a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C). In some embodiments, the deprotecting of (b) further includes contacting the compound of Formula 4o (e.g., Compound 4o) with hydrogen gas. In some embodiments, the PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0580] PATENT

[0581] ATTORNEY DOCKET NO.: 51432-059WO2 deprotecting of (b) includes an alcoholic solvent. In some embodiments, the alcoholic solvent is methanol.

[0582] In some embodiments, the deprotecting of (b) is carried out at room temperature (e.g., 25 °C).

[0583] In some embodiments, the deprotecting of (b) is carried out according to the following scheme:

[0584] Formula 4o Formula 5

[0585] 5 In some embodiments, the deprotecting of (b) is carried out according to the following scheme:

[0586] Compound 4o Compound 5

[0587] In some embodiments, the isomerizing of (c) further includes contacting the compound of

[0588] Formula 5 (e.g., Compound 5) with a base. In some embodiments, the base is a non-nucleophilic base. In some embodiments, the non-nucleophilic base is quinidine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or

[0589] 10 1 ,5-diazabicyclo(4.3.0)non-5-ene (DBN). In some embodiments, the non-nucleophilic base is quinidine. In some embodiments, the isomerizing of (c) is carried out using a 1 :1 stoichiometric ratio of base relative to the compound of Formula 5 (e.g., Compound 5). In some embodiments, the isomerizing of (c) produces a mixture of at least about 80% trans isomer (e.g., 80% trans, 85% trans, 90% trans, 95%, or 99% trans). In some embodiments, the isomerizing of (c) is carried out at a temperature of at least 20 °C (e.g., 20 °C, 25 °C, or 30 °C). In some embodiments, the isomerizing of (c) is carried out at a temperature from 20 °C to 30 °C. In some embodiments, the isomerizing of (c) is carried out according to the following scheme:

[0590] Formula 5 Formula 4p

[0591] In some embodiments, the isomerizing of (c) is carried out according to the following scheme:

[0592] Compound 5 Compound 4p

[0593] 20 In some embodiments, the coupling of (d) further includes contacting the compound of Formula 4p (e.g., Compound 4p) with an uronium coupling reagent. In some embodiments, the uronium coupling reagent is COMU, HATU, HBTU, HCTU, TATU, TOTU, or TBTU. In some embodiments, the coupling agent is HATU. In some embodiments, the coupling of (d) further includes contacting the compound of Formula 4p (e.g., Compound 4p) and the compound of Formula 4h (e.g., Compound 4h HCI) with a base. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0594] PATENT

[0595] ATTORNEY DOCKET NO.: 51432-059WO2

[0596] In some embodiments, the base is an organic base. In some embodiments, the organic base is lutidine or triethylamine (TEA). In some embodiments, the coupling of (d) is carried out using a 1 .8:1 stoichiometric ratio of the compound of Formula 4h (e.g., Compound 4h HCI) relative to the compound of Formula 4p (e.g., Compound 4p). In some embodiments, the coupling of (d) is carried out using a 1 .5:1 stoichiometric

[0597] 5 ratio of uronium coupling reagent relative to the compound of Formula 4p (e.g., Compound 4p). In some embodiments, the coupling of (d) is carried out using a 10:1 stoichiometric ratio of base relative to the compound of Formula 4p (e.g., Compound 4p). In some embodiments, the coupling of (d) is carried out at a temperature of at least -15 °C (e.g., -15°C, -10°C, -5 °C, or 0 °C). In some embodiments, the coupling of (d) is carried out at a temperature from -15 °C to -5 °C. In some embodiments, the coupling of (d) is

[0598] 10 carried out according to the following scheme:

[0599] 1.8 eq.

[0600] O R4 / DCM / -15-5 C /

[0601] Bocm

[0602] Formula 4p Formula 4q

[0603] In some embodiments, the coupling of (d) is carried out according to the following scheme:

[0604] 1.8 eq.

[0605] C ompoun p

[0606] Compound 4q

[0607] In another aspect, the disclosure provides a method of preparing a compound of Formula 4-I I :

[0608] 15 Formula 4-II wherein PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0609] PATENT ATTORNEY DOCKET NO.: 51432-059WO2 m is 1 or 2; and

[0610] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0611] 5 R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;

[0612] R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and the method including: a) O-sulfonating a compound of Formula 4q to form a compound of Formula 4r:

[0613] Formula 4q Formula 4r

[0614] 15 b) deprotecting the compound of Formula 4r to form a compound of Formula 4s:

[0615] Formula 4r Formula 4s

[0616] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0617] PATENT

[0618] ATTORNEY DOCKET NO.: 51432-059WO2 c) coupling the compound of Formula 4s with a compound of Formula 4k to form a compound of

[0619] Formula 4t:

[0620] Formula 4s Formula 4t .and

[0621] 5 d) hydrolyzing the compound of Formula 4t to form the compound of Formula 4-I I :

[0622] Formula 4t Formula 4-11

[0623] In some embodiments, the method includes the preparation of Compound 4-II:

[0624] Compound 4-II the method including:

[0625] 10 a) O-sulfonating Compound 4q to form Compound 4r:

[0626] Compound 4q Compound 4r . b) deprotecting Compound 4r to form Compound 4s: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0627] PATENT

[0628] ATTORNEY DOCKET NO.: 51432-059WO2

[0629] Compound 4r Compound 4s . c) coupling Compound 4s with Compound 4k to form Compound 4t: d) hydrolyzing Compound 4t to form Compound 4-II:

[0630] 5 Compound 4t Compound 4-11

[0631] In some embodiments, the O-sulfonating of (a) further includes contacting the compound of Formula 4f (e.g., Compound 4f) with an O-sulfonating reagent, a base, and a pyridinyl catalyst. In some embodiments, the O-sulfonating reagent is methanesulfonyl chloride, phenyl triflimide, N,N- bis(trifluoromethanesulfonyl)aniline, 4-nitrophenyl trifluoromethanesulfonate, trifluoromethanesulfonyl

[0632] 10 chloride, or 4-toluenesulfonyl chloride (TsCI). In some embodiments, the O-sulfonating reagent is 4- toluenesulfonyl chloride (TsCI). In some embodiments, the base is an organic base. In some embodiments, the organic base is triethylamine (TEA). In some embodiments, the pyridinyl catalyst is 4- dimethylaminopyridine (DMAP). In some embodiments, the O-sulfonating of (a) is carried out using a 1 .2:1 stoichiometric ratio of O-sulfonating reagent relative to the compound of Formula 4q (e.g.,

[0633] 15 Compound 4q). In some embodiments, the O-sulfonating of (a) is carried out using a 3:1 stoichiometric ratio of base relative to the compound of Formula 4q (e.g., Compound 4q). In some embodiments, the hydrolyzing of (a) is carried out at a temperature of at least 20 °C (e.g., 20 °C, 25 °C, or 30 °C). In some embodiments, the hydrolyzing of (a) is carried out at a temperature from 20 °C to 30 °C. In some embodiments, the O-sulfonating of (a) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0634] PATENT

[0635] ATTORNEY DOCKET NO.: 51432-059WO2

[0636] Formula 4q Formula 4r

[0637] In some embodiments, the O-sulfonating of (a) is carried out according to the following scheme:

[0638] Compound 4q Compound 4r

[0639] In some embodiments, the deprotecting of (b) further includes contacting the compound of

[0640] 5 Formula 4r (e.g., Compound 4r) with an acid. In some embodiments, the acid is an organic acid. In some embodiments, the organic acid is trifluoroacetic acid. In some embodiments, the acid is an inorganic acid. In some embodiments, the inorganic acid is HCI. In some embodiments, the deprotecting of (b) is carried out using a 6:1 stoichiometric ratio of the acid relative to the compound of Formula 4i (e.g., Compound 4i). In some embodiments, the deprotecting of (b) is carried out in water. In some embodiments, the

[0641] 10 deprotecting of (b) is carried out in an organic solvent. In some embodiments, the organic solvent is selected from the group consisting of dichloromethane (DCM), dimethylformamide (DMF), ethyl acetate, ether, tetrahydrofuran (THF), acetonitrile, N-methyl-2-pyrrolidinone (NMP), and DMSO. In some embodiments, the organic solvent is DCM. In some embodiments, the deprotecting of (b) is carried out at a temperature of at least 20 °C (e.g., 20 °C, 25 °C, 30 °C, or 35 °C). In some embodiments, the

[0642] 15 deprotecting of (b) is carried out at a temperature from 20 °C to 30 °C. In some embodiments, the deprotecting of (b) is carried out according to the following scheme:

[0643] Formula 4r Formula 4s PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0644] PATENT

[0645] ATTORNEY DOCKET NO.: 51432-059WO2

[0646] In some embodiments, the deprotecting of (b) is carried out according to the following scheme:

[0647] Compound 4r Compound 4s

[0648] In some embodiments, the coupling of (c) further includes contacting the compound of Formula 4s (e.g., Compound 4s) and the compound of Formula 4k (e.g., Compound 4k) with a base. In some

[0649] 5 embodiments, the base is an organic base. In some embodiments, the organic base is triethylamine (TEA). In some embodiments, the coupling of (c) further includes contacting the compound of Formula 4s (e.g., Compound 4s) and the compound of Formula 4k (e.g., Compound 4k) with an organophosphorus ester. In some embodiments, the organophosphorus ester is tributyl phosphate (TBP). In some embodiments, the coupling of (c) is carried out using a 4:1 stoichiometric ratio of the base relative to the

[0650] 10 compound of Formula 4s (e.g., Compound 4s). In some embodiments, the coupling of (c) is carried out using a 1 .3:1 stoichiometric ratio of the compound of Formula 4k (e.g., Compound 4k) relative to the compound of Formula 4s (e.g., Compound 4s). In some embodiments, the coupling of (c) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, or 10 °C) for 2 hours, then carried out a temperature of at least 20 °C (e.g., 20 °C, 25 °C, or 30 °C) for 3 hours. In some embodiments, the coupling of (c) is carried

[0651] 15 out at a temperature from 0 °C to 10 °C for 2 hours, then carried out a temperature from 20 °C to 30 °C for 3 hours. In some embodiments, the coupling of (c) is carried out according to the following scheme:

[0652] Formula 4k

[0653] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0654] PATENT

[0655] ATTORNEY DOCKET NO.: 51432-059WO2

[0656] In some embodiments, the coupling of (c) is carried out according to the following scheme:

[0657] Compound 4k

[0658] Compound 4s Compound 4t

[0659] In some embodiments, the hydrolyzing of (d) further includes contacting the compound of Formula 4t (e.g., Compound 4t) with a base. In some embodiments, the base is an alkali base. In some embodiments, the alkali base is selected from LiOH, NaOH, KOH, Mg(OH)2, or Ba(OH)2. In some embodiments, the alkali base is NaOH. In some embodiments, the hydrolyzing of (d) is carried out using a 3:1 stoichiometric ratio of alkali base relative to the compound of Formula 4t (e.g., Compound 4t). In some embodiments, the hydrolyzing of (d) includes contacting the compound of Formula 4t (e.g., Compound 4t) with water. In some embodiments, the hydrolyzing of (d) is carried out in a polar protic

[0660] 10 solvent. In some embodiments, the polar protic solvent is an alcoholic solvent. In some embodiments, the alcoholic solvent is methanol. In some embodiments, the hydrolyzing of (d) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, 25 °C, or 30 °C). In some embodiments, the hydrolyzing of (d) is carried out at a temperature from 0 °C to 25 °C. In some embodiments, the hydrolyzing of (d) is carried out according to the following scheme:

[0661] Formula 4t Formula 4-11

[0662] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0663] PATENT

[0664] ATTORNEY DOCKET NO.: 51432-059WO2

[0665] In some embodiments, the hydrolyzing of (d) is carried out according to the following scheme:

[0666] Compound 4t Compound 4-11

[0667] In another aspect, the disclosure provides a method of preparing a compound of Formula 5: HO Boe

[0668] Compound 5

[0669] 5 wherein m is 1 or 0; the method comprising: a) protecting Compound 5a to form Compound 5b:

[0670] Compound 5a Compound 5b . b) alkylating Compound mpound of Formula 5c: wherein X2and X3are halogen; c) deprotecting a compound of Formula 5c to form a compound of Formula 5d:

[0671] °bn 4) - in

[0672] Ts H )

[0673] Formula 5c Formula 5d d) protecting the compound of Formula 5d to form a compound of Formula 5e:

[0674] HBoc

[0675] Compound 5d Compound 5e . e) trans-esterifying the compound of Formula 5e to form a compound of Formula 5f: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0676] PATENT

[0677] ATTORNEY DOCKET NO.: 51432-059WO2 Q ) - mEto^ " )

[0678] I i rn Boc HO Boc

[0679] Formula 5e Formula 5f f) isomerizing the compound of Formula 5f to form a trans isomer of a compound of Formula 5g:

[0680] HO Boc HO Boc

[0681] Formula 5f Formula 5g .an(-| g) hydrolyzing the compound of Formula 5g to form the compound of Formula 5:

[0682] HO Boc HO Boc

[0683] 5 Formula 5g Formula 5

[0684] In some embodiments, X2and X3are independently selected from bromine, chlorine, or iodine. In some embodiments, X2and X3are iodine.

[0685] In another aspect, the disclosure provides a method of preparing Compound 6d:

[0686] OBn

[0687] OH

[0688] 0 Boc

[0689] Compound 6d the method including: a) protecting Compound 6a to form Compound 6b:

[0690] Compound 6a Compound 6b b) alkylating Compound 6b with an allyl halide to form Compound 6c:

[0691] Compound 6b Compound 6c

[0692] 15 wherein X4is a halogen; and PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0693] PATENT

[0694] ATTORNEY DOCKET NO.: 51432-059WO2 c) cyclizing Compound 6c to form Compound 6d:

[0695] Compound 6c Compound 6d

[0696] In some embodiments, the protecting of (a) further includes contacting Compound 6a with a methoxylation reagent and a base. In some embodiments, the methoxylation reagent is methyl

[0697] 5 trifluoromethanesulfonate (TfOMe). In some embodiments, the base is an organic base. In some embodiments, the organic base is N,N-diisopropylethylamine (DIEA). In some embodiments, the protecting of (a) is carried out using a 1 .2:1 stoichiometric ratio of methoxylation reagent relative to Compound 6a. In some embodiments, the protecting of (a) is carried out using a 1 .2:1 stoichiometric ratio of base relative to Compound 6a. In some embodiments, the protecting of (a) is carried out at a temperature of at least 0 °C (e.g., 0 °C, 5 °C, 10 °C, 15 °C, 20 °C, or 25 °C). In some embodiments, the protecting of (a) is carried out at a temperature from 0 °C to 20 °C.

[0698] In some embodiments, the protecting of (a) is carried out according to the following scheme:

[0699] Compound 6a Compound 6b

[0700] In some embodiments, the alkylating of (b) further includes contacting Compound 6b with a base

[0701] 15 and a phosphoramide. In some embodiments, the base is a metal silylamide. In some embodiments, the metal silylamide is potassium bis(trimethylsilyl)amide (KHMDS) or sodium bis(trimethylsilyl)amide (NaHMDS). In some embodiments, the metal silylamide is potassium bis(trimethylsilyl)amide (KHMDS). In some embodiments, the phosphoramide is hexamethylphosphoramide (HMPA). In some embodiments, the allyl halide is selected from allyl bromide, allyl chloride, or allyl iodide. In some embodiments, the allyl halide is allyl bromide. In some embodiments, the alkylating of (b) is carried out at a temperature at or below -70 °C (e.g., -70 °C, -75 °C, -78 °C, -80 °C, or -85 °C). In some embodiments, the alkylating of (b) is carried out at a temperature from -70 °C to -80 °C.

[0702] In some embodiments, the alkylating of (b) is carried out according to the following scheme:

[0703] Compound 6b Compound 6c

[0704] 25 In some embodiments, X4is bromine, chlorine, or iodine. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0705] PATENT

[0706] ATTORNEY DOCKET NO.: 51432-059WO2

[0707] In some embodiments, the cyclizing of (c) further includes contacting Compound 6c with an oxidizing reagent. In some embodiments, the oxidizing reagent is a periodate salt. In some embodiments, the periodate salt is sodium periodate (NalO4). In some embodiments, the cyclizing of (c) further includes contacting Compound 6c with an osmate catalyst. In some embodiments, the osmate catalyst is

[0708] 5 potassium osmate (e.g., K2OSO4). In some embodiments, the cyclizing of (c) is carried out using a 3:1 stoichiometric ratio of oxidizing reagent relative to Compound 6c. In some embodiments, the cyclizing of (c) is carried out using a 0.01 :1 stoichiometric ratio of osmate catalyst relative to Compound 6c. In some embodiments, the cyclizing of (c) further includes a mixture of an alcoholic solvent and water. In some embodiments, the alcoholic solvent is methanol. In some embodiments, the cyclizing of (c) is carried out at a temperature of at least 10 °C (e.g., 10 °C, 15 °C, 20 °C, 25 °C, or 30 °C). In some embodiments, the cyclizing of (c) is carried out at a temperature from 15 °C to 25 °C.

[0709] In some embodiments, the cyclizing of (c) is carried out according to the following scheme:

[0710] In another aspect, the disclosure provides a method of preparing a compound of Formula 6:

[0711] 15 wherein p is 1 or 2;

[0712] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0713] R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; the method including: a) reducing a compound of Formula 6d to form a compound of Formula 6e:

[0714] 25

[0715] Formula 6d PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0716] PATENT

[0717] ATTORNEY DOCKET NO.: 51432-059WO2 b) deprotecting the compound of Formula 6e to form a compound of Formula 6f:

[0718] Formula 6e Formula 6f c) reducing the compound of Formula 6f to form a compound of Formula 6g:

[0719] Formula 6f Formula 6g .and

[0720] 5 d) coupling the compound of Formula 6g with a compound of Formula 6h to form the compound of Formula 6:

[0721] Formula 6h

[0722] Formula 6g

[0723] In some embodiments, the reducing of (a) further includes contacting the compound of Formula 6d (e.g., Compound 6d) with a reducing reagent and an acid. In some embodiments, the reducing

[0724] 10 reagent is a borohydride or a silane reducing reagent. In some embodiments, the reducing reagent is a silane reducing reagent. In some embodiments, the silane reducing reagent is triethylsilane (EtsSiH). In some embodiments, the acid is an organic acid. In some embodiments, the organic acid is trifluoroacetic acid (TFA). In some embodiments, the reducing of (a) is carried out using a 1 .5:1 stoichiometric ratio of reducing reagent relative to Compound 6d. In some embodiments, the reducing of (a) is carried out using a 5:1 stoichiometric ratio of acid relative to Compound 6d. In some embodiments, the reducing of (a) is carried out at a temperature of at least 10 °C (e.g., 10 °C, 15 °C, 20 °C, 25 °C, or 30 °C). In some embodiments, the reducing of (a) is carried out at a temperature from 15 °C to 25 °C.

[0725] In some embodiments, the reducing of (a) is carried out according to the following scheme:

[0726] OBn

[0727] OBn O

[0728] O Boc

[0729] Formula 6d Formula 6e

[0730] 20 In some embodiments, the reducing of (a) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0731] PATENT

[0732] ATTORNEY DOCKET NO.: 51432-059WO2

[0733] O Boc

[0734] Compound 6d Compound 6e

[0735] In some embodiments, the deprotecting of (b) further includes contacting the compound of Formula 6e (e.g., Compound 6e) with a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon (Pd / C). In some embodiments, the deprotecting of (b) further includes contacting

[0736] 5 the compound of Formula 6e (e.g., Compound 6e) with hydrogen gas. In some embodiments, the deprotecting of (b) is carried out at a temperature of at least 10 °C (e.g., 10 °C, 15 °C, 20 °C, 25 °C, or 30 °C). In some embodiments, the deprotecting of (b) is carried out at a temperature from 15 °C to 25 °C. In some embodiments, the deprotecting of (b) is carried out according to the following scheme: O oc

[0737] Formula 6e Formula 6f

[0738] 10 In some embodiments, the deprotecting of (b) is carried out according to the following scheme: O oc

[0739] Compound 6e Compound 6f

[0740] In some embodiments, the reducing of (c) further includes contacting the compound of Formula 6f (e.g., Compound 6f) with a reducing reagent. In some embodiments, the reducing reagent is a borohydride reducing reagent. In some embodiments, the borohydride reducing reagent is lithium borohydride (LiBH4). In some embodiments, the reducing of (c) is carried out using a 1 .5:1 stoichiometric ratio of reducing reagent relative to the compound of Formula 6f (e.g., Compound 6f). In some embodiments, the reducing of (c) is carried out at a temperature of at least 0 °C (0 °C, 10 °C, 20 °C, 30 °C, 40°C, 50 °C, or 60 °C). In some embodiments, the reducing of (c) is carried out at a temperature range from 0 °C to 50 °C. In some embodiments, the reducing of (c) is carried out according to the

[0741] 20 following scheme:

[0742] Formula 6f Formula 6g

[0743] In some embodiments, the reducing of (c) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0744] PATENT

[0745] ATTORNEY DOCKET NO.: 51432-059WO2

[0746] Formula 6f Formula 6g

[0747] In some embodiments, the coupling of (d) further includes contacting the compound of Formula 6g (e.g., Compound 6g) with an uronium coupling reagent. In some embodiments, the uronium coupling reagent is COMU, HATU, HBTU, HCTU, TATU, TOTU, or TBTU. In some embodiments, the coupling

[0748] 5 agent is HATU. In some embodiments, the coupling of (d) further includes contacting the compound of Formula 6g (e.g., Compound 6g) and the compound of Formula 6h (e.g., Compound 6h) with a base. In some embodiments, the base is an organic base. In some embodiments, the organic base is lutidine, triethylamine (TEA), or N,N-diisopropylethylamine (DIEA). In some embodiments, the organic base is N,N-diisopropylethylamine (DIEA).

[0749] 10 In some embodiments, the coupling of (d) is carried out according to the following scheme:

[0750] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0751] PATENT

[0752] ATTORNEY DOCKET NO.: 51432-059WO2

[0753] In some embodiments, the coupling of (d) is carried out according to the following scheme: p g

[0754] Compound 6

[0755] In another aspect, the disclosure provides a method of preparing a compound of Formula 7d:

[0756] 5 wherein n is 0 or 1 ;

[0757] R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0758] R3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally

[0759] 10 substituted Ci-Ce alkynyl; the method including: a) coupling a compound of Formula 2 with a sodium salt of Compound 3 to form a compound of

[0760] Formula 7a:

[0761] 15 b) cyclizing the compound of Formula 7a to form a compound of Formula 7b: PCT / US25 / 48606 30 September 2025 (30.09.2025) c) deprotecting the compound of Formula 7b to form a compound of Formula 7c: d) deprotecting the compound of Formula 7c to form the compound of Formula 7d:

[0762] 5 the method including: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0763] PATENT

[0764] ATTORNEY DOCKET NO.: 51432-059WO2 a) coupling Compound 2 with the sodium salt of Compound 3 to form Compound 7a: b) cyclizing Compound 7a to form Compound 7b:

[0765] 5 c) deprotecting Compound 7b to form Compound 7c: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0766] PATENT

[0767] ATTORNEY DOCKET NO.: 51432-059WO2

[0768] In some embodiments, the coupling of (a) further includes contacting the compound of Formula 2 (e.g., Compound 2) and the sodium salt of Compound 3 with a palladium catalyst. In some embodiments, the palladium catalyst is cataCXium® Pd G3. In some embodiments, the coupling of (a) further includes contacting the compound of Formula 2 (e.g., Compound 2) and the sodium salt of Compound 3 with a

[0769] 5 phosphate salt. In some embodiments, the phosphate salt is a potassium phosphate salt. In some embodiments, the potassium phosphate salt is K3PO4. In some embodiments, the coupling of (a) is carried out using a 0.98:1 stoichiometric ratio of the sodium salt of Compound 3 relative to the compound of Formula 2 (e.g., Compound 2). In some embodiments, the coupling of (a) is carried out using a 2.6:1 stoichiometric ratio of the phosphate salt relative to the compound of Formula 2 (e.g., Compound 2). In some embodiments, the coupling of (a) is carried out at room temperature (e.g., 25 °C) for 1 hour, then carried out a temperature of at least 55 °C (e.g., 55 °C, 60 °C, 65 °C, or 70 °C) for 13 hours. In some embodiments, the coupling of (a) is carried out from 20 to 30 °C for 1 hour, then carried out a temperature from 60 °C to 70 °C for 13 hours.

[0770] In some embodiments, the coupling of (a) is carried out according to the following scheme:

[0771] 15

[0772] In some embodiments, the coupling of (a) is carried out according to the following scheme:

[0773] In some embodiments, the cyclizing of (b) further includes contacting the compound of Formula

[0774] 7a (e.g., Compound 7a) with a carbodiimide coupling reagent, an anti-racemization agent, and a base. In some embodiments, the carbodiimide coupling reagent is EDCI, the anti-racemization agent is HOBt, and the base is N,N-diisopropylethylamine (DIEA). In some embodiments, the cyclizing of (b) is carried out using a 2:1 stoichiometric ratio of the carbodiimide coupling reagent relative to the compound of Formula 7a (e.g., Compound 7a). In some embodiments, the cyclizing of (b) is carried out using a 2:1 stoichiometric ratio of the base relative to the compound of Formula 7a (e.g., Compound 7a). In some

[0775] 25 embodiments, the cyclizing of (b) is carried out using a 1 :1 stoichiometric ratio of the anti-racemization agent relative to the compound of Formula 7a (e.g., Compound 7a). In some embodiments, the cyclizing of (b) is carried out at a temperature of at least 20 °C (20 °C, 25 °C, 30 °C). In some embodiments, the cyclizing of (b) is carried out at room temperature (e.g., 25 °C). PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0776] PATENT

[0777] ATTORNEY DOCKET NO.: 51432-059WO2

[0778] In some embodiments, the cyclizing of (b) is carried out according to the following scheme:

[0779] In some embodiments, the cyclizing of (b) is carried out according to the following scheme:

[0780] 5 In some embodiments, the deprotecting of (c) further includes contacting the compound of

[0781] Formula 7b (e.g., Compound 7b) with a fluoride ion source. In some embodiments, the fluoride ion source is tetra-n-butylammonium fluoride (TBAF). In some embodiments, the deprotecting of (c) is carried out using a 1 :1 stoichiometric ratio of the fluoride ion source relative to the compound of Formula 7b (e.g., Compound 7b). In some embodiments, the deprotecting of (c) is carried out at a temperature of at least 0 10 °C (e.g., 0 °C, 5 °C, or 10 °C). In some embodiments, the deprotecting of (c) is carried out according to the following scheme: PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0782] PATENT

[0783] ATTORNEY DOCKET NO.: 51432-059WO2

[0784] In some embodiments, the deprotecting of (c) is carried out according to the following scheme:

[0785] In some embodiments, the deprotecting of (d) further includes contacting the compound of

[0786] Formula 7c (e.g., Compound 7c) with an acid. In some embodiments, the acid is an inorganic acid. In

[0787] 5 some embodiments, the inorganic acid is HCI. In some embodiments, the acid is an organic acid. In some embodiments, the organic acid is trifluoroacetic acid. In some embodiments, the deprotecting of (d) is carried out using at least 2-fold excess equivalents of the acid relative to the compound of Formula 7c

[0788] (e.g., Compound 7c). In some embodiments, the cyclizing of (b) is carried out at a temperature of at least

[0789] 20 °C (20 °C, 25 °C, 30 °C). In some embodiments, the deprotecting of (d) is carried out at room

[0790] 10 temperature (e.g., 25 °C). In some embodiments, the deprotecting of (d) is carried out according to the following scheme:

[0791] In some embodiments, the deprotecting of (d) is carried out according to the following scheme:

[0792] 15 In another aspect, the disclosure provides a method of preparing a compound of Formula 7e: PCT / US25 / 48606 30 September 2025 (30.09.2025) wherein n is 0 or 1 ; m is 1 or 2;

[0793] 5 R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted

[0794] Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and R3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl;

[0795] R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce

[0796] 10 alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;

[0797] R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted

[0798] 15 Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0799] X1is halogen;

[0800] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0801] PATENT

[0802] ATTORNEY DOCKET NO.: 51432-059WO2 the method including coupling a compound of Formula 7d with a compound 4-I to form the compound of Formula 7e:

[0803] In some embodiments, the coupling is carried out according to the following scheme:

[0804] In another aspect, the disclosure provides a method of preparing a compound of Formula A: wherein n is 0 or 1 ;

[0805] 10 m is 1 or 2;

[0806] R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; and

[0807] R3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl;

[0808] 15 R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or

[0809] R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; and PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0810] PATENT

[0811] ATTORNEY DOCKET NO.: 51432-059WO2

[0812] R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; the method including cyclizing a compound of Formula 7e to form the compound of Formula A:

[0813] 5

[0814] In some embodiments, the cyclizing is carried out according to the following scheme:

[0815] 10 In any of the foregoing aspects, n is 0. In any of the foregoing aspects, n is 1 .

[0816] In any of the foregoing aspects, m is 1 . In any of the foregoing aspects, m is 2.

[0817] In any of the foregoing aspects, p is 1 . In any of the foregoing aspects, p is 2.

[0818] In any of the foregoing aspects, R1is optionally substituted C1-C4 alkyl or optionally substituted C1-C4 heteroalkyl. In any of the foregoing aspects, R1is optionally substituted C1-C4 alkyl. In any of the foregoing aspects, R1is methyl. In any of the foregoing aspects, R1is optionally substituted C1-C4 heteroal aspects, , , s

[0819] F . In any of the foregoing aspects, R2is F .

[0820] 20 The methods described herein can be used to prepare compounds of Tables 1 and 2. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0821] PATENT ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0822] PATENT

[0823] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0824] PATENT

[0825] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0826] PATENT

[0827] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0828] PATENT

[0829] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0830] PATENT

[0831] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0832] PATENT

[0833] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0834] PATENT

[0835] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0836] PATENT

[0837] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0838] PATENT

[0839] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0840] PATENT

[0841] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0842] PATENT

[0843] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0844] PATENT

[0845] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0846] PATENT

[0847] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0848] PATENT

[0849] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0850] PATENT

[0851] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0852] PATENT

[0853] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0854] PATENT

[0855] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0856] PATENT

[0857] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0858] PATENT

[0859] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0860] PATENT

[0861] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0862] PATENT

[0863] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0864] PATENT

[0865] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0866] PATENT

[0867] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0868] PATENT

[0869] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0870] PATENT

[0871] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0872] PATENT

[0873] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0874] PATENT

[0875] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0876] PATENT

[0877] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0878] PATENT

[0879] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0880] PATENT

[0881] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0882] PATENT

[0883] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0884] PATENT

[0885] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0886] PATENT

[0887] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0888] PATENT

[0889] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0890] PATENT

[0891] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0892] PATENT

[0893] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0894] PATENT

[0895] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0896] PATENT

[0897] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0898] PATENT

[0899] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0900] PATENT

[0901] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0902] PATENT

[0903] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0904] PATENT

[0905] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0906] PATENT

[0907] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0908] PATENT

[0909] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0910] PATENT

[0911] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0912] PATENT

[0913] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0914] PATENT

[0915] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0916] PATENT

[0917] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0918] PATENT

[0919] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0920] PATENT

[0921] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0922] PATENT

[0923] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0924] PATENT

[0925] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0926] PATENT

[0927] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0928] PATENT

[0929] ATTORNEY DOCKET NO.: 51432-059WO2

[0930] Note that some compounds are shown with bonds as flat or wedged. In some instances, the relative stereochemistry of stereoisomers has been determined; in some instances, the absolute stereochemistry

[0931] 5 has been determined. In some instances, a single Example number corresponds to a mixture of stereoisomers. All stereoisomers of the compounds of the foregoing table are contemplated by the present invention. In particular embodiments, an atropisomer of a compound of the foregoing table is contemplated. Brackets are to be ignored.

[0932] 10 Table 2: Certain Compounds of the Present Invention PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0933] PATENT

[0934] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0935] PATENT

[0936] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0937] PATENT

[0938] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0939] PATENT

[0940] ATTORNEY DOCKET NO.: 51432-059WO2 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0941] PATENT

[0942] ATTORNEY DOCKET NO.: 51432-059WO2

[0943] EXAMPLES

[0944] The disclosure is further illustrated by the following examples and synthesis examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein

[0945] 5 described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure or scope of the appended claims.

[0946] Example 1. Synthetic Procedure for Compound 8 - (S)-3-bromo-2-(1-methoxyethyl)pyridine.

[0947] Detailed below is a general synthetic procedure for Compound 8 - (S)-3-bromo-2-(1 - methoxyethyl)pyridine.

[0948] To a reactor was charged toluene (2,100 L, 7 V) and 3-bromopicolinonitrile (300 kg, 1 ,639 mol, 1 equiv). The resulting mixture was cooled to, and maintained at, -20 °C. To this was charged MeMgCI (3 M

[0949] 20 in THF, 601 L, 1 ,803 mol, 1 .1 equiv). The resulting mixture was heated to, and maintained at, 10-20 °C for 16 hours at which point HPLC analysis showed reaction completion.

[0950] The reaction mixture was charged into pre-cooled (-10 to 0 °C) 4 M aqueous HCI (1 ,070 L, 2.6 equiv) at -10 to 10 °C and resulting mixture was maintained at 15-25 °C for 30 minutes. The phases were separated, and the aqueous phase extracted with toluene (600 L x 5, 2 V x 5). The combined organic layers were washed with saturated aqueous NaHCOs (100 L, 0.3 V) and then concentrated (50-60 °C, - 0.08 MPa) to -200 L (0.7 V) to afford crude 1 -(3-bromopyridin-2-yl)ethan-1 -one (Compound 8a) (346 kg, 93.7% a / a purity, 83.4% w / w assay, 88% yield) as a brown oil which was used directly in the next step.

[0951] LRMS (ESI+)

[0952] 30 Calculated for C7H7BrNO (M+H+): 199.97055

[0953] Found: 200.0

[0954] 1H NMR (400 MHz, DMSO-d6) PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0955] PATENT

[0956] ATTORNEY DOCKET NO.: 51432-059WO2

[0957] <58.66 (dd, J = 4.6, 1 .3 Hz, 1 H), 8.22 (dd, J = 8.2, 1 .3 Hz, 1 H), 7.52 (dd, J = 8.2, 4.6 Hz, 1 H), 2.61 (s, 3H).

[0958] To a reactor was charged potassium phosphate buffer (0.2 M, pH = 6-8-7.2, 2,000 L, 10 V), glucose (594 kg, 3,297 mol, 3.3 equiv), GDH (4 kg, 2% w / w), NADP (2 kg, 1% w / w), KRED (2 kg, 1% w / w), and a solution of 1 -(3-bromopyridin-2-yl)ethan-1 -one (Compound 8a) (200 kg, 999.83 mol, 1 equiv) in DMSO (200 L, 1 V) at 25-30 °C. Note: the pH was maintained at 6-5-7 as needed, using 2 M aqueous NaOH. The reaction mixture was maintained at 28-32 °C for 6 hours at which point HPLC analysis showed reaction completion.

[0959] To the reaction mixture was charged diatomaceous earth (40 kg, 20% w / w) and MTBE (800 L, 4 V). The resulting mixture was filtered, and the cake was washed with MTBE (200 L, 1 V). The resulting phases were separated, and the aqueous phase extracted again with MTBE (500 L x 3, 2.5 V x 3). The

[0960] 15 combined organic phases were washed with brine (100 L, 0.5 V) and concentrated (45-55 °C, -0.08 MPa) to afford (S)-1 -(3-bromopyridin-2-yl)ethan-1 -ol (Compound 8b) (204 kg, 97.8% a / a purity, 89.6% w / w assay, 90% yield).

[0961] Part 3 - Alternative Synthesis of Compound 8b - (S)-1 -(3-bromopyridin-2-yl)ethan-1 -ol.

[0962] Step 2

[0963] Compound 8b

[0964] 20 Compound 8a

[0965] To a reactor was charged triethylamine (47 kg, 464.46 mol, 2.8 equiv). This was cooled to, and maintained at, 0-10 °C. To this was charged formic acid (19 kg, 412.82 mol, 2.5 equiv) and RuCI(p- cymene)[(S,S)-Ts-DPEN] (0.55 kg, 864.49 mmol, 0.005 equiv). The resulting mixture was heated to, and maintained at, 30-35 °C. To this was charged 1 -(3-bromopyridin-2-yl)ethan-1 -one (Compound 8a) (36.7 kg, 165.12 mol, 1 equiv), rinsing the charging port with additional triethylamine (2 kg, 19.76 mol, 0.12 equiv). The reaction mixture temperature was maintained at 30-35 °C for 6 hours at which point HPLC analysis showed reaction completion.

[0966] The reaction mixture was concentrated (30-35 °C) to remove triethylamine. To the resulting mixture was charged water (170 kg) and EtOAc (310 kg) at 15-25 °C. The phases were separated, and

[0967] 30 the aqueous phases extracted with EtOAc (160 kg x 2). The combined organic phases were washed with brine (158 kg x 2), dried over anhydrous Na2SO4, and filtered, washing the spent drying agent cake with EtOAc (40 kg). The combined filtrates were cooled to, and maintained at, 0-10 °C and to this was charged PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0968] PATENT

[0969] ATTORNEY DOCKET NO.: 51432-059WO2

[0970] 35% w / w HCI in MeOH (55 kg, 3.2 equiv). The resulting mixture was maintained at 0-10 °C for 12 hours before being filtered, washing the product with EtOAc (40 kg). The product was dissolved in water (66 kg) and EtOAc (170 kg) and the resulting solution was cooled to, and maintained at, 5-15 °C. To this was charged a solution of NaHCOs (33 kg) in water (170 kg). The phases were separated, and the aqueous

[0971] 5 phases extracted with EtOAc (170 kg x 3). The combined organic phases were washed with brine (158 kg x 2), dried over anhydrous Na2SO4, and filtered, washing the spent drying agent cake with EtOAc (120 kg). The filtrate was concentrated (40-45 °C) to afford (S)-1 -(3-bromopyridin-2-yl)ethan-1 -ol (Compound 8b) (30.0 kg, >99.9% a / a purity, 95% w / w assay, 86% yield) as a dark brown oil.

[0972] LRMS (ESI+)

[0973] Calculated for C7H9BrNO (M+H+): 201 .98620

[0974] Found: 202.0

[0975] 1H NMR (400 MHz, DMSO-d6)

[0976] 15 58.56 (dd, J = 4.6, 1 .4 Hz, 1 H), 8.02 (dd, J = 8.0, 1 .4 Hz, 1 H), 7.26 (dd, J = 8.0, 4.6 Hz, 1 H), 5.13

[0977] - 5.04 (m, 2H), 1 .37 (d, J = 6.0 Hz, 3H).

[0978] 20 To a reactor was charged THF (2,025 L, 5 V) and t-BuONa (231 kg, 2,404 mol, 1 .2 equiv). The resulting mixture was cooled to, and maintained at, 0-10 °C. To this was charged a solution of (S)-1 -(3- bromopyridin-2-yl)ethan-1 -ol (3) (405 kg, 2,004 mol, 1 equiv) in THF (800 L, 2 V) and Mel (340 kg, 2,395 mol, 1 .2 equiv). The resulting reaction mixture was maintained at 0-10 °C for 16 hours at which point HPLC analysis showed reaction completion.

[0979] 25 To the reaction mixture was charged 7.5% w / w aqueous NH3 (520 L, 1 .3 V) at 0-10 °C and MTBE (1 ,200 L, 3 V). The phases were separated, and the aqueous layer extracted with MTBE (1 ,200 L, 3 V). The combined organic phases were washed with brine (200 L, 0.5 V) and concentrated (50-60 °C, -0.08 MPa) to afford crude (S)-3-bromo-2-(1 -methoxyethyl)pyridine (Compound 8). The crude (S)-3-bromo-2-(1 - methoxyethyl)pyridine (Compound 8) was distilled (120 °C, 600 Pa) to afford (S)-3-bromo-2-(1 - methoxyethyl)pyridine (Compound 8) (445 kg, 99.3% a / a purity, 90.2% w / w assay, 93% yield) as a colorless solid (solidified after packaging).

[0980] LRMS (ESI+)

[0981] Calculated for CsHnBrNO (M+H+): 216.00185

[0982] 35 Found: 216.00

[0983] 1H NMR (400 MHz, CDCI3) PCT / US25 / 48606 30 September 2025 (30.09.2025)

[0984] PATENT

[0985] ATTORNEY DOCKET NO.: 51432-059WO2

[0986] <58.61 (d, J = 3.2 Hz, 1 H), 7.83 (q, J = 1 .6, 6.8 Hz, 1 H), 7.08 (q, J = 3.6, 4.8 Hz, 1 H), 4. 92 (q, J =

[0987] 6.4 Hz, 1 H), 3.31 (s, 3H), 1 .48 (d, J = 6.8 Hz, 3H).

[0988] Example 2 - Synthetic Procedure for Compound 9 - 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione.

[0989] 5 Detailed below is a general synthetic procedure for Compound 9 - 3,3-dimethyldihydro-2 / 7-pyran-

[0990] 2,6(3 / - / )-dione.

[0991] Step 2

[0992] Step 1 20% w / w aq. NaCIO2, 9

[0993] Part 1 - Synthesis of Compound 9a - 4,4-dimethyl-5-oxopentanenitrile.

[0994] Step 1 hydroquinone,

[0995] Compound 9a

[0996] To a reactor was charged 1 ,4-dioxane (1 ,552 L, 5 V), hydroquinone (1 .55 kg, 14.1 mol, 0.0033 equiv), and 5% w / w aqueous NaOH (341 .4 kg, 426.78 mol, 0.1 equiv). The resulting mixture was heated to, and maintained at, 70-75 °C. To this was charged isobutyraldehyde (310.6 kg, 4,307.3 mol, 1 equiv) and acrylonitrile (285.7 kg, 5,384.5 mol, 1 .25 equiv) over 8 hours. The reaction mixture was maintained at

[0997] 15 70-75 °C for 8 hours at which point GC analysis showed reaction completion.

[0998] The reaction mixture was then cooled to, and maintained at, 20-25 °C. The pH was adjusted to 5- 6 with 3.5% w / w aqueous HCI (required 172.5 kg) and concentrated (45 °C, -0.03 atm) until no organic solvent was distilled. The remaining residue was cooled to, and maintained at, 20-25 °C. To this was charged DCM (1 ,552 L, 5 V) and water (620 L, 2 V). The phases were separated, and the organic phase concentrated (45 °C, -0.03 atm) until no solvent was distilled to afford crude 4,4-dimethyl-5- oxopentanenitrile (Compound 9a) as a brown oil (626.6 kg, 70.8% a / a purity, 43.5% w / w assay, 51% yield).

[0999] LRMS (ESI+)

[1000] 25 Calculated for C7H12NO (M+H+): 126.09134

[1001] Found: 126.0 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1002] PATENT

[1003] ATTORNEY DOCKET NO.: 51432-059WO2

[1004] 1H NMR (400 MHz, CDCI3)

[1005] <59.37 (s, 1 H), 2.30 - 2.19 (m, 2H), 1 .88 - 1 .77 (m, 2H), 1 .06 (s, 6H).

[1006] To a reactor was charged water (1 ,1 15 kg, 5 V), KH2PO4 (13.8 kg, 101 .4 mol, 0.057 equiv), DMSO (164.0 kg, 2,099.1 mol. 1 .2 equiv), and crude 4,4-dimethyl-5-oxopentanenitrile (Compound 9a) (455.3 kg, 49.0% w / w assay, 1 ,782.3 mol, 1 equiv). The resulting mixture was cooled to, and maintained at, 10-20 °C. To this was charged 20% w / w aqueous NaCIC (1 ,185.0 kg, 2,620.5 mol, 1 .5 equiv) over 20 hours. The reaction mixture was then maintained at a temperature of 10-20 °C for 1 hour at which point GC analysis showed reaction completion. This afforded crude 4-cyano-2,2-dimethylbutanoic acid (Compound 9b) which was used directly in the next step.

[1007] To the mixture of crude 4-cyano-2,2-dimethylbutanoic acid (Compound 9b) was charged KOH

[1008] 15 (361 .5 kg, 6,442.7 mol, 3.6 equiv). The resulting mixture was extracted with MTBE (800 kg x 2, 4.9 V x 2). The aqueous phase was then heated to, and maintained at, 90-100 °C for 15 hours at which point GC analysis showed reaction completion.

[1009] The reaction mixture was cooled to, and maintained at, 15-25 °C. The pH was adjusted to 1 -2 with 30% w / w aqueous HCI (required 1 ,058 kg, 4.9 equiv). The resulting mixture was extracted with

[1010] 20 MTBE (1 ,058 kg x 2, 6.4 V x 2). The combined organic phases were washed with 5% w / w aqueous NaCI (378 kg x 2, 1 .7 V x 2) and concentrated (40-45 °C, -0.03 atm) to 670 L (3 V) affording crude 2,2- dimethylpentanedioic acid (Compound 9c) which was used directly in the next step.

[1011] To the mixture of crude 2,2-dimethylpentanedioic acid (Compound 9c) was charged AC2O (614.6 kg, 6,020.1 mol, 3.4 equiv) at 40-45 °C. The resulting mixture was concentrated (40-45 °C, -0.03 atm) to removed MTBE. The reaction mixture was heated to, and maintained at, 80-85 °C for 2 hours at which point GC analysis showed reaction completion.

[1012] The reaction mixture was then concentrated (70-75 °C, -0.03 atm) to remove AcOH and Ac2O until no solvent was distilled. This afforded crude 3,3-dimethyldihydro-2 / 7-pyran-2,6(3 / - / )-dione (Compound 9) (390.5 kg, 86.3% a / a purity, 69.3% w / w assay, 107% crude yield) which was used directly

[1013] 30 in the next step. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1014] PATENT

[1015] ATTORNEY DOCKET NO.: 51432-059WO2

[1016] To a reactor was charged n-heptane (574.0 kg, 1 .86 V for crude weight). This was cooled to, and maintained at, -10 to -5 °C. To this was charged a solution of crude 3,3-dimethyldihydro-2 / 7-pyran-

[1017] 5 2,6(3H)-dione (Compound 9) (454.0 kg, 84.1 % w / w assay) in MTBE (667.2, 2 V for crude weight) over 10 hours. The resulting mixture was maintained at -10 to -5 °C for 1 .5 hours and then filtered.

[1018] The filter cake was dissolved in MTBE (572 kg, 2 V for assay weight). To the resulting solution was charged activated carbon (19.1 kg, 0.05% w / w for assay weight). This was maintained at 15-25 °C for 8 hours. The resulting solution was then filtered, washing the spent carbon cake with MTBE (18 kg,

[1019] 10 0.05 V). The filtrate was then added to pre-cooled (-10 to -5 °C) n-heptane (518.4 kg, 2 V for assay weight) over 9 hours. The resulting mixture was maintained at -10 to -5 °C for 2 hours. This was then filtered at -10 to -5 °C. The product was dried (25-30 °C, -0.03 atm) for 16 hours to afford 3,3- dimethyldihydro-2 / 7-pyran-2,6(3 / - / )-dione (Compound 9) (212.0 kg, 100% a / a purity, 98.3% w / w assay, 55% yield) as an off-white solid.

[1020] 15

[1021] To a reactor was charged AC2O (5.4 L) and 2,2-dimethylpentanedioic acid (Compound 9c) (2,573 g, 98.8% w / w assay and 506 g, 90.9% w / w assay, 18.74 mol, 1 equiv). The resulting reaction mixture was

[1022] 20 heated to, and maintained at, 1 10 °C for 1 hour at which point GC analysis showed reaction completion.

[1023] The reaction mixture was concentrated (70 °C, -0.03 atm) to remove AcOH and AC2O until no solvent was distilled. The residue was combined with another batch (2,2-dimethylpentanedioic acid (Compound 9c) (6,610 g, 90.8% w / w assay)) and distilled (1 10-120 °C, -0.005 atm) until no product was distilled. The obtained fraction was triturated with n-heptane (35 L), filtered, and the product dried (25 °C,

[1024] 25 -0.005 atm) to afford 3,3-dimethyldihydro-2 / 7-pyran-2,6(3 / - / )-dione (Compound 9) (6.66 kg, 99.6% a / a purity, 98.56% w / w assay, 82% yield) as an off-white solid.

[1025] LRMS (ESI+)

[1026] Calculated for C7H11O3 (M+H+): 143.07027

[1027] 30 Found: 143.0

[1028] 1H NMR (300 MHz, CDCI3)

[1029] <52.82 (t, J = 7.0 Hz, 2H), 1 .85 (t, J = 7.0 Hz, 2H), 1 .35 (s, 6H).

[1030] 35 Part 5 - Alternative Synthesis of Compound 9c - 2,2-dimethylpentanedioic acid. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1031] PATENT

[1032] ATTORNEY DOCKET NO.: 51432-059WO2

[1033] To a reactor was charged 65% w / w aqueous HNO3 (3.3 L) and concentrated H2SO4 (500 mL) at 25 °C. The resulting mixture was heated to, and maintained at, 70-80 °C. To this was charged 4,4- dimethyl-5-oxopentanenitrile (Compound 9a) (2.21 kg, 90.5% w / w assay, 15.98 mol, 1 equiv) in portions

[1034] 5 over 24 hours. The reaction mixture was then maintained at 70-75 °C for 1 hour at which point GC analysis showed reaction completion.

[1035] The reaction mixture was cooled to 25 °C and then charged into ice cold water (10 kg) during which time solid precipitated. The resulting mixture was extracted with MTBE (10 L x 1 followed by 5 L x 2). The combined organic phases were washed with water (2 L x 1 ), washed with brine (2 L x 1 ), dried over anhydrous Na2SC>4, filtered, and then concentrated (45 °C, -0.03 atm) until no solvent was distilled. This afforded 2,2-dimethylpentanedioic acid (Compound 9c) (2.6 kg, 98.8% w / w assay, 100% yield) as a white solid.

[1036] LRMS (ESI-)

[1037] 15 Calculated for C7H11O4 (M-H+): 159.06628

[1038] Found: 159.2

[1039] 1H NMR (400 MHz, CDCI3)

[1040] <52.42 (t, J = 7.5 Hz, 2H), 1 .92 (t, J = 7.5 Hz, 2H), 1 .23 (s, 6H).

[1041] Example 3 - Synthetic Procedure for Compound 10 - (12M)-(S)-3-(5-bromo-2-(2-(1- methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1 H-indol-3-yl)-2,2-dimethylpropan-1-ol.

[1042] Detailed below is a general synthetic procedure for Compound 10 - (12M)-(S)-3-(5-bromo-2-(2-(1 -

[1043] 25 methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 F / -indol-3-yl)-2,2-dimethylpropan-1 -ol.

[1044] Part 1 - Synthesis of Compound 10a - (S)-5-(2-(1-methoxyethyl)pyridin-3-yl)-2,2-dimethyl-5- oxopentanoic acid. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1045] PATENT

[1046] ATTORNEY DOCKET NO.: 51432-059WO2

[1047] Compound 8 Compound 9 Compound 10a

[1048] To the reactor A was charged THF (230.5 kg, 2 V) and 7-PrMgCI ■ LiCI (465.0 kg, 1 .3 mol / L, 1 .03 equiv) under nitrogen protection with stirring. The reactor A was cooled to, and maintained at, -25 to -15 °C. A solution of (S)-3-bromo-2-(1 -methoxyethyl)pyridine (Compound 8) (129.7 kg, 600.2 mol, 1 .0 equiv)

[1049] 5 in THF (350.4 kg, 3 V) was added to the reactor dropwise. The reaction mixture was stirred for 2 hours at which point HPLC analysis showed reaction completion.

[1050] To the reactor B was charged THF (577.4 kg, 5 V) and 3,3-dimethyldihydro-2 / 7-pyran-2,6(3 / - / )- dione (Compound 9) (89.2 kg, 627.5 mol, 1 .05 equiv). The reactor B was cooled to, and maintained at, - 15 to -5 °C with stirring. The solution of reactor A was charged to reactor B dropwise. A solution of 3,3- dimethyldihydro-2 / 7-pyran-2,6(3 / - / )-dione (Compound 9) (853 g, 6.0 mol, 0.1 equiv) in THF (34.6 kg, 0.3 V) was added to the reaction mixture and stirred for an additional 5 hours at which point HPLC analysis showed reaction completion.

[1051] The reaction mixture was quenched by adding water (3 V) at -10 to 0 °C. The resulting mixture was adjusted to 15 to 25 °C and stirred for at least 0.5 hours, n-heptane (3 V) and 4% NaOH aq. solution

[1052] 15 (3 V) were added to the organic phase. After stirring for 0.5 hours, the phases were separated, and aqueous layer was adjusted to pH = 7.5 ± 0.3 with KHSC maintaining the temperature between 25 to 15 °C. The aqueous phase was washed with n-heptane (5 V x 1 , 2 V x 1 ). The aqueous phase was filtered, and the filtrate was adjusted to pH = 5.7 to 7.0 with KHSC . The crystal seed of (S)-5-(2-(1 - methoxyethyl)pyridin-3-yl)-2,2-dimethyl-5-oxopentanoic acid (Compound 10a) (15% w / w) was added to

[1053] 20 the solution. The solution was acidified to pH = 5.5 ± 0.2 with KHSC . The slurry was stirred for at least 5 hours at 15 to 25 °C and filtered to afford (S)-5-(2-(1 -methoxyethyl)pyridin-3-yl)-2,2-dimethyl-5- oxopentanoic acid (Compound 10a) (1 15.3 kg, 98.2% a / a purity, 63% yield) as a light yellow solid.

[1054] Part 2 - Alternative synthesis of Compound 10a - (S)-5-(2-(1-methoxyethyl)pyridin-3-yl)-2,2-dirnethyl-5-

[1055] Compound 8 Compound 9 Compound 10a

[1056] To a reactor was charged THF (1 ,250 L, 10 V) and (S)-3-bromo-2-(1 -methoxyethyl)pyridine (Compound 8) (125 kg, 578 mol, 1 equiv) under nitrogen protection. The resulting clear yellow solution was cooled to, and maintained at, -25 to -15 °C. / - PrMgCI ■ LiCI (467 L, 583 mol, 1 .05 equiv) was added to

[1057] 30 the reactor, dropwise (1 L / min). The reaction mixture was stirred for 1 hour at -15 to -5 °C. To the reaction mixture was added 3,3-dimethyldihydro-2 / 7-pyran-2,6(3 / - / )-dione (Compound 9) (86.35 kg, 607 mol, 1 .05 equiv) in THF (375 L, 3 V) (2 L / min) under nitrogen protection maintained between -15 to -5 °C. The PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1058] PATENT

[1059] ATTORNEY DOCKET NO.: 51432-059WO2 reaction mixture was stirred for 12 hours between -12 to -8 °C at which point HPLC analysis showed reaction completion.

[1060] To the reaction mixture was added water (375 L, 3 V) at 0 to 10 °C. The mixture was concentrated (40 to 45 °C, -0.09 MPa) to -550 L and a mixture of AcOH (62.5 L, 0.5 V) in water (1 ,250 L,

[1061] 5 10 V) was charged. The aqueous layer was extracted into EtOAc (1 ,250 L, 10 V, x 2) and saved. The combined organic layers were washed with water (1 ,250 L, 10 V). The combined aqueous layers were extracted into EtOAc (1 ,250 L, 10 V). The combined organic layers were concentrated (40 to 45 °C, -0.09 MPa) to - 150 L then solvent swapped to n-heptane (375 L, 3 V, x 3) then concentrated (40 to 45, -0.09 MPa) to -60 L. A solution of MTBE / n-heptane (1 :1 , 375 L, 3 V) was charged and the resulting mixture was stirred at 15 to 20 °C for 16 hours under nitrogen. The mixture was filtered, and the filter cake was dried under nitrogen (35 to 40 °C, 12 to 24 h) to afford (S)-5-(2-(1 -methoxyethyl)pyridin-3-yl)-2,2-dimethyl- 5-oxopentanoic acid (Compound 10a) (91 .73 kg, 99.8% a / a purity, 56.8% yield) as an off-white solid.

[1062] LCMS (ESI+)

[1063] 15 Calculated for C15H22NO4 (M+H): 280.15433

[1064] Found: 280.1

[1065] 1H NMR (400 MHz, DMSO-d6)

[1066] <5 12.2 (s, 1 H), 8.59 (dd, J = 4.8, 5.2 Hz, 1 H), 7.89 (dd, J = 7.6, 8.0 Hz, 1 H), 7.40 -7.37 (m, 1 H),

[1067] 20 4.58 - 4.53 (m, 1 H), 3.1 1 (s, 3H), 2.81 - 2.77 (m, 2H), 1 .82 - 1 .78 (m, 2H), 1 .42 (d, J = 6.4 Hz, 3H), 1 .12 (s, 6H).

[1068] 25 Compound 10c 1 / 2 H2SO4

[1069] To a reactor was charged water (522 L, 2.5 V) and H2SO4 (150.7 kg, 1537 mol, 2.0 equiv). (S)-5- (2-(1 -methoxyethyl)pyridin-3-yl)-2,2-dimethyl-5-oxopentanoic acid (Compound 10a) (215.6 kg, 771 .8 mol, 1 .0 equiv) and 4-bromophenylhydrazine hydrochloride (Compound 10b) (189.5 kg, 847.9 mol, 1 .1 equiv) were added to the reactor at 10 to 30 °C. The reaction mixture was heated to 70 to 75 °C and stirred for at least 0.5 hours. The reaction mixture was then heated to 90 to 100 °C for 32 hours at which point HPLC analysis showed reaction completion.

[1070] After completion, the reaction was cooled to 60 to 65 °C. Water (1 185.8 kg, 5.5 V) and NaOH (30 wt% in water, 189.3 kg, 1 .9 equiv) were added, and the mixture was stirred at 60 to 65 °C for 5 hours. The mixture was cooled to 20 to 30 °C and stirred for 2 hours. The mixture was filtered and washed with

[1071] 35 water (800 L, 3 V). The wet cake was added to water (1022.5 kg) and H2SO4 (53.9 kg) at 30 to 20 °C. The mixture was warmed to 80 to 85 °C and stirred for 5 hours. The mixture was then cooled to 25 to 30 °C PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1072] PATENT

[1073] ATTORNEY DOCKET NO.: 51432-059WO2 and stirred for 16 hours. The slurry was then filtered and washed with water (1020 L, 3 V). The filter cake was dried under nitrogen at 45 to 55 °C for 36 hours to afford (S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2, 2-dimethylpropanoic acid (Compound 10c1 / z H2SO4) (281 .5 kg, 99.6% a / a purity, 73% yield) as a yellow solid.

[1074] 5

[1075] Compound 10c 1 / 2 H2SO4

[1076] To a reactor was charged water (840 L, 5 V) and H2SO4 (257 kg, 4485 mol, 4 equiv) maintaining the reactor at 10 to 20 °C. (S)-5-(2-(1 -methoxyethyl)pyridin-3-yl)-2,2-dimethyl-5-oxopentanoic acid (Compound 10a) (183 kg, 1 122 mol, 1 equiv) was charged portion-wise maintaining 10 to 20 °C. 4- bromophenylhydrazine hydrochloride (Compound 10b HCI) (153.7 kg, 1068 mol, 1 .1 equiv) was charged portion-wise maintaining 10 to 20 °C. The resulting mixture was slowly heated to 95 to 100 °C and maintained for 18 hours at which point the HPLC analysis showed reaction completion.

[1077] 15 The reaction mixture was gradually cooled to, and maintained at, 50 to 60 °C while NaOH (20% wt, 1 ,040 L) was added until pH = 4 to 5. K2HPO4 was added (sat. aq., 37.5 L) until pH = 6.2 to 6.8. The precipitated solids were isolated via centrifuge and the cake was washed with water (745 L, 5 V). The filter cake was dried under nitrogen (45 to 50 °C, 24 h) to afford (S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2, 2-dimethylpropanoic acid (Compound 10c1 / 2 H2SO4) (550 kg,

[1078] 20 94.5% a / a purity, 81 .6% yield) as a yellow solid.

[1079] LCMS (ESI+)

[1080] Calculated for C2i H24BrN2O3 (M+H+): 431 .09648

[1081] Found: 430.9

[1082] 1H NMR (400 MHz, DMSO-d6)

[1083] <5 12.1 (s, 1 H), 1 1 .4 (s, 1 H), 8.70 (s, 1 H), 7.82 - 7.77 (m, 2H), 7.45 - 7.20 (m, 3H), 4.19 (d, J = 5.6 Hz 1 H), 2.93 (s, 4 H), 2.78 (s, 1 H), 1 .36 (d, J = 4.0 Hz, 3 H), 0.88 (d, J = 5.2 Hz, 6 H).

[1084] 30 Part 5 - Synthesis of Compound 10d - methyl (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol- 3-yl)-2,2-dimethylpropanoate. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1085] PATENT

[1086] ATTORNEY DOCKET NO.: 51432-059WO2

[1087] Compound 10c 1 / 2 H2SO4

[1088] Compound 10d

[1089] To a reactor was charged MeOH (1 ,375 L, 1 ,086 kg, 5 V), DMF (2.8 kg, 1 wt%), and (S)-3-(5- bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoic acid (Compound 10c1 / 2 H2SO4) (274.9 kg, 636 mol, 1 .0 equiv) followed by SOCI2 (67.5 kg, 636 mol, 1 .0 equiv) at 50 to 60 °C. The

[1090] 5 reaction mixture was stirred at 65 °C for 5 hours at which point the HPLC analysis showed reaction completion.

[1091] The reaction mixture was cooled to 20 to 25 °C and was charged with Na2COs (288.7 kg, 6.0 equiv) and water (2750 L, 10 V). The mixture was filtered, and the filter cake was washed with water (41 1 L, 1 .5 V). The filter cake was dried under nitrogen (50 to 55 °C, 14 h) to afford methyl (S)-3-(5-bromo-2- (2-(1 -methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate (Compound 10d) (239.6 g, 99.3% a / a purity, 95.8% yield) as a white solid.

[1092] Part 6 - Alternative synthesis of Compound 10d- methyl (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3- yl)- 1 H-indol-3-yl)-2,2-dimethylpropanoate.

[1093] Compound 10c 1 / 2 H2SO4

[1094] 15 Compound 10d

[1095] To a reactor was charged MeOH (1360 L, 5 V) and (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin- 3-yl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoic acid (Compound 10c1 / 2 H2SO4) (272 kg, 642 mol, 1 .0 equiv) followed by SOCI2 (75.3 kg, 706 mol, 1 .1 equiv) at 50 to 60 °C. The reaction mixture was stirred at 65 °C for 12 hours at which point the HPLC analysis showed reaction completion.

[1096] The reaction mixture was cooled to 10 °C and adjusted to pH = 7 to 8 with Na2COs (10 wt% in water, 1632 kg) then charged with water (816 L, 3 V) at 10 to 15 °C. The mixture was filtered, and the filter cake was triturated with water (1 ,360 L, 5 V) at 10 to 2 °C for 6 hours. The mixture was filtered, and the filter cake was washed with water (272 L, 1 V). The filter cake was dried under nitrogen (45 to 50 °C, 24 h) to afford methyl (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2,2-

[1097] 25 dimethylpropanoate (Compound 10d) (415 kg, 99.5% a / a purity, 96.1 % yield) as a white solid.

[1098] LCMS (ESI+)

[1099] Calculated for C22H26BrN2O3 (M+H+): 445.1 1213 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1100] PATENT

[1101] ATTORNEY DOCKET NO.: 51432-059WO2

[1102] Found: 445.3

[1103] 1H NMR (300 MHz, DMSO-d6)

[1104] 511 .41 (s, 1 H), 8.72 (dd, J = 4.7, 1 .8 Hz, 1 H), 7.81 (dd, J = 7.7, 1 .8 Hz, 1 H), 7.65 (d, J = 1 .9 Hz,

[1105] 5 1 H), 7.47 (dd, J = 7.8, 4.7 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 7.22 (dd, J =8.6, 1 .9 Hz, 1 H), 4.23 (q, J = 6.3 Hz, 1 H), 3.32 (s, 9H), 2.95 (s, 4H), 1 .39 (d, J = 6.3 Hz, 3H), 0.94 (s, 6H).

[1106] Part 7 - Synthesis of Compound 10e - methyl (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl) - 1 H-indol-3-yl) -2,2-dimethylpropanoate

[1107] Compound 10d

[1108] Compound 10e

[1109] To a reactor was charged DMF (1 163.1 kg, 5 V), methyl (S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate Compound 10d) (239.04 kg, 536.7 mol, 1 .0 equiv), and CS2CO3 (245.94, 754.8 mol, 1 .4 equiv). The reactor was rinsed with DMF (454.6 kg, 2 V). The reaction mixture was cooled to 15 to 20 °C and 2,2,2-trifluoroethyl trifluoromethanesulfonate (170 kg,

[1110] 15 732.4 mol, 1 .35 equiv) was added. The reaction mixture was stirred at 15 to 20 °C for 16 hours at which point the HPLC analysis showed reaction completion.

[1111] After completion the reaction was quenched with AcOH (64.4 kg, 2.0 equiv) and water (1435.0 kg, 6 V) at 15 to 20 °C. The resulting mixture was extracted with MTBE two times (5 V, 2 V). The combined organic layers were concentrated to 3 to 4 V at 35 to 45 °C. The concentrated mixture was diluted with EtOH (4 V) and further concentrated to about 3 to 4 V under reduced pressure at 35 to 45 °C. The previous unit operation was repeated until the MTBE content in EtOH solution was below 0.5% w / w. The resulting EtOH solution of methyl (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate (Compound 10e) (664 kg solution, 98.3% a / a purity) was used directly in the next step.

[1112] 25

[1113] Part 8 - Alternative synthesis of Compound 10e - methyl (S)-3-(5-bromo-2-(2-(1- methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1 H-indol-3-yl)-2,2-dimethylpropanoate PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1114] PATENT

[1115] ATTORNEY DOCKET NO.: 51432-059WO2

[1116] Compound 10d

[1117] Compound 10e

[1118] To a reactor was charged DMF (6.52 L, 7 V) and methyl (S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate (Compound 10d) (932 g, 2.05 mol, 1.0 equiv). The reaction mixture was cooled to, and maintained at, 0 to 5 °C. CS2CO3 (1 .07 kg, 3.29 mol, 1 .6

[1119] 5 equiv) was added followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (763 g, 3.29 mol, 1 .6 equiv). The mixture was stirred at 0 to 5 °C for 16 hours at which point the HPLC analysis showed reaction completion.

[1120] To the reaction mixture was added water (5,592 mL, 6 V) at 0 to 20 °C. The reaction mixture was extracted into MTBE (4.66 L, 5 V, x 2). The combined organic layers were washed with brine (2,796 mL, 3 V). The organic layer was solvent swapped for THF (1 ,864 mL, 2 V) until residual MTBE < 1% then charge THF (932 mL, 1 V) to obtain a solution of methyl (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3- yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate (Compound 10e) (1050 g, 98.51 % a / a purity).

[1121] 15 LCMS (ESI+)

[1122] Calculated for C24H2?BrF3N2O3 (M+H+): 527.11517

[1123] Found: 527.6

[1124] 1H NMR (300 MHz, DMSO-d6)

[1125] <58.77 (dt, J = 4.8, 1 .4 Hz, 1 H), 7.86 - 7.75 (m, 1 H), 7.73 - 7.62 (m, 2H), 7.55 (ddd, J = 7.8, 6.0, 4.7 Hz, 1 H), 7.40 (ddd, J = 8.8, 4.0, 1 .9 Hz, 1 H), 5.37 (dd, J = 16.5, 8.6 Hz, 1 H), 4.82 (dd, J = 17.9, 9.0 Hz, 1 H), 4.46 (dd, J = 16.4, 9.5 Hz, OH), 3.93 (dt, J = 18.4, 6.2 Hz, 1 H), 3.66 - 3.56 (m, 2H), 3.46 (d, J = 13.2 Hz, 3H), 3.06 (s, 1 H), 2.94 (s, 2H), 1 .84 - 1 .70 (m, 2H), 1 .32 (dd, J = 37.8, 6.2 Hz, 3H), 1.05 - 0.87 (m, 7H).

[1126] 25

[1127] Part 9 - Synthesis of Compound 10 mixture - (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 H-indol-3-yl)-2,2-dimethylpropan-1 -ol PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1128] PATENT

[1129] ATTORNEY DOCKET NO.: 51432-059WO2

[1130] Compound 10e Compound 10-mix

[1131] To a reactor was charged the EtOH solution of methyl (S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate (Compound 10e) (145 kg, 1 .0 equiv, 5 V) at 15 to 20 °C under nitrogen. To the mixture was charged CaCl2 (60.04 kg, 541 .0

[1132] 5 mol, 1 .0 equiv) at 20 to 30 °C portion-wise, followed by addition of NaBH4(51 .04 kg, 1349.2 mol, 2.5 equiv) at 20 to 30 °C. The reaction mixture was agitated at 20 to 30 °C under nitrogen for 14 hours at which point the HPLC analysis showed reaction completion.

[1133] The reaction was quenched by dropwise addition of aq. HCI (3 M) to the point of pH = 1 to 2. NaOH (30% w / w in water) was added to the mixture to adjust the pH = 4 to 4.5. The resulting mixture was concentrated to 3 to 5 V. The concentrated mixture was further diluted with MTBE (891 .2 kg, 5 V) and water (1197.5 kg, 5 V). The organic layer was washed sequentially with water (718.5 kg, 3 V), aq. NaOH (484.0 kg, 2 V), and water (718.5 kg, 3 V). The organic layer was concentrated to 3 to 5 V at 45 to 60 °C. The concentrated mixture was diluted with IPA (756.3 kg, 4 V) and further concentrated to about 3 to 4 V under reduced pressure at 45 to 60 °C. The previous unit operation was repeated until the MTBE content

[1134] 15 in IPA solution was below 2% w / w to afford (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10 mixture) (247.6 kg, 98.8% a / a purity, 92% yield) as a 1 .46:1 mixture of diastereomers as a solution in IPA.

[1135] Part 10 - Alternative Synthesis of Compound 10 mixture - (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3- yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol ture

[1136] To a reactor was charged a THF solution of methyl (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin- 3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoate (Compound 10e) (1 ,135 g, 2.15 mol, 1 .0 equiv) under nitrogen at 15 to 20 °C. The Compound 10e storage drum was rinsed with THF (2,271

[1137] 25 mL, 2 V) which was added to the reaction mixture. The reaction mixture was gradually warmed to, and maintained at, 50 to 60 °C and LiBH4(2 M in THF, 1 .61 L, 3.23 mol,1 .5 equiv) was added dropwise. The PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1138] PATENT

[1139] ATTORNEY DOCKET NO.: 51432-059WO2 reaction was stirred at 60 to 65 °C for 24 hours at which point the HPLC analysis showed reaction completion.

[1140] HCI (0.5 M, 5,677 mL, 5 V) was charged to a reactor at, and maintained to, 10 to 30 °C. The reaction mixture was charged to this reactor dropwise. HCI (0.5 M, 2,271 L, 2V) was charged to the

[1141] 5 reactor to adjust the pH = 4 to 5. MTBE (5,677 L, 5 V) was charged to the reactor and stirred for 0.5 to 1 hour before being allowed to settle for 0.5 hours and the layers were separated. MTBE (3,406 L, 3 V) was charged to the aqueous layer and stirred for 0.5 to 1 hour before being allowed to settle for 0.5 hours. The combined organic layers were washed sequentially with NaOH (2% wt, 2,271 mL, 2 V) and brine (2,271 mL, 2 V). The organic layer was concentrated (40 to 45 °C, -0.09 MPa) to afford an MTBE solution of (S)-

[1142] 10 3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 - ol (Compound 10 mixture) (994 g, 95.84% a / a purity).

[1143] Compound 10g - 2,2,2-trifluoroethyl 3-(5-bromo-2-(2-((S)-1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-2, 7a-di hydro- 1 H-indol-3-yl)-2,2-dimethylpropanoate

[1144] To a reactor was charged DMF (770 L, 7 V) and (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3- yl)-1 / 7-indol-3-yl)-2,2-dimethylpropanoic acid (Compound 10c1 / 2 H2SO4) (110 kg, 262.7 mol, 1 .0 equiv) at 10 to 20 °C under nitrogen. The reaction mixture was cooled to, and maintained at, 0 to 5 °C. CS2CO3 (208 kg, 637 mol, 2.5 equiv) was charged followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (148 kg, 637 mol, 2.5 equiv) dropwise. The reaction mixture was stirred at 0 to 5 °C for 16 hours at which point the HPLC analysis showed reaction completion.

[1145] 25 To the reaction mixture was charged water (600 L, 6 V) at 0 to 20 °C followed by MTBE (550 L, 5 V). The layers were separated, and the organic layer was washed with brine (330 L, 3 V) then concentrated (40 to 50 °, -0.09 MPa) to ~190 L. The reaction mixture solvent was swapped for THF (220 L, 2 V) until residual MTBE < 1 %. THF (1 10 L, 1 V) was charged to afford a solution of 2,2,2-trifluoroethyl 3-(5-bromo-2-(2-((S)-1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-2,7a-dihydro-1 / 7-indol-3-yl)-2,2- dimethylpropanoate (Compound 10g) (123.6 kg, 97.5% yield) used crude in the next step.

[1146] LCMS (ESI+)

[1147] Calculated for C25H26BrFeN2O3 (M+H+): 595.10255

[1148] Found: 595.0

[1149] 351H NMR (400 MHz, DMSO-d6) PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1150] PATENT

[1151] ATTORNEY DOCKET NO.: 51432-059WO2

[1152] <58.76 (d, J = 4.8 Hz, 1 H), 7.83 - 7.77 (m, 2H), 7.68 - 7.64 (m, 1 H), 7.57 - 7.52 (m, 1 H), 7.43 - 7.39 (m, 1 H), 4.50 - 4.43 (m, 2H), 3.59 (t, J = 12 Hz, 1 H), 3.04 (s, 1 H), 2.92 (s, 2H), 2.88 (s, 2H), 2.73 (s, 2H), 1 .76 - 7.73 (m, 1 H), 1 .37 (d, J = 8.0 Hz, 1 H), 1 .23 (d, J = 8.0 Hz, 1 H), 0.98 (d, J = 20 Hz, 6H).

[1153] 5

[1154] Compound 10 mixture - (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 H- indol-3-yl) -2, 2-dimethylpropan- 1 -ol

[1155] To a reactor was charged a THF solution of 2,2,2-trifluoroethyl 3-(5-bromo-2-(2-((S)-1 - methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-2,7a-dihydro-1 / 7-indol-3-yl)-2,2-dimethylpropanoate Compound 10g) (123.6 kg, 207 mol, 1 .0 equiv) under nitrogen. The Compound 10g storage drum was rinsed with THF (247 L, 2 V) which was added to the reactor. The reaction mixture was gradually warmed to, and maintained at, 50 to 60 °C and LiBH4 (2 M in THF, 155.7 L, 311 mol, 1 .5 equiv) was added dropwise. The reaction was stirred at 60 to 65 °C for 24 hours at which point the HPLC analysis showed reaction completion.

[1156] 15 HCI (0.5 M, 618 L, 5 V) was charged to a reactor at, and maintained to, 10 to 30 °C. The reaction mixture was charged to this reactor dropwise. HCI (0.5 M, 247 L, 2V) was charged to the reactor to adjust the pH = 4 to 5. MTBE (618 L, 5 V) was charged to the reactor and stirred for 0.5 to 1 hour before being allowed to settle for 0.5 hours and the layers were separated. MTBE (370 L, 3 V) was charged to the aqueous layer and stirred for 0.5 to 1 hour before being allowed to settle for 0.5 hours. The combined

[1157] 20 organic layers were washed sequentially with NaOH (2% wt, 247 L, 2 V) and brine (247 L, 2 V). The organic layer was concentrated (40 to 45 °C, -0.09 MPa) to -1300 L to afford (S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10 mixture) (93.55 kg, 90.12% a / a purity) as an MTBE solution.

[1158] Part 12 - Synthesis of Compound 10 - (12M)-(S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)- 1 H-indol-3-yl)-2,2-dimethylpropan-1 -ol

[1159] Compound 10 - (12M)-(S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1 H-indol- 3-yl)-2,2-dimethylpropan-1-ol

[1160] 30

[1161] Condition 1: Column chromatography

[1162] A mixture of atropisomers of (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10 mixture) (19.0 kg) was treated with SiO2(30.0 kg). The mixture in silica gel was purified via flash column chromatography (240 kg SiO2, PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1163] PATENT

[1164] ATTORNEY DOCKET NO.: 51432-059WO2

[1165] 0^100% EtOAc in n-heptane). Fractions containing pure (12M)-(S)-3-(5-bromo-2-(2-(1 - methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) (-1000 L) were concentrated to -25 L. To the concentrated residue was added n-heptane (100 L) and the resulting mixture was concentrated to -25 L. To the concentrated residue was added n-heptane (100 L)

[1166] 5 and the resulting mixture was concentrated to -25 L. The residue was diluted with n-heptane (100 L) and the mixture was stirred at 15 to 20 °C for 12 hours. The mixture was filtered, and the filter cake was dried in the oven under vacuum to afford (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) (18.0 kg, 98.9% a / a) as a white solid.

[1167] Condition 2: Resolution by D-camphor-10-sulfonic acid

[1168] To a reactor was charged (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10 mixture) (247.6 kg) as a solution in IPA and IPA (1314.0 kg, 1 .2 V). The reaction mixture was then pumped through a continuous reactor and

[1169] 15 quenching reactor (the continuous reactor: 210 to 230 °C, quenching reactor: 0 to 20 °C, back pressure value: 4.00 ± 0.20 MPa) with flow rate of 80.0 L / h. The equilibrated reaction solution was charged to a reactor while remaining agitated at 10 to 30 °C at which point the HPLC analysis showed an acceptable ratio of atropisomers. D-camphor-10-sulfonic acid (D-CSA) (150.0 kg, 645.7 mol, 1 .3 equiv) was added to the reaction mixture followed by IPA (21 .5 kg, 0.1 V) to rinse the charging port. The reaction mixture was

[1170] 20 stirred at 20 to 30 °C for 2 hours and then stirred at 50 to 56 °C for 2 hours. The reaction mixture was heated to, and maintained at, 40 to 46 °C then (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 - (2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) D-CSA salt seed (250 g, 0.1 % w / w Compound 10 mix input) was charged to the reaction mixture. After 2 h, the resolution solution was cooled to, and maintained at, -9 to -3 °C. After 4 h, the resulting suspension was filtered and washed with

[1171] 25 IPA (212.0 kg, 1 .0 V). The filter cake was re-suspended in IPA (2,500 L, 10 V) and agitated at 67 to 70 °C for 3 to 4 hours. The resolution mixture was cooled to, and maintained at, 5 °C for 2 hours. The resulting mixture (assay weight 200.0 kg, 1 .0 equiv) was suspended in MTBE (700 L, 3.5 V) at 15 to 25 °C, followed by water (800 L, 4 V). The pH was adjusted to pH = 8 to 10 by slowly charging aq. NaOH (30% w / w). The mixture was agitated at 15 to 25 °C for 30 minutes. The organic phase was separated and

[1172] 30 washed with water (600 L, 3 V, x 3). The organic layer was concentrated to 1 to 2 V (200 to 400 L) then n-heptane (600 L, 3 V) was charged. The organic layer was concentrated to 2 to 3 V (400 to 600 L) under reduced pressure. The solvent swap to n-heptane was repeated twice. The concentrated mixture was charged with n-heptane (600 L, 3 V) and the mixture was agitated at 50 to 60 °C for 3 hours. The mixture was cooled to, and maintained at, 15 to 25 °C and stirred for 1 hour. The slurry was filtered and washed with n-heptane (1 .2 V). The filter cake was dried at 45 to 55 °C to afford Compound 10 as an off-white solid (143.6 kg, 99.05% a / a purity, 58% yield). To further control impurities, the solid was re-suspended in THF / n-heptane (v / v=1 :4, 5 V) and agitated at 67 to 70 °C for 3 to 4 hours. The mixture was cooled to, and maintained at, 5 °C for 2 hours. The slurry was filtered and washed with n-heptane (1 .5V). The wet cake was dried at 45 to 55 °C to afford (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-

[1173] 40 trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) as an off-white solid. To recover (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trif luoroethyl)-1 H-indol-3-yl)-2,2- PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1174] PATENT

[1175] ATTORNEY DOCKET NO.: 51432-059WO2 dimethylpropan-1 -ol (Compound 10), the filtrate from the resolution process was charged into a reactor. The solution was concentrated to 4 to 5 V under vacuum at no more than 50 °C. 30% w / w aq. NaOH solution was added to the concentrated residue to adjust pH = 8 to 10 at 15 to 30 °C. The mixture was concentrated to 0.8 to 1 .2 V under vacuum at no more than 50 °C. MTBE (5 V) and water (5 V) were

[1176] 5 added to the residue. The biphasic system was stirred at 20 to 30 °C for 0.5 hours. The organic phase was separated and washed with water (5 V). The organic phase was then concentrated to 1 .2 to 1 .6 V at no more than 50 °C. The concentrated residue was diluted with IPA (1 .6 V) and the mixture was then concentrated to 1 .2 to 1 .6 V at no more than 50 °C. The solvent swap with IPA was repeated then IPA (3 V) was added to the concentrated residue. The solution was subjected to the equilibrium process and CSA salt formation again. The recovery solution was pumped through the continuous reactor and quenching reactor (the continuous reactor: 210 to 230 °C; quenching reactor: 0 to 20 °C; back pressure: 4.00 ± 0.20 MPa) with flow rate of 80.0 L / h. The equilibrated solution was charged to reactor, while remaining agitated, at 10 to 30 °C at which point the HPLC analysis showed an acceptable ratio of atropisomers (> 1 .77). D-camphor-10-sulfonic acid (D-CSA) (1 .3 equiv) was added to the mixture followed

[1177] 15 by IPA (0.1 V) to rinse the charging port. The reaction mixture was stirred at 20 to 30 °C for 2 hours and then stirred at 50 to 56 °C for 2 hours. (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) D-CSA salt seed (0.1 % w / w) was charged to the reaction mixture at 40 to 46 °C and then stirred at 40 to 46 °C for 2 hours. The solution was cooled to, and maintained at, -9 to -3 °C. After 4 h, the resulting mixture was filtered and washed with

[1178] 20 IPA (1 .0 V). The filter cake (1 .0 equiv) was suspended in MTBE (3.5 V) at 15 to 25 °C, followed by adding water (4 V). The pH was adjusted to pH = 8 to 10 by slowly charging aq. NaOH (30% w / w). The mixture was agitated at 15 to 25 °C for 0.5 hours. The organic phase was separated and washed with water (3 V, x 3). The organic layer was concentrated to 1 to 2 V. The concentrated mixture was diluted with n- heptane (3 V) and further concentrated to about 2 to 3 V under reduced pressure, repeated twice. The

[1179] 25 concentrated mixture was diluted with n-heptane (3 V) and the mixture was agitated at 50 to 60 °C for 3 hours. The mixture was cooled to, and maintained at, 15 to 25 °C for 1 hours. The slurry was filtered and washed with n-heptane (1 .2 V). The wet cake was dried at 45 to 80 °C to afford (12M)-(S)-3-(5-bromo-2- (2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trif luoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) as an off-white solid.

[1180] 30

[1181] Condition 3: Resolution by methanesulfonic acid

[1182] To a solution of (S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trif luoroethyl)-1 / 7-indol- 3-yl)-2,2-dimethylpropan-1 -ol (Compound 10 mixture) in toluene was charged xylene (3 V). The mixture was concentrated to 2.5 to 3.5 V and heated to, and maintained at, 132 to 142 °C. After 24 h, the mixture was cooled to 60 to 70 °C at which point the HPLC analysis showed reaction completion. The residue was cooled to, and maintained at, 15 to 25 °C and charged with 2-MeTHF (5 V). The mixture was washed with aq. HCI (0.2 M, 3 V, x 2). The organic phase was separated and extracted into aq. HCI (3 M, 3 V, x 2). The combined aqueous layers were washed with MTBE (3 V). The aqueous phase was adjusted to pH = 8 to 10 with NaOH (30 wt% in water). The aqueous phase was extracted into IPAc (5 V). The organic

[1183] 40 phase was separated and washed with water (3 V). The organic phase was concentrated to 2 to 3 V under reduced pressure. IPAc (5 V) was added, and the mixture was concentrated to 2 to 3 V under PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1184] PATENT

[1185] ATTORNEY DOCKET NO.: 51432-059WO2 reduced pressure, repeated once. The concentrated residue was diluted with IPAc (5 V). To the solution was added methanesulfonic acid (MSA) (0.35 equiv) at 10 to 30 °C. The mixture was heated to, and maintained at, 25 to 35 °C. After 4 h, the slurry was filtered, and the filter cake was washed with IPAc (2V). The filter cake was collected and subject to recovery. To the filtrate was added 5% aq. NaHCOs (3

[1186] 5 V) until the pH = 8. To the biphasic system was added water (3 V). The organic phase was separated and concentrated to 1 .8 to 2.3 V under vacuum at no more than 45 °C. The concentrated residue was diluted with MeOH (7 V). The resulting solution was concentrated to 1 .8 to 2.3 V under vacuum at no more than 45 °C. To the MeOH solution was added MSA (1 .0 equiv) at 10 to 30 °C. The mixture was stirred at 40 °C for 0.5 hours until all solids are dissolved. To the solution was added water (2.4 V) over 2 hours followed by (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trif luoroethyl)-1 H-indol-3-yl)-2,2- dimethylpropan-1 -ol (Compound 10) seed (10% w / w). The mixture was stirred at 40 °C for 4 hours before water (1 .8 V) was added dropwise. Another portion of water (6 V) was added dropwise and the mixture was stirred for 1 hour. The mixture was cooled to 20 °C and the slurry was stirred for 4 hours. The slurry was filtered, and the filter cake was washed with MeOH / water (v / v=1 :3.5, 1 .8 V). The wet cake was dried

[1187] 15 in the oven at 50 to 55 °C for 16 hours to afford (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)- 1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) as a white solid. To recover (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trif luoroethyl)-1 H-indol-3-yl)-2,2- dimethylpropan-1 -ol (Compound 10), the MeOH / water filtrate was concentrated under vacuum and combined with the mesylate filter cake. Aq. NaOH (30% w / w) was added to adjust the pH to 8 to 10.

[1188] 20 MTBE (5 V) was added to the reaction mixture. The mixture was stirred for 1 h at 15 to 25 °C. The organic phase was separated and concentrated to 1 .5 to 3 V. The concentrated residue was diluted with MTBE (5 V) and concentrated to 1 .5 to 3 V, repeated twice. The recovery solution was concentrated to 1 .5 to 2.5 V then charged with xylene (3 V). The mixture was heated to, and maintained at, 138 to 143 °C. After 24 h, the mixture was cooled to 60 °C. To the mixture was added IPA (6.3 V) and the resulting

[1189] 25 solution was concentrated to 2 to 3 V under vacuum, repeated twice. To the solution was added D- camphor-10-sulfonic acid (D-CSA) (1 .3 equiv) at 10 to 20 °C. The mixture was cooled to, and maintained at, -5 to 0 °C for 14 hours. The slurry was filtered and washed with IPA (2 V). The filter cake was dried at 45 to 80 °C to afford (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 H- indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) as an off-white solid.

[1190] 30

[1191] LCMS (ESI+)

[1192] Calculated for C23H27BrF3N2O2 (M+H+): 499.12025

[1193] Found: 499.1

[1194] 1H NMR (400 MHz, DMSO-d6)

[1195] <58.75 (dd, J = 4.8, 5.2 Hz, 1 H), 7.98 (d, J = 1 .6 Hz, 1 H), 7.78 - 7.76 (m, 1 H), 7.66 - 7.63 (m, 1 H), 7.54 - 7.53 (m, 1 H), 7.40 - 7.38 (m, 1 H), 5.39 - 5.30 (m, 1 H), 4.60 - 4.56 (m, 1 H), 4.51 - 4.42 (m, 1 H), 3.98 - 3.93 (m, 1 H), 3.33 (s, 2H), 3.03 - 2.94 (m, 3H), 2.60 - 2.50 (m, 1 H), 2.29 - 2.26 (m, 1 H), 1 .36 (d, J = 6.4 Hz, 2H), 0.60 (s, 6H).

[1196] 40 PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1197] PATENT

[1198] ATTORNEY DOCKET NO.: 51432-059WO2

[1199] Example 4 - Synthetic Procedure for Compound 1b - A / '-(1-cyclopropylpiperidin-4-ylidene)-4- methylbenzenesulfonohydrazide.

[1200] Detailed below is a general synthetic procedure for Compound 1 b - N'-(1 -cyclopropylpiperidin-4- ylidene)-4-methylbenzenesulfonohydrazide.

[1201] Compound 1b

[1202] 5 Compound 1a

[1203] To a reactor was charged EtOH (581 L, 7 V) and 4-methylbenzenesulfonohydrazide (122.1 kg, 656 mol, 1 .1 equiv). The resulting mixture was heated to, and maintained at, 40 to 45 °C. To this mixture was charged 1 -cyclopropylpiperidin-4-one (Compound 1 a) (83.0 kg, 596 mol, 1 equiv) in EtOH (83 L, 1 V) over 1 to 3 hours under nitrogen. The mixture was stirred at 40 to 45 °C for 12 hours at which point HPLC analysis showed reaction completion.

[1204] The reaction mixture was cooled to 0 to 10 °C and stirred for 1 to 2 hours, filtered and washed with EtOH (42 L, 0.5 V), and dried (15 to 20 °C, -0.06 to -0.08 MPa) to afford A / '-(1 -cyclopropylpiperidin-4- ylidene)-4-methylbenzenesulfonohydrazide (Compound 1b) (161 .2 kg, 97.7% a / a purity, 98.7% w / w assay, 87% yield) as a white solid.

[1205] 15

[1206] LCMS (ESI+)

[1207] Calculated for C15H22N3O2S (M+H+): 308.14272

[1208] Found: 308.14

[1209] 201H NMR (400 MHz, CDCI3)

[1210] <57.83-7.86 (d, J = 4.2 Hz, 2H), 7.31 -7.33 (d, J = 4.2 Hz, 2H), 2.64 - 2.72 (m, 4H), 2.44 (s, 3H), 2.30-2.34 (m, 4H), 1 .58 - 1 .64 (m, 1 H), 0.45 - 0.47 (m, 2H), 0.40-0.45 ( t, J = 3.8 Hz, 2H).

[1211] Example 5 - Synthetic Procedure for Compound 1c - A / '-(1-cyclopropylpiperidin-4-ylidene)-4- methoxybenzenesulfonohydrazide.

[1212] Detailed below is a general synthetic procedure for Compound 1c - A / '-(1 -cyclopropylpiperidin-4- ylidene)-4-methoxybenzenesulfonohydrazide. o 0 A

[1213] Compound 1a Compound 1c

[1214] To a reactor was charged EtOH (70 mL, 7 V) and 4-methoxybenzenesulfonohydrazide (B2) (16.0

[1215] 30 g, 0.08 mol, 1 .1 equiv). The resulting mixture was heated to, and maintained at, 55 to 60 °C. To this mixture was charged 1 -cyclopropylpiperidin-4-one (Compound 1 a) (10.0 g, 0.07 mol, 1 equiv) in EtOH (10 mL, 1 V). The mixture was stirred at 55 to 60 °C for 10 hours at which point HPLC analysis showed reaction completion. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1216] PATENT

[1217] ATTORNEY DOCKET NO.: 51432-059WO2

[1218] The reaction mixture was cooled to 0 to 10 °C and stirred for 30 minutes, filtered and washed with EtOH (5 mL, 0.5 V), and dried (15 to 20 °C, -0.06 to -0.08 MPa) to afford N'-(1 -cyclopropylpiperidin-4- ylidene)-4-methoxybenzenesulfonohydrazide (Compound 1 c, 12.08 g, 98.2% a / a purity, 52% yield) as a white solid.

[1219] 5

[1220] LCMS (ESI+)

[1221] Calculated for C15H22N3O2S (M+H+): 324.13764

[1222] Found: 324.2

[1223] 101H NMR (400 MHz, MeOD-d3)

[1224] 57.84 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 2.70 (dt, J = 15.8, 6.0 Hz, 4H), 2.40 (t, J = 6.1 Hz, 2H), 2.29 (t, J = 5.9 Hz, 2H), 1 .69 (tt, J = 6.9, 3.7 Hz, 1 H), 0.55 - 0.44 (m, 2H), 0.47 - 0.38 (m, 2H).

[1225] Example 6 - Synthetic Procedure for Compound 2 - (12M)-(S)-3-(5-bromo-2-(5-(1- cyclopropylpiperidin-4-yl)-2-(1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1 H-indol-3-yl)-2,2- dimethylpropan-1-ol.

[1226] Detailed below is a general synthetic procedure for Compound 2 - (12M)-(S)-3-(5-bromo-2-(5-(1 - cyclopropylpiperidin-4-yl)-2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-

[1227] 20 dimethylpropan-1 -ol. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1228] PATENT

[1229] ATTORNEY DOCKET NO.: 51432-059WO2

[1230] Compound 2a

[1231] To a reactor was charged n-heptane (475 L, 2.5 V), THF (475 L, 2.5 V), and (12M)-(S)-3-(5-

[1232] 5 bromo-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trif luoroethyl)-1 F / -indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 10) (190 kg, 380.76 mol, 1 equiv). The reaction mixture was cooled to, and maintained at, 0 to 10 °C then 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (HBpin) (51 .1 kg, 399.8 mol, 1 .05 equiv) was added dropwise over 1 hour. The resulting mixture was warmed to, and maintained at, 25 to 35 °C for 3 hours at which point1H NMR analysis showed reaction completion. (12M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4, 4,5,5-

[1233] 10 tetramethyl-1 ,3,2-dioxaborolan-2-yl)oxy)propyl)-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2, 2, 2-trifluoroethyl)- 1 / 7-indole (Compound 2a) was used directly in the next step.

[1234] A reactor containing a solution of (12M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)oxy)propyl)-2-(2-(1 -methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indole (Compound 2a) in n-heptane (475 L, 2.5 V) and THF (475 L, 2.5 V) was cooled to 20 to 25 °C. To this mixture was sequentially charged octamethyl-2,2’-bi-1 ,3,2-dioxaborolane (B2Pin2) (1 15.9 kg, 456.91 mol,

[1235] 20 1 .2 equiv), 2-(tert-butylperoxy)-2-methylpropane (dtbpy) (2.04 kg, 7.61 mol, 0.02 equiv), and (1 ,5- cyclooctadiene)(methoxy)iridium(l) dimer ([lr(OMe)(COD)]2) (1 .26 kg, 1 .90 mol, 0.01 equiv). The resulting PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1236] PATENT

[1237] ATTORNEY DOCKET NO.: 51432-059WO2 mixture was heated to, and maintained at, 30 to 35 °C for 15 hours at which point HPLC analysis showed reaction completion.

[1238] The reaction mixture was cooled to, and maintained at, 0 to 10 °C. To this mixture was slowly charged a solution of water (19 L, 0.1 V) and THF (85 L, 0.5 V), followed by MTBE (760 L, 4 V) then

[1239] 5 water (760 L, 4 V). The resulting mixture was stirred for 2 hours at 0 to 10 °C then centrifuged. The resulting filtrate was warmed to, and maintained at, 20 to 30 °C and NaCI (25% in water, 380 L, 2 V) was added. After 10 to 30 minutes, the organic layer was collected and to the aqueous layer was charged MTBE (380 L, 2 V). The combined organic layers were washed with NaCI (25% in water, 760 L, 4 V) and concentrated (40 to 45 °C, -0.09 MPa) to 2 to 3 V. To the resulting mixture was added 1 ,4-dioxane (380 L, 2 V) and the mixture was concentrated to 2 V to afford (12M)-(S)-3-(5-bromo-2-(2-(1 -methoxyethyl)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2- dimethylpropan-1 -ol (Compound 2b) (207 kg, 90.2% a / a purity, 39.4% w / w assay, 97% yield) as a red solution in 1 ,4-dioxane.

[1240] 15 Part 3 - Alternative synthesis of Compound 2b - ( 12M)-(S)-3-(5-bromo-2-(2-(1-methoxyethyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropan- 1-oi.

[1241] To a reactor was charged n-heptane (4 V), dtbpy (1 .6 mol%) at 25 °C, followed by adding

[1242] 20 Compound 10 (1 .0 equiv) and B2Pin2 (2.0 equiv). N2 was bubbled under surface of reaction mixture for 1 h. [lr(OMe)(COD)]2 (0.8 mol%) was added to the suspension under the atmosphere of N2. The reaction mixture was stirred under N2 gas until all the solids were dissolved. The reaction mixture was then stirred at 55 °C for 2 h. After completion, the reaction solution was washed with water (3 V) twice. The organic phase was concentrated to dryness and used for the next step.

[1243] LCMS (ESI+)

[1244] Calculated for C23H2sBBrF3N2O4 (M-2,3dimethylbutane+H+): 543.12721

[1245] Found: 543.2

[1246] 301H NMR (300 MHz, CDCI3)

[1247] <59.11 (d, J = 1 .7 Hz, 1 H), 8.10 (t, J = 1 .5 Hz, 1 H), 7.92 (d, J = 1 .9 Hz, 1 H), 7.40 (dd, J = 8.7, 1 .9 Hz, 1 H), 7.29 (s, 1 H), 4.73 (s, 1 H), 4.47 (q, J = 8.6 Hz, 2H), 4.03 (q, J = 6.2 Hz, 1 H), 3.82 - 3.72 (m, 1 H), 3.58 - 3.45 (m, 2H), 3.04 (s, 3H), 2.74 (d, J = 14.1 Hz, 1 H), 2.23 (d, J = 14.1 Hz, 1 H), PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1248] PATENT

[1249] ATTORNEY DOCKET NO.: 51432-059WO2

[1250] 1.91 - 1.83 (m, 1 H), 1.46 (d, J = 6.2 Hz, 4H), 1.36 (s, 12H), 1.28 (d, J = 5.2 Hz, 35H), 0.95 - 0.85 (m, 5H), 0.76 (d, J = 10.4 Hz, 6H).

[1251] To a reactor at 15 to 30 °C was charged 1 ,4-dioxane (3,040 L, 17.37 V), (12M)-(S)-3-(5-bromo-2- (2-(1 -methoxyethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 H- indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 2b) (175 kg assay, 279.8 mol, 1 equiv), and A / '-(1 - cyclopropylpiperidin-4-ylidene)-4-methylbenzenesulfonohydrazide (Compound 1 b) (133.45 kg, 419.7 mol, 1 .5 equiv). After 2 h, the reaction solution was transferred to a holding vessel. To the reactor maintained at 15 to 30 °C was charged 1 ,4-dioxane (800 L, 4.57 V) and CS2CO3 (310.02 kg, 951 .5 mol, 3.4 equiv). This reaction solution was heated to, and maintained at, 98 to 105 °C. To the reaction mixture was added the prepared solution of Compound 2b and Compound 1 b in 1 ,4-dioxane over 4 to 6 hours. The reaction

[1252] 15 mixture was stirred at 98 to 105 °C for 4 to 6 hours at which point HPLC analysis showed reaction completion.

[1253] The reaction mixture was cooled to 20 to 25 °C. To the reaction mixture was added water (875 L, 5 V). The reaction mixture was cooled to, and maintained at, 10 to 20 °C, and HCI (4M in water, 438 L, 2.5V) was charged until a pH from 6 to 7 was achieved. The reaction mixture was concentrated (40 to 50

[1254] 20 °C) to a minimum volume then charged with MTBE (875 L, 5 V). The reaction mixture was cooled to, and maintained at, 10 to 20 °C, and HCI (4M in water, 298 L, 1 ,7V) was charged until a pH = 1 .4 to 1 .5 was achieved. The layers were separated, and the aqueous layer was washed with MTBE (875 L, 5 V). To the aqueous layer was charged MTBE (875 L, 5 V) followed by NaOH (2M in water) until a pH = 7 to 8 was achieved. The reaction mixture was concentrated (40 to 50 °C) to 350 L (-2 V) and solvent swapped with n-heptane (350 L, 2 V) until residual MTBE < 5,000 ppm. The reaction mixture was warmed to, and maintained at, 90 to 100 °C for 2 hours after which the solution was cooled to, and maintained at, 50 to 60 °C. To the reaction mixture was added (12M)-(S)-3-(5-bromo-2-(5-(1 -cyclopropylpiperidin-4-yl)-2-(1 - methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 2 seed, 525 g). After 2 h, the reaction was cooled to, and maintained at, 15 to 25 °C. After 6 h, the mixture

[1255] 30 was filtered to afford crude Compound 2 (138 kg) and to the filter cake was charged MTBE (830 L, 6 V). The mixture was stirred at 15 to 25 °C for 1 to 2 hours then pumped through a CUNO filter. The filtrate was concentrated to -400 L (3 V) and solvent swapped with n-heptane (414 L, 3 V) until residual MTBE < 10,000 ppm. The mixture was stirred at 20 to 30 °C for 1 to 2 hours then centrifuged. The filter cake was dried under vacuum to obtain (12M)-(S)-3-(5-bromo-2-(5-(1 -cyclopropylpiperidin-4-yl)-2-(1 - PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1256] PATENT

[1257] ATTORNEY DOCKET NO.: 51432-059WO2 methoxyethyl)pyridin-3-yl)-1 -(2,2,2-trifluoroethyl)-1 / 7-indol-3-yl)-2,2-dimethylpropan-1 -ol (Compound 2) (61 .6 kg, 98.1 % a / a purity, 96.05% w / w assay, 29% yield) as an off-white solid.

[1258] LCMS (ESI+)

[1259] 5 Calculated for Csi F oBrFsNsC (M+H+): 622.22505

[1260] Found: 622.50

[1261] 1H NMR (400 MHz, DMSO-d6)

[1262] 68.64 (d, J = 1 .0 Hz, 1 H), 7.94 (d, J = 0.8 Hz, 1 H), 7.59 (t, J = 15.6 Hz, 2H), 7.38 - 7.36 (m, 1 H),

[1263] 10 5.34 - 5.28 (m, 1 H), 4.56 (t, J = 5.2 Hz, 1 H), 4.40 - 4.33 (m, 1 H), 3.91

[1264] - 3.88 (m, 1 H), 3.02 - 2.98 (m, 4 H), 2.87 (s, 3H), 2.59 (d, J = 7.0 Hz, 2H), 2.26 - 2.16 (m, 3H),

[1265] 1 .75 (d, J = 5.8 Hz, 2H), 1 .61 - 1 .56 (m, 3H) , 1 .34 - 1 .33 (m, 3H) , 0.60

[1266] (s, 6H), 0.41 - 0.28 (m, 4H).

[1267] 15 Example 7 - Synthetic Procedure for Compound 3e bis HCI salt - methyl (S)-hexahydropyridazine- 3-carboxylate bis HCI salt.

[1268] Detailed below is a general synthetic procedure for Compound 3e bis HCI salt - methyl (S)- hexahydropyridazine-3-carboxylate bis HCI salt.

[1269] Compound 3e 2HCI

[1270] 20 To a reactor was charged MeOH (750 L, 5.0 vol.) and (S)-1 ,2-bis(tert-butoxycarbonyl) hexahydropyridazine-3-carboxylic acid (150 kg, 451 mol, 1 .0 eq.). SOCI2 (107 kg, 902 mol, 2.0 eq.) was added dropwise into the mixture at 10-20 °C. The reaction mixture was warmed to 35-40 °C and stirred for 43 hours at which point HPLC analysis showed reaction completion. The reaction mixture was concentrated to -300 L (-2 V). Dioxane (300 L, 2 V) was added into the mixture and concentrated to

[1271] 25 -300 L (-2 V) 3 times. The resulting mixture was diluted with DCM (300 L, 2 V) to afford a dioxane / DCM solution of methyl (S)-hexahydropyridazine-3-carboxylate bis HCI salt (Compound 3e bis HCI salt) (675 kg, 15 % w / w assay, 100% yield) which was used directly in the next step.

[1272] MS (ESI+)

[1273] 30 Calculated for C6H13N2O2 (M+H+): 145.09715

[1274] Found: 145.10

[1275] 1H NMR (400 MHz, DMSO-d6)

[1276] 63.96 (dd, J = 10.5, 2.5 Hz, 1 H), 3.63 (s, 3H), 3.06 (s, 1 H), 2.91 (dd, J = 16.2, 7.4 Hz, 1 H), 1 .89

[1277] 35 (d, J = 10.6 Hz, 2H), 1 .78 (dd, J = 9.8, 3.4 Hz, 1 H), 1 .65 - 1 .47 (m, 1 H). PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1278] PATENT

[1279] ATTORNEY DOCKET NO.: 51432-059WO2

[1280] Example 8 - Synthetic Procedure for Compound 3 Na salt - (S)-1-((S)-3-(3-borono-5-

[1281] ((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3- carboxylate Na salt.

[1282] Detailed below is a general synthetic procedure for Compound 3 Na salt - (S)-1 -((S)-3-(3-borono-

[1283] 5 5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3- carboxylate Na salt.

[1284] Part 1 - Synthesis of Compound 3b - methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-

[1285] ((triisopropylsilyl)oxy)phenyl)propanoate.

[1286] Step 1

[1287] Compound 3a Compound 3b

[1288] To a reactor, DCM (765 L, 5 V), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3- hydroxyphenyl)propanoate (Compound 3a) (153 kg, 518 mol, 1 .0 equiv) and imidazole (88 kg, 1 ,295 mol, 2.5 equiv) were added at room temperature. The reactor was cooled to 10-15 °C. TIPSCI (150 kg, 777 mol, 1 .5 equiv) was added to the reactor slowly at the same temperature. The reactor was warmed to

[1289] 15 room temperature. The mixture was stirred for 2 hours at which point HPLC analysis showed reaction completion. Water (765 L, 5 V) was added to the reactor. The mixture was separated. The organic layer was collected, and the aqueous layer was extracted with DCM (765 L, 5 V). All organic layers were combined. The combined mixture was washed with aq. citric acid (10 wt%, 765 L, 5 V), aq NaHCCh (10 wt%, 765 L, 5 V) and water (765 L, 5 V). The mixture was concentrated to -200 L (-1 .3 V). Dioxane (310 L, 2 V) was added, and the mixture was concentrated to - 200 L (1 .3 V) 3 times to afford methyl (S)-2- ((tert-butoxycarbonyl)amino)-3-(3-((triisopropylsilyl)oxy)phenyl)propanoate (Compound 3b) dioxane colorless solution (940 kg, 25 % w / w assay, 100% yield) which was used directly in the next step.

[1290] MS (ESI+)

[1291] 25 Calculated for C24H4i NNaO5Si (M+Na+): 474.26462

[1292] Found: 474

[1293] 1H NMR (400 MHz, CDCI3) PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1294] PATENT

[1295] ATTORNEY DOCKET NO.: 51432-059WO2

[1296] <57.08 (t, J = 7.8 Hz, 1 H), 6.79 - 6.56 (m, 3H), 5.03 (d, J = 7.8 Hz, 1 H), 4.51 (dd, J = 13.4, 6.0 Hz, 1 H), 3.66 (s, 3H), 2.98 (m, J = 5.7 Hz, 2H), 1 .38 (s, 9H), 1 .26 - 1 .1 1 (m, 3H), 1 .05 (d, J = 7.2 Hz, 18H).

[1297] 5 Part 2 - Synthesis of Compound 3c - methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-

[1298] 1,3, 2-dioxaborolan-2-yl) -5-(( triisopropylsilyl)oxy)phenyl)propanoate.

[1299] To a reactor, dioxane (250 L, 2.1 V), (S)-2-((tert-butoxycarbonyl)amino)-3-(3- ((triisopropylsilyl)oxy)phenyl)propanoate (Compound 3b) dioxane solution (465 kg, 25 % w / w assay, 257 mol, 1 .0 equiv), Pin2B2 (196 kg, 772 mol, 3.0 equiv), DTBPy (3.1 kg, 1 1 .6 mol, 0.045 equiv), lr(OMe)(COD)2 (2.6 kg, 4 mol, 0.015 equiv). The reactor was inerted by N2 and warmed to 80-85 °C. The mixture was stirred for 2 hours at which point HPLC analysis showed reaction completion. The reactor was cooled down to room temperature. The mixture was added slowly to brine (10 wt%, 1 160 L, 10 V) at 10-25 °C. The resulting mixture was stirred for 2 hours. The mixture was separated. The organic layer

[1300] 15 was collected. The aqueous layer was extracted with MTBE (580 L, 5 V). All organic layers were combined and washed with brine (10 wt%, 1 160 L, 10 V) two times. The mixture was concentrated to -230 L (-2 V). MeOH (350 L, 3 V) was added to the mixture and the mixture was concentrated to -300 L (-2.5 V). MeOH (350 L, 3 V) was added to the mixture and the mixture was concentrated to -400 V (-3.5 V) to afford methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-

[1301] 20 ((triisopropylsilyl)oxy)phenyl)propanoate (Compound 3c) MeOH black solution (683 kg, 22 % w / w assay, 100% yield) which was used directly in the next step.

[1302] MS (ESI+)

[1303] Calculated for CsobfeBNNaOySI (M+Na+): 600.34983

[1304] Found: 600

[1305] 1H NMR (400 MHz, CDCI3)

[1306] <57.14 (s, 1 H), 7.09 (s, 1 H), 6.70 (s, 1 H), 5.01 (d, J = 7.9 Hz, 1 H), 4.49 (m, 1 H), 3.57 (s, 3H), 3.12 - 2.86 (m, 2H), 1 .39 (s, 9H), 1 .29 (s, 12H), 1 .26 - 1 .1 1 (m, 3H), 1 .06 (d, J = 7.2 Hz, 18H).

[1307] 30

[1308] Part 3 - Synthesis of Compound 3d - (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid. PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1309] PATENT

[1310] ATTORNEY DOCKET NO.: 51432-059WO2

[1311] To a reactor, MeOH (100 L, 0.7 V), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (Compound 3c) MeOH solution (683 kg, 22 % w / w assay, 260 mol, 1 .0 equiv) were added at 5-10 °C. The reactor was cooled to

[1312] 5 -0 °C. LiOH solution (aq, 4.8 wt%, 740 L, 910 mol, 5 V) was added to the reactor. The mixture was stirred for 3-5 hours at -0-10 °C at which point HPLC analysis showed reaction completion. The mixture was filtered via diatomite (44 kg, 0.3 w / w). The filtrate was extracted with DCM (1500 L, 10 V) two times. All organic layers were combined. HCI solution (aq, 8.2 wt%, 1200 L, 8 V) was added slowly to the combined organic mixture at 0-15 °C. The resulting mixture was extracted with DCM (750 L, 5 V) two times. The

[1313] 10 combined DCM solution was washed with water (750 L, 5 V) and was concentrated to -300 L (-2 V). n- Heptane (450 L, 3 V) was added slowly to the mixture. The mixture was concentrated to -450 L (-3 V) for two times. The mixture was cooled to 15-25 °C. n-Heptane (300 L, 2 V) was added to the mixture. The mixture was filtered after stirring for 1 hour. The cake was washed with n-heptane (150 L, 1 V). (S)-2- ((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoic acid (Compound 3d) (1 13 kg, 97 % w / w assay, 75% yield) was obtained as a light yellow solid in 75% yield after drying which was used directly in the next step.

[1314] MS (ESI+)

[1315] Calculated for C24H43BNOsSi (M-Boc+H+): 464.29981

[1316] 20 Found: 464.0

[1317] PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1318] PATENT

[1319] ATTORNEY DOCKET NO.: 51432-059WO2

[1320] 1H NMR (400 MHz, DMSO-d6)

[1321] <512.61 (s, 1 H), 7.15 (s, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 6.97 (s, 1 H), 6.91 (s, 1 H), 4.02 (m, 1 H), 2.96 (m, 1 H), 2.76 (m, 1 H), 1 .40 - 1 .18 (m, 24H), 1 .05 (d, J = 7.3 Hz, 18H).

[1322] 5 Part 4 - Synthesis of Compound 3f - methyl (S)-1 -((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3- carboxylate.

[1323] To a reactor, DCM (1400 L, 6.2 V), methyl (S)-hexahydropyridazine-3-carboxylate bis HCI salt (Compound 3e Bis HCI salt) DCM solution (672 kg, 15 % w / w assay, 545 mol, 1 .1 equiv) were added at room temperature. The reactor was cooled to -0 °C. NMM (45 kg, 545 mol, 1 .1 equiv), (S)-2-((tert- butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5- ((triisopropylsilyl)oxy)phenyl)propanoic acid (Compound 3d) (230 kg, 496 mol, 1 .0 equiv), HOBt (1 .1 kg, 10 mol, 0.02 equiv), EDCI (110 kg, 768 mol, 1 .55 equiv) were added slowly to the reactor at 0-10 °C. The

[1324] 15 mixture was stirred at the same temperature for 1 -3 hours at which point HPLC analysis showed reaction completion. The mixture was washed with water (1400 L, 6 V, 3 times; 900 L, 4 V, 2 times). The mixture was concentrated to -460 L (-2 V). MeOH (460 L, 2 V) was added to the mixture and concentrated to -460 L (-2 V) for 2 times. MeOH (230 L, 1 V) was added to the mixture to afford methyl (S)-1 -((S)-2-((tert- butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-

[1325] 20 (triisopropylsilyl)oxy)phenyl)propanoyl)hexahydro- pyridazine-3-carboxylate (Compound 3f) MeOH light yellow solution (666 kg, 42 % w / w assay, 100% yield) which was used directly in the next step.

[1326] MS (ESI+)

[1327] Calculated for CssHeoBNsOsSi (M+H+): 690.43155

[1328] Found: 690.0

[1329] 1H NMR (400 MHz, CDCI3)

[1330] <57.17 (s, 1 H), 7.13 (d, J = 2.1 Hz, 1 H), 6.78 (s, 1 H), 5.42 (m, 1 H), 5.22 (m, 1 H), 4.24 (m, 1 H),

[1331] 30 3.69 (s, 3H), 2.74 - 2.86 (m, 4H), 1 .81 (m, 1 H), 1 .73 (m, 1 H), 1 .59 (m, 1 H), 1 .52 - 1 .44 (m, 1 H), 1.40 (s, 9H), 1.31 (s, 12H), 1.27 - 1.18 (m, 4H), 1.05 (d, J = 7.3 Hz, 18H). PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1332] PATENT

[1333] ATTORNEY DOCKET NO.: 51432-059WO2

[1334] Part 5 - Synthesis of Compound 3 Na salt - (S)-1-((S)-3-(3-borono-5-((triisopropylsilyl)oxy)phenyl)- 2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate Na salt.

[1335] To a reactor, MeOH (1 160 L, 8.3 V), methyl (S)-1 -((S)-2-((tert-butoxycarbonyl)amino)-3-(3-

[1336] 5 (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl) hexahydropyridazine-3-carboxylate (Compound 3f) MeOH solution (333 kg, 42 % w / w assay, 203 mol, 1 .0 equiv) were added at room temperature. The reactor was cooled to -0 °C. LiOH (aq, 1050 L, 1 wt%, 7.5 V, 2.5 equiv) was added slowly to the reactor at 0-10 °C. The mixture was stirred for 5-7 hours at which point HPLC analysis showed reaction completion. Citric acid solution (aq, 10 wt%, 220 L, 1 .5 V) was added. MeOH in the mixture was removed by distillation. LiOH solution (aq, 6 wt%, 42 L, 0.3 V), MTBE (1400 L, 10 V) was added to the mixture. The resulting mixture was stirred for 0.5 hours and was separated. The aqueous layer was washed with MTBE (700 L, 5 V) followed by the addition of sat brine (aq, 280 L, 2 V). The resulting aqueous layer was extracted with EtOAc (700 L, 5 V) 3 times. All extracts solutions were combined. The combined solution was washed with a mixture of solutions (aq, 700 L, 3

[1337] 15 wt% NaHCO3, 6 wt% Na2CO3, 5V) 6 times. The EtOAc solution was concentrated to -440 L (-3 V). MeCN (880 L, 6 V) was added to the solution and was concentrated to -880 L (-6 V) 3 times. DCM (700 L, 5 V) was added. The resulting solution was charged with MeCN (1400 L, 10 V) slowly at room temperature. The mixture was concentrated to -2000 L (-14 V) and cooled to room temperature and stirred for 1 hour. The mixture was filtered, and cake was rinsed with MeCN (140 L, 1 V) 3 times to afford (S)-1 -((S)-3-(3-

[1338] 20 borono-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3- carboxylate Na salt (Compound 3 Na salt) (1 10 kg, 86 wt%, 765% yield) as a white solid.

[1339] MS (ESI+)

[1340] Calculated for C28H49BN3O8Si (M+H+): 594.33765 Found: 594.40

[1341] 1H NMR (400 MHz, MeOD)

[1342] <57.20-6.69 (m, 3H), 5.29 (m, 1 H), 4.39 (m, 1 H), 3.30 (m, 1 H), 3.00 (m, 1 H), 2.79-2.70 (m, 2H), 2.08 (m, 1 H), 1 .86 (m, 1 H), 1 .72 - 1 .55 (m, 2H), 1 .40 (m, 9H), 1 .29-1 .25 (m, 3H), 1 .11 -1 .13 (m,

[1343] 30 18H). PCT / US25 / 48606 30 September 2025 (30.09.2025)

[1344] PATENT

[1345] ATTORNEY DOCKET NO.: 51432-059WO2

[1346] Biological Assays

[1347] Disruption of B-Raf Ras-binding Domain (BRAFRBD) Interaction with K-Ras by Compounds of the Invention (also called a FRET assay or an MO A assay)

[1348] The purpose of this biochemical assay is to measure the ability of test compounds to facilitate

[1349] 5 ternary complex formation between a nucleotide-loaded K-Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAFRBDconstruct, inhibiting K-Ras signaling through a RAF effector. Data is reported as IC50 values. Other Ras variants may be used.

[1350] In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1 % BSA, 100 mM NaCI and 5 mM MgCl2, tagless cyclophilin A, His6-K-Ras-GMPPNP, and GST-BRAFRBDare combined in a 384- well assay plate at final concentrations of 25 pM, 12.5 nM and 50 nM, respectively. Compound is present in plate wells as a 10-point 3-fold dilution series starting at a final concentration of 30 pM. After incubation at 25°C for 3 hours, a mixture of Anti-His Eu-W1024 and anti-GST allophycocyanin is then added to assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction incubated for an additional 1 .5 hours. TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm).

[1351] 15 Compounds that facilitate disruption of a K-Ras:RAF complex are identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells.

[1352] Each of Examples A1 -A450 exhibited an IC50 of less than 2 pM in at least one of the following: K-Ras Q61 H, G12C, G12D, G12R, G12S, G12V, G12A, G13C, G13D and wild-type; N-Ras Q61 K, Q61 R, Q61 L, G12C and wild-type; and H-Ras G13R and WT.

[1353] 20

[1354] Other Embodiments

[1355] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure come within known or customary practice within the art to which the invention pertains and may be applied to the essential features set forth herein.

[1356] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[1357] 30

Claims

PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2CLAIMS1 . A method of preparing a compound of Formula 1 :Formula 1 the method comprising condensing a compound of Formula 1 a and a compound of Formula 1 b to form the compound of Formula 1 :Fowherein n is 0 or 1 ;R1is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substitutedCi-Ce alkynyl, or optionally substituted C1-C4 heteroalkyl; andR2is optionally substituted C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl.

2. The method of claim 1 , wherein the compound of Formula 1 is Formula 1 c:Formula 1c wherein q is 0 or 1 .PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO23. The method of claim 1 or 2, wherein the compound of Formula 1 is Compound 1 b, Compound 1 c,Compound 1 d, Compound 1 e, Compound 1 f, or Compound 1 g:A method of preparing a compound of Formula 2:wherein n is 0 or 1 ;R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andR3is optionally substituted Ci-Ce alkyl;PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 the method comprising coupling a compound of Formula 2b with a compound of Formula 1 to form the compound of Formula 2:

5. A sodium salt of Compound 3:Compound 3 Na saltA method of preparing the sodium salt of claim 5, the method comprising: a) protecting Compound 3a to form Compound 3b:Compound 3a Compound 3b b) borylating Compound 3b to form Compound 3c:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 c) hydrolyzing Compound 3c to form Compound 3d:d) coupling Compound 3d with Compound 3e«2HCI to form Compound 3f:e) hydrolyzing Compound 3f form the sodium salt of Compound 3:

7. The method of claim 6, wherein the hydrolyzing and borylating of (b) further comprises contacting Compound 3b with an iridium catalyst.

8. A method of preparing a compound of Formula 4f as a racemic mixture of cis and trans isomers:Formula 4f (mixture of cis / trans isomers, racemic) wherein m is 1 or 2;PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 the method comprising: a) N-alkylating Compound 4a with a compound of Formula 4b to form a compound of Formula 4c:Compound 4a Formula 4b Formula 4c b) acetylating the compound of Formula 4c by i) deprotonating the compound of Formula 4c using a base to form a deprotonated compound of Formula 4c; and ii) coupling the deprotonated compound of Formula 4c with Compound 4d to form a compound of Formula 4e:Formula 4eCompound 4d c) cyclizing and protecting the compound of Formula 4e to form a racemic mixture of a compound of Formula 4f:Formula 4e Formula 4f (cis only, racemic) .anc| d) isomerizing the compound of Formula 4f to form a mixture of cis and trans isomers of the compound of Formula 4f:Formula 4f Formula 4f(cis only, racemic) (mixture of cis / trans isomers, racemic)9. The method of claim 8, wherein the cyclizing of (c) further comprises contacting the compound of Formula 4e with a palladium catalyst.

10. The method of claim 8, wherein the isomerizing of (d) produces a mixture of cis and trans isomers of the compound of Formula 4f, wherein the mixture comprises at least about 80% trans isomer.PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO21 1 . A method of preparing a compound of Formula 4u:Formula 4u wherein m is 1 or 2;R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; andR6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; the method comprising: a) hydrolyzing a mixture of cis and trans isomers of a compound of Formula 4f to form a compound of Formula 4g that is enantiomerically pure:Formula 4f Formula 4g (mixture of cis / trans isomers, racemic) b) coupling the compound of Formula 4g with a compound of Formula 4h to form a compound ofFormula 4i:Formula 4i c) deprotecting the compound of Formula 4i to form a compound of Formula 4j:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2Formula 4i Formula 4j .anc| d) coupling the compound of Formula 4j with a compound of Formula 4k to form the compound ofFormula 4u:

12. The method of claim 1 1 , wherein the hydrolyzing of (a) further comprises contacting the compound of Formula 4f with a serine endoprotease.

13. A method of preparing a compound of Formula 4-I:Formula 4-1 wherein m is 1 or 2;R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;R6is optionally substituted Ci-Ce alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andX1is halogen;PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 the method comprising: a) deprotecting a compound of Formula 4I to form a compound of Formula 4m:Formula 4I Formula 4m b) halogenating the compound of Formula 4m to form a compound of Formula 4n:Formula 4m Formula 4n .anc| c) deprotecting the compound of Formula 4n to form the compound of Formula 4-I:Formula 4n Formula 4-I14. The method of claim 13, wherein the deprotecting of (a) further comprises contacting the compound of Formula 4I with a palladium catalyst.PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO215. A method of preparing a compound of Formula 4q:Formula 4q wherein m is 1 or 2; andR4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; the method comprising: a) hydrolyzing a mixture of cis and trans isomers of a compound of Formula 4f to form a compound of Formula 4o:Formula 4f Formula 4o (mixture of cis / trans isomers, racemic) b) deprotecting the compound of Formula 4o to form a compound of Formula 5:Formula 4o Formula 5 c) isomerizing the compound of Formula 5 to form a compound of Formula 4p that is enantiomerically pure:Formula 5 Formula 4p .andd) coupling the compound of Formula 4p with a compound of Formula 4h to form the compound of Formula 4q:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2Formula 4hFormula 4q16. The method of claim 15, wherein the deprotecting of (b) further comprises contacting the compound of Formula 4o with a palladium catalyst.

17. A method of preparing a compound of Formula 4-II:Formula 4-II wherein m is 1 or 2; andR4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andthe method comprising: a) O-sulfonating a compound of Formula 4q to form a compound of Formula 4r:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2b) deprotecting the compound of Formula 4r to form a compound of Formula 4s:Formula 4r Formula 4s c) coupling the compound of Formula 4s with a compound of Formula 4k to form a compound ofFormula 4t:d) hydrolyzing the compound of Formula 4t to form the compound of Formula 4-11:Formula 4t Formula 4-11PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO218. The method of claim 17, wherein R7is19. A method of preparing a compound of Formula 5:HO BocCompound 5 wherein m is 1 or 0; the method comprising: a) protecting Compound 5a to form Compound 5b:Compound 5a Compound 5b . b) alkylating Compound 5b with X2-CH2(CH2)m-X3to form a compound of Formula 5c:Compound 5b Formula 5c wherein X2and X3are halogen; c) deprotecting a compound of Formula 5c to form a compound of Formula 5d:Formula 5c Formula 5d d) protecting the compound of Formula 5d to form a compound of Formula 5e:Boc Compound 5d Compound 5e . e) trans-esterifying the compound of Formula 5e to form a compound of Formula 5f:Boc HO BocFormula 5e Formula 5fPCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 f) isomerizing the compound of Formula 5f to form a trans isomer of a compound of Formula 5g:g) hydrolyzing the compound of Formula 5g to form the compound of Formula 5:Formula 5g Formula 520. The method of claim 19, wherein X2and X3are independently selected from bromine, chlorine, or iodine.21 . A method of preparing Compound 6d:Compound 6d the method comprising: a) protecting Compound 6a to form Compound 6b:Compound 6a Compound 6b b) alkylating Compound 6b with an allyl halide to form Compound 6c:Compound 6b Compound 6c wherein X4is a halogen; andPCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 c) cyclizing Compound 6c to form Compound 6d:Compound 6c Compound 6d22. The method of claim 21 , wherein the cyclizing of (c) further comprises contacting Compound 6c with an oxidizing agent.

23. The method of claim 22, wherein the oxidizing agent is a periodate salt.

24. The method of claim 22 or 23, wherein the cyclizing of (c) further comprises contacting Compound 6c with an osmate catalyst.

25. The method of any one of claims 21 -24, wherein X4is bromine, chlorine, or iodine.

26. A method of preparing a compound of Formula 6:Formula 6 wherein p is 1 or 2; andR4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; the method comprising: a) reducing a compound of Formula 6d to form a compound of Formula 6e:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 b) deprotecting the compound of Formula 6e to form a compound of Formula 6f:Formula 6e Formula 6f c) reducing the compound of Formula 6f to form a compound of Formula 6g:Formula 6f Formula 6g .andd) coupling the compound of Formula 6g with a compound of Formula 6h to form the compound of Formula 6:Formula 6hFormula 6g27. The method of claim 26, wherein the reducing of (a) further comprises contacting the compound of Formula 6d with a silane reducing agent.

28. The method of claim 26, wherein the deprotecting of (b) further comprises contacting the compound of Formula 6e with a palladium catalyst.

29. The method of claim 26, wherein the deprotecting of (c) further comprises contacting a compound of Formula 6f with a reducing agent.

30. The method of any one of claims 26-29, wherein p is 1 .PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO231 . A method of preparing a compound of Formula 7d:wherein n is 0 or 1 ;R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substitutedCi-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andR3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl; the method comprising: a) coupling a compound of Formula 2 with a sodium salt of Compound 3 to form a compound ofFormula 7a:b) cyclizing the compound of Formula 7a to form a compound of Formula 7b:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 c) deprotecting the compound of Formula 7b to form a compound of Formula 7c:

32. The method of claim 31 , wherein the coupling of (a) further comprises contacting a compound ofFormula 2 and the sodium salt of Compound 3 with a palladium catalyst.

33. A method of preparing a compound of Formula 7e:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2 the method comprising coupling a compound of Formula 7d with a compound 4-I to form the compound ofFormula 7e:wherein n is 0 or 1 ; m is 1 or 2;R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andR3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl;R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl;R6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andX1is halogen.

34. A method of preparing a compound of Formula A:the method comprising cyclizing a compound of Formula 7e to form the compound of Formula A:PCT / US25 / 48606 30 September 2025 (30.09.2025)PATENTATTORNEY DOCKET NO.: 51432-059WO2wherein n is 0 or 1 ; m is 1 or 2;R2is optionally substituted C1-C4 alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl; andR3is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, or optionally substituted Ci-Ce alkynyl;R4and R5are each independently optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted Ci-Ce cycloalkyl, or optionally substituted C1-C7 heterocycloalkyl; or R4and R5are taken together to form optionally substituted C3-C6 cycloalkyl or optionally substituted C3-C7 heterocycloalkyl; andR6is optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce alkenyl, optionally substituted Ci-Ce alkynyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C7 heterocycloalkyl.

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